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Nucleosome Positioning in Cancer Diagnostics (Vladimir Teif)05 Sep 202400:40:44

In this episode of the Epigenetics Podcast, we caught up with Vladimir Teif from the University of Essex to talk about his work on nucleosome positioning in development and disease.

Vladimir's research has been pivotal in understanding nucleosome positioning and its implications for cell differentiation, particularly in embryonic stem cells and cancer. We discuss his groundbreaking studies that first mapped nucleosome positions in various cell types and how these findings led to uncovering the intricate relationships between nucleosome stability, transcription factors, and DNA modifications such as methylation. This understanding has immense significance for cancer diagnostics, where knowing the spatial arrangement of nucleosomes could influence how aggressive a cancer type might be, or how a patient might respond to treatment.

Transitioning from foundational research to clinical applications, Vladimir elaborates on his exciting work with liquid biopsies. By analyzing cell-free DNA from blood plasma, researchers can infer the nucleosome positioning and, ultimately, the presence of cancer without the need for invasive tissue biopsies. We explore how this new approach holds potential for earlier detection of cancers and more effective patient stratification, demonstrating a profound shift in how we leverage epigenetic data in clinical settings.

 

References

  • Vladimir B. Teif, Karsten Rippe, Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities, Nucleic Acids Research, Volume 37, Issue 17, 1 September 2009, Pages 5641–5655, https://doi.org/10.1093/nar/gkp610

  • Teif, V., Vainshtein, Y., Caudron-Herger, M. et al. Genome-wide nucleosome positioning during embryonic stem cell development. Nat Struct Mol Biol 19, 1185–1192 (2012). https://doi.org/10.1038/nsmb.2419

  • Beshnova DA, Cherstvy AG, Vainshtein Y, Teif VB (2014) Regulation of the Nucleosome Repeat Length In Vivo by the DNA Sequence, Protein Concentrations and Long-Range Interactions. PLoS Comput Biol 10(7): e1003698. https://doi.org/10.1371/journal.pcbi.1003698

  • Shtumpf, M., Piroeva, K.V., Agrawal, S.P. et al. NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA. Chromosoma 131, 19–28 (2022). https://doi.org/10.1007/s00412-021-00766-9

     

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The Effect of Histone Demethylases on Gene Expression and Cancer Cell Stability (Johnathan Whetstine)29 Aug 202400:39:37

In this episode of the Epigenetics Podcast, we talked with Johnathan Whetstine from Fox Chase Cancer Center about his work on how histone demethylases affect gene expression and cancer cell stability.

The Interview start by discussing a pivotal paper from Jonathan's lab in 2010, where they identified a role for the KDM4A histone demethylase in replication timing and cell cycle progression. They elaborate on the discoveries made regarding the link between histone marks, replication timing, and gene expression control. Jonathan explains the impact of microRNAs on regulating KDM4A and how protein turnover rates can influence cellular responses to treatments like mTOR inhibitors.

Further, they explore the causal relationship between histone marks and replication timing, demonstrating how alterations in epigenetic regulation can affect genome stability. Jonathan shares insights from his latest research on H3K9 methylation balance at the MLL-KM2A locus, elucidating how these epigenetic modifications regulate amplifications and rearrangements in cancer cells. The episode concludes with a discussion on the establishment of the Cancer Epigenetics Institute at Fox Chase Cancer Center, aiming to bridge academia and industry to accelerate translational research in cancer epigenetics.

 

References

  • Black, J. C., Allen, A., Van Rechem, C., Forbes, E., Longworth, M., Tschöp, K., Rinehart, C., Quiton, J., Walsh, R., Smallwood, A., Dyson, N. J., & Whetstine, J. R. (2010). Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. Molecular cell, 40(5), 736–748. https://doi.org/10.1016/j.molcel.2010.11.008

  • Mishra, S., Van Rechem, C., Pal, S., Clarke, T. L., Chakraborty, D., Mahan, S. D., Black, J. C., Murphy, S. E., Lawrence, M. S., Daniels, D. L., & Whetstine, J. R. (2018). Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications. Cell, 174(4), 803–817.e16. https://doi.org/10.1016/j.cell.2018.06.018

  • Van Rechem, C., Ji, F., Chakraborty, D., Black, J. C., Sadreyev, R. I., & Whetstine, J. R. (2021). Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell reports, 37(1), 109799. https://doi.org/10.1016/j.celrep.2021.109799

  • Gray, Z. H., Chakraborty, D., Duttweiler, R. R., Alekbaeva, G. D., Murphy, S. E., Chetal, K., Ji, F., Ferman, B. I., Honer, M. A., Wang, Z., Myers, C., Sun, R., Kaniskan, H. Ü., Toma, M. M., Bondarenko, E. A., Santoro, J. N., Miranda, C., Dillingham, M. E., Tang, R., Gozani, O., … Whetstine, J. R. (2023). Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement. Cell, 186(21), 4528–4545.e18. https://doi.org/10.1016/j.cell.2023.09.009

 

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Comparing CUT&Tag to ENCODE ChIP-Seq in Alzheimer's Disease Samples (Sarah Marzi)18 Apr 202400:46:47

In this episode of the Epigenetics Podcast, we talked with Sarah Marzi from the UK Dementia Research Institute at Imperial College London about her work on epigenetic changes in Alzheimer's Disease, and comparing CUT&Tag to ENCODE ChIP-Seq using limited cell samples.

The interview discusses Sarah Marzi's work on ChIP-Seq experiments and their significance in understanding Alzheimer's disease from an epigenetic perspective. The discussion touches on the widespread dysregulation and changes in acetylation, particularly in genes associated with Alzheimer's risk, providing insights into potential links between epigenetic insults and disease onset.

Moving on to the technical aspects of the study, the interview examines the strategic use of CUT&Tag. It explores the challenges and optimizations involved in accurately profiling limited cell samples. The dialogue also compares CUT&Tag to ENCODE ChIP-Seq, highlighting the complexities of peak calling and data interpretation across different methodologies.

 

References

  • Kumsta, R., Marzi, S., Viana, J. et al. Severe psychosocial deprivation in early childhood is associated with increased DNA methylation across a region spanning the transcription start site of CYP2E1. Transl Psychiatry 6, e830 (2016). https://doi.org/10.1038/tp.2016.95

  • Marzi, S. J., Schilder, B. M., Nott, A., Frigerio, C. S., Willaime‐Morawek, S., Bucholc, M., Hanger, D. P., James, C., Lewis, P. A., Lourida, I., Noble, W., Rodriguez‐Algarra, F., Sharif, J., Tsalenchuk, M., Winchester, L. M., Yaman, Ü., Yao, Z., The Deep Dementia Phenotyping (DEMON) Network, Ranson, J. M., & Llewellyn, D. J. (2023). Artificial intelligence for neurodegenerative experimental models. Alzheimer’s & Dementia, 19(12), 5970–5987. https://doi.org/10.1002/alz.13479

  • Marzi, S. J., Leung, S. K., Ribarska, T., Hannon, E., Smith, A. R., Pishva, E., Poschmann, J., Moore, K., Troakes, C., Al-Sarraj, S., Beck, S., Newman, S., Lunnon, K., Schalkwyk, L. C., & Mill, J. (2018). A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nature Neuroscience, 21(11), 1618–1627. https://doi.org/10.1038/s41593-018-0253-7

  • Hu, D., Abbasova, L., Schilder, B. M., Nott, A., Skene, N. G., & Marzi, S. J. (2022). CUT&Tag recovers up to half of ENCODE ChIP-seq peaks in modifications of H3K27 [Preprint]. Genomics. https://doi.org/10.1101/2022.03.30.486382

 

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The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi)22 Oct 202000:43:58

In this episode of the Epigenetics Podcast, we caught up with Dr. Oded Rechavi, Professor at the University of Tel Aviv, to talk about his work on the role of small RNAs in transgenerational inheritance in C. elegans.

The most prominent example of transgenerational inheritance is the Dutch famine of 1944 during World War II. Effects of this famine could be observed in the grandchildren of people that lived through this hunger winter, but the molecular mechanisms involved remain largely unknown. The guest of this podcast episode, Dr. Rechavi, has taken on the challenge to unravel parts of this puzzle by studying transgenerational epigenetics in C. elegans.

It was already known that small RNA molecules could play a role in passing on information from one generation to the next, but it was not clear what exactly was being inherited. Was it RNAs? Or chromatin modifications? Or something else?

Dr. Rechavi made several important discoveries in his journey to answer these questions. He started out by showing that RNAi provides an antiviral protection mechanism in C. elegans that can be passed on over multiple generations. He then went on to show that starvation in one generation leads to changes in the lifespan of future generations, and investigate how long this memory could last. Simple dilution of the parental RNA in future generations could not be the answer because the inherited phenotypes lasted much longer than would be possible if this were the case. This led Dr. Rechavi to the discovery that small RNAs were amplified in each generation, and the effect of a stimulus could affect multiple generations. More recently, Dr. Rechavi and his team studied the interplay of neurons and the germ line and how information can be passed on from the brain to the germ line.

In this interview, we cover how Dr. Rechavi chose C. elegans as a model organism, discuss his first major discoveries in the field of transgenerational effects of starvation, and what role epigenetic factors play in this process.

 

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Development of Site-Specific ChIP Technologies (Hodaka Fujii)01 Oct 202000:42:06

In this episode of the Epigenetics Podcast, we caught up with Dr. Hodaka Fujii, Professor of Biochemistry and Genome Biology at Hirosaki University Graduate School of Medicine and School of Medicine, to talk about his work on the development of locus-specific ChIP technologies.

The goal of conventional chromatin immunoprecipitation (ChIP) assays is to find genomic locations of transcription factor binding or genome-wide profiles of histone tail modifications.  In contrast to that, the guest of this episode, Dr. Fujii, has developed methods such as insertional chromatin immunoprecipitation (iChIP) and engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) to identify the factors that are binding to specific sites on the genome.

In iChIP, LexA binding sites are inserted into the genomic region of interest. In parallel, the DNA-binding domain of LexA, fused with FLAG epitope tags and a nuclear localization signal, is expressed in the same cells. After crosslinking and chromatin preparation, the resulting chromatin is immunoprecipitated with an antibody against the tag. This allows proteins or RNA interacting with the region of interest to be analyzed with the appropriate downstream application. The enChIP takes a similar approach, but does not require insertion of the LexA binding sites. Instead, a FLAG-tagged dCas9 protein together with the respective guide RNA are used to target the region of the genome of interest. After the IP and the purification DNA, RNA, or proteins can be analyzed accordingly. The lack of the requirement of to insert the LexA binding sites into the genome makes enChIP much more straightforward than iChIP.

In this interview, we discuss the story behind how Dr. Fujii got into the field of epigenetics, how he developed iChIP, and how the method was improved over the years. Furthermore, we discuss the development of enChIP and how this can be used as an alternate method to Hi-C.

 

References

 

 

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Regulation of Chromatin Organization by Histone Chaperones (Geneviève Almouzni)17 Sep 202000:38:43

In this episode of the Epigenetics Podcast, we caught up with Geneviève Almouzni, Ph.D., Research Director at the CNRS at Institut Curie in Paris, to talk about her work on the regulation of chromatin organization by histone chaperones.

Geneviève Almouzni got her Ph.D. from Université Pierre-et-Marie-Curie in 1988 under the supervision of Marcel Méchali. She then moved to the United States to work as a postdoc in the National Institutes of Health in the laboratory of Professor Alan Wolffe. In 1994, she returned to Paris and became a Junior Group Leader at Institut Curie and became a Group Leader there in 2000. In 2013, she took over the direction of research at the Institut Curie and became the third woman to hold this position, after Marie Curie and Irène Joliot-Curie.

Geneviève Almouzni’s research focuses on the assembly of chromatin and the identification of histone chaperones. Histone chaperones are necessary for the establishment and maintenance of chromatin, as they help to assemble the nucleosomes out of the core histones and DNA. This occurs both when the polymerase transcribes through a nucleosome and after DNA replication and repair.

The Almouzni group has identified and characterized multiple histone chaperones, including CAF-1, HirA, and HJURP. Furthermore, they investigated how post-translational modifications on soluble histones influence the final epigenetic state of the nucleosome and the reassembly of chromatin after DNA replication. In the last couple of years, the group has focused on the unraveling the link between the structure of chromatin at centromeres and cancer.

In this interview, we discuss the focus of the Almouzni lab on histone chaperones, how the lab was able to identify its first one with CAF-1, how histone PTMs on soluble histones influence the deposition on the DNA, and how the chromatin on centromeres is involved in cancer.

 

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How the "Fragile Nucleosome" Science Community Came to Life (Christine Cucinotta, Melvin Noe Gonzalez)10 Sep 202000:41:20

In this episode of the Epigenetics Podcast, we caught up with Dr. Christine Cucinotta and Dr. Melvin Noe Gonzalez to talk about how they brought the #fragilenucleosome seminar series and Discord channel to life.

 

Christine Cucinotta and Melvin Noe Gonzales are part of the organizing committee of the independent scientific community "Fragile Nucleosome." This community consists of a Discord channel with more than 1,000 members, a biweekly seminar series, a mentoring program, and a journal club series. The Fragile Nucleosome is organized exclusively by early-career scientists, without external sponsors or under the roof of a single graduate program or university.

 

In this interview, Christine and Melvin share the story on how the Fragile Nucleosome community got started, what has happened so far, and what the future plans are for the #fragilenucleosome.

 

 

References

 

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Epigenetic Influence on Memory Formation and Inheritance (Isabelle Mansuy)03 Sep 202000:38:50

In this episode of the Epigenetics Podcast, we caught up with Professor Isabelle Mansuy, Ph.D., from the University of Zürich and the ETH Zürich, to talk about her work on epigenetic influences on memory formation and inheritance.

 

Dr. Mansuy received her Ph.D. from the Friedrich Miescher Institute, Basel, Switzerland in 1994. After doing a postdoc at the Center for Neurobiology and Behavior at the Howard Hughes Medical Institute at the Columbia University in New York, she moved to Zürich and became Assistant Professor in Neurobiology at the Department of Biology at the Swiss Federal Institute of Technology in 1998. In 2004 Dr. Mansuy became Professor at the Brain Research Institute of the University Zurich, where, in 2007, she became Managing Director. Since 2013 she has been a full Professor in Neuroepigenetics at the University of Zürich and at the ETH in Zürich.

 

Dr. Isabelle Mansuy's work centers around the formation of memories and how those memories are inherited. She started to work on memory formation in the beginning of her research career, where she investigated the influence of calcineurin and Zif268 in this process. In the early 2010s she pivoted and transitioned to work on transgenerational epigenetic inheritance. To investigate this field of research she created an unbiased experiment that allowed her to study the transgenerational influence of early life stress, which she was able to observe for across up to 4 generations through the germline.

 

If you want to learn more about the challenges and obstacles that needed to be overcome to create this novel experimental approach to tackle the questions of and which epigenetic factors might influence transgenerational epigenetic inheritance, don't miss out on this episode.

 

 

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Influence of Dynamic RNA Methylation on Gene Expression (Chuan He)20 Aug 202000:41:22

In this episode of the Epigenetics Podcast, we caught up with Dr. Chuan He, John T. Wilson Distinguished Service Professor at University of Chicago, to talk about his work on the influence of dynamic RNA methylation on gene expression. RNA methylation is an important biological process, and cellular RNA methylation levels can have profound impacts on normal cellular differentiation and cancer cell proliferation.

Dr. He received his Ph.D. from MIT in 2000 and went on to do his postdoctoral work at Harvard University. He then became Assistant Professor at the University of Chicago in 2002, was promoted to Associate Professor in 2008, and in 2014 he became the John T. Wilson Distinguished Service Professor at the University of Chicago.  From 2012 to 2017 he was Director of the Institute for Biophysical Dynamics at the University of Chicago.

Chuan He's current research focuses on understanding the reversible RNA modification m6A. This modification was discovered in the 1980s, but work from Dr. He's laboratory showing that m6A was indeed a transient epigenetic modification by the discovery of the first m6A demethylase FTO in 2011 rekindled the interest in this modification. In the following years Dr. He and his team identified and characterized additional m6A enzymes, including the m6A eraser ALKBH5, the m6A readers YTH and HNRNP, and the m6A writer complex METTL3/14. 

METTL3/14 is a core complex in this regulatory network, and it requires an accessory factor WTAP, which mediates cellular m6A RNA methylation. The current work in the He lab focuses on how the methylation selectivity of this complex is achieved.

In this interview, we discuss the story of how the He lab discovered the members of the family of proteins that read, write, and erase RNA modifications and how those RNA modifications act in the field of epigenetics.

 

References

 

 

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How to Publish in Nature: Lessons from the ENCODE Consortium (Michelle Trenkmann, Senior Editor at Nature)06 Aug 202000:35:08

In this episode of the Epigenetics Podcast, we caught up with Dr. Michelle Trenkmann, Senior Editor at Nature. We discussed her work as an editor at Nature and how she contributed to the ENCODE 3 publications, which are the results of the third phase of the ENCODE project. Dr. Trenkmann also talked about how to get your research published in Nature and what it’s like to review high profile scientific articles.

 

ENCODE References

 

 

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The Role of Non-Histone Proteins in Chromosome Structure and Function During Mitosis (Bill Earnshaw)23 Jul 202001:04:51

In this episode of the Epigenetics Podcast, we caught up with Professor Bill Earnshaw, Wellcome Trust Principal Research Fellow at the University of Edinburgh, to talk about his work on the role of non-histone proteins in chromosome structure and function during mitosis.

 

In the beginning of Bill Earnshaw's research career little was known about the structure that holds the two individual sister chromatids together. This led to Bill pioneering in the use of autoantibodies for the identification and cloning of key chromosomal proteins. He used serum from a scleroderma patient to identify and clone human centromeric proteins, which paved the way for the molecular characterization of the metazoan kinetochore.

 

Later the chromosomal passenger complex (CPC) was identifies in his lab using biochemical studies. This complex contains Aurora B kinase plus its targeting and regulatory subunits INCENP, Survivin, and Borealin/Dasra B. 

 

More recently, he teamed up with the laboratories of Job Dekker and Leonid Mirny. In this collaboration they used a system for synchronous mitotic entry developed by Kumiko Samejima.These studies used a combination of chemical biology, gene targeting, Hi-C genomics, and polymer modeling to explore the roles of condensin I and condensin II in mitotic chromosome formation. The results revealed that during prophase interphase higher-order chromatin organization breaks down and subsequently condensin II and condensin I work together to form hierarchical loops that give chromosomes their compact morphology.

 

In this interview, we discuss the story on how centromeric proteins were first identified using sera from human scleroderma patients, how the chromosomal passenger complex was discovered, and how condensin I and II work together in chromatin loop formation.

 

 

References

 

 

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Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)02 Jul 202000:36:13

In this episode of the Epigenetics Podcast, we caught up with Dr. Dirk Schübeler, Director of the Friedrich Miescher Institute (FMI) in Basel, Switzerland, to talk about his work on the effects of DNA methylation on chromatin structure and transcription.

 

Dirk Schübeler was born in Germany and started his scientific career in Braunschweig, Germany. After his postdoc at the Fred Hutchinson Cancer Research Center in Seattle, he joined the FMI in 2003 and never left. He was recently appointed as the Director of the FMI in March 2020.

 

Dirk Schübeler’s research focuses on DNA methylation and its effects on chromatin and transcription. It is widely known that DNA methylation leads to gene silencing, but many of the mechanisms and regulatory factors involved in this process remain understudied. Therefore, Dirk Schübeler and his team set out to characterize the DNA methylation profiles in normal human somatic cells and compare them with the methylation profiles in transformed human cells. More recent work in his lab led by postdoc Tuncay Baubec focused on factors that bind to methylated DNA regions and modify chromatin structure. The factors they studied include the MBD protein family and also proteins like DNMT3B.

 

In this interview, we discuss the impact of DNA methylation on chromatin states, how CpG-binding factors influence those processes, and we also talk about his new role as Director of the Friedrich Miescher Institute.

 

References

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CpG Islands, DNA Methylation, and Disease (Adrian Bird)18 Jun 202000:47:10

In this episode of the Epigenetics Podcast, we caught up with Sir Adrian Bird, Buchanan Professor of Genetics at the University of Edinburgh to talk about his work on CpG islands, DNA methylation, and the role of DNA methylation in human diseases.

 

Adrian Bird has been a pioneer in studying the CpG dinucleotide sequence. The CpG dinucleotide is distributed genome-wide and has several properties expected of a genomic signaling module. The influence of CpG signaling on prozesses like development, differentiation, and disease is hardly understood. Adrian Bird's work indicates that proteins that bind methylated CpGs recruit chromatin modifying enzymes to promote gene silencing. On the other hand, proteins that bind unmethylated CpGs lead to the formation of active, open chromatin. These results suggest that CpGs have a gobal effect on genome activity.

 

In neurons MeCP2 is almost as abundant as histones and is probably one of the best studied Proteins that bind to methyl-CpGs. Children who lack MeCP2 acquire serious neurological disorders, in particular Rett Syndrome. Rett Syndrome is caused by defects of a single gene, which lead to the opportunity to study its molecular mechanism, which involves MeCP2 in detail. Adrian Bird created a mouse model of Rett Syndrome which has lead to the discovery that reintroducing a functional MeCP2 gene in mice can lead to a "curation" of the symptoms.

  

In this interview, podcast host Stefan Dillinger and Adrian discuss CpG islands, DNA methylation, and how the discovery of MeCP2 lead to the discovery of a possible treatment of Rett Syndrome.

 

References

  • S. Lindsay, A. P. Bird (1987) Use of restriction enzymes to detect potential gene sequences in mammalian DNA (Nature) DOI: 10.1038/327336a0 
  • R. R. Meehan, J. D. Lewis, … A. P. Bird (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs (Cell) DOI: 10.1016/0092-8674(89)90430-3 
  • R. R. Meehan, J. D. Lewis, A. P. Bird (1992) Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA (Nucleic Acids Research) DOI: 10.1093/nar/20.19.5085 
  • Eric U. Selker, Nikolaos A. Tountas, … Michael Freitag (2003) The methylated component of the Neurospora crassa genome (Nature) DOI: 10.1038/nature01564 
  • Robert J. Klose, Shireen A. Sarraf, … Adrian P. Bird (2005) DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG (Molecular Cell) DOI: 10.1016/j.molcel.2005.07.021 
  • Jacky Guy, Jian Gan, … Adrian Bird (2007) Reversal of neurological defects in a mouse model of Rett syndrome (Science (New York, N.Y.)) DOI: 10.1126/science.1138389 
  • Daniel H. Ebert, Harrison W. Gabel, … Michael E. Greenberg (2013) Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR (Nature) DOI: 10.1038/nature12348

 

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The Role of Hat1p in Chromatin Assembly (Mark Parthun)04 Apr 202400:47:30

In this episode of the Epigenetics Podcast, we talked with Mark Parthun from Ohio State University about his work on the role of Hat1p in chromatin assembly.

Mark Parthun shares insights into his pivotal paper in 2004 that explored the link between type B histone acetyltransferases and chromatin assembly, setting the stage for his current research interests in epigenetics. He highlights the role of HAT1 in acetylating lysines on newly synthesized histones, its involvement in double-strand break repair, and the search for phenotypes associated with HAT1 mutations.

The discussion expands to a collaborative research project between two scientists uncovering the roles of HAT1 and NASP as chaperones in chromatin assembly. Transitioning from yeast to mouse models, the team investigated the effects of HAT1 knockout on mouse phenotypes, particularly in lung development and craniofacial morphogenesis. They also explored the impact of histone acetylation on chromatin dynamics and its influence on lifespan, aging processes, and longevity.

 

References

  • Parthun, M. R., Widom, J., & Gottschling, D. E. (1996). The Major Cytoplasmic Histone Acetyltransferase in Yeast: Links to Chromatin Replication and Histone Metabolism. Cell, 87(1), 85–94. https://doi.org/10.1016/S0092-8674(00)81325-2

  • Kelly, T. J., Qin, S., Gottschling, D. E., & Parthun, M. R. (2000). Type B histone acetyltransferase Hat1p participates in telomeric silencing. Molecular and cellular biology, 20(19), 7051–7058. https://doi.org/10.1128/MCB.20.19.7051-7058.2000

  • Ai, X., & Parthun, M. R. (2004). The nuclear Hat1p/Hat2p complex: a molecular link between type B histone acetyltransferases and chromatin assembly. Molecular cell, 14(2), 195–205. https://doi.org/10.1016/s1097-2765(04)00184-4

  • Nagarajan, P., Ge, Z., Sirbu, B., Doughty, C., Agudelo Garcia, P. A., Schlederer, M., Annunziato, A. T., Cortez, D., Kenner, L., & Parthun, M. R. (2013). Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. PLoS genetics, 9(6), e1003518. https://doi.org/10.1371/journal.pgen.1003518

  • Agudelo Garcia, P. A., Hoover, M. E., Zhang, P., Nagarajan, P., Freitas, M. A., & Parthun, M. R. (2017). Identification of multiple roles for histone acetyltransferase 1 in replication-coupled chromatin assembly. Nucleic Acids Research, 45(16), 9319–9335. https://doi.org/10.1093/nar/gkx545

  • Popova, L. V., Nagarajan, P., Lovejoy, C. M., Sunkel, B. D., Gardner, M. L., Wang, M., Freitas, M. A., Stanton, B. Z., & Parthun, M. R. (2021). Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones. Nucleic Acids Research, 49(21), 12136–12151. https://doi.org/10.1093/nar/gkab1044

 

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Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)04 Jun 202000:41:49

In this episode of the Epigenetics Podcast, we caught up with Leonid Mirny, Ph.D., from MIT to talk about his work on biophysical modeling of the 3-D structure of chromatin.

Leonid Mirny was part of the initial Hi-C paper titled "Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome" that was published in 2009 in the journal Science. Since then, technology has evolved and Dr. Mirny's group has developed a method called Micro-C that improves the Hi-C protocol by using MNase digestion to increase the resolution to nucleosomal level. This led to the visualization of interactions that were already predicted by his previous biophysical models.

Furthermore, Leonid Mirny worked on finding the mechanism by which chromatin loops are formed. He and his team proposed that loop extrusion underlies TAD formation. In this process, factors like cohesin and CTCF form progressively larger loops but stall at TAD boundaries due to interactions of CTCF with TAD boundaries. He used polymer simulations to show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops.

In this interview, we chatted with Dr. Mirny about the details of Hi-C, the development of Micro-C and how it compares to Hi-C, and how biophysical modeling helps to unravel the mechanisms behind loop extrusion. 

 

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From Nucleosome Structure to Function (Karolin Luger) 19 May 202000:36:27

In this episode of the Epigenetics Podcast, we caught up with Karolin Luger, Ph.D., from the University of Colorado in Boulder to talk about her work on solving the crystal structure of the nucleosome and on how histone chaperones like FACT act on chromatin.

During her postdoc with Timothy Richmond at the Swiss Federal Institute of Technology in Zürich, Karolin Luger was the first author on an all-time classic paper called "Crystal structure of the nucleosome core particle at 2.8 A resolution" which was published in Nature. This article was published more than 20 years ago now and it has been cited about 9000 times.

After completing her postdoc, she moved to Colorado to set up her own lab where she continued to work on the structure of the nucleosome and the factors that influence their structure. The most recent Nature paper published by her lab investigated how the FACT complex promotes both disassembly and reassembly of nucleosomes during gene transcription, DNA replication, and DNA repair.  

In this interview, we discuss the efforts that went into solving the crystal structure of the nucleosome back in 1997, her work on histone chaperones, and her recent work on how FACT keeps nucleosomes intact after gene transcription.

 

References 

  • K. Luger, A. W. Mäder, … T. J. Richmond (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution (Nature) DOI: 10.1038/38444
  • Yang Liu, Keda Zhou, … Karolin Luger (2020) FACT caught in the act of manipulating the nucleosome (Nature) DOI: 10.1038/s41586-019-1820-0

 

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Identification of Functional Elements in the Genome (Bing Ren)07 May 202000:43:02

In this episode of the Epigenetics Podcast, we caught up with Bing Ren, Ph.D., from the University of California, San Diego and the Ludwig Institute for Cancer Research to talk about his work on identifying functional elements of the genome and higher order genome structure.

 

Dr. Ren’s lab invented an approach using chromatin immunoprecipitation-based methods for the identification of transcription factor binding sites and chromatin modification status genome-wide. His group  was a major part of the ENCODE Project and the demonstration of this being an effective method for genome-wide mapping of cis-elements, has made their approach very popular among colleagues from the field.

 

His lab recently discovered Topologically associating domains (TADs), which partition the human genome into a few thousand megabase-sized domains. Interactions occur predominantly within TADs but seldom between them and are surprisingly stable during development and are evolutionarily conserved. This organisatorial pattern helps explain how enhancers, who are often located kilobases away, influence their target genes.

 

In this interview, we discuss the road of Bing Ren's scientific career, his role in the ENCODE Project and Roadmap Epigenome Consortia, and the discovery of Topologically associating domains (TADs).

 

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Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)23 Apr 202000:47:05

In this episode of the Epigenetics Podcast, we caught up with Erez Lieberman Aiden, Ph.D. from Baylor College of Medicine and Rice University in Houston to talk about his work on developing Hi-C and investigating the three-dimensional structure of the genome. He was the first author on a publication in the journal Science titled "Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome" which was the paper that first introduced the Hi-C method in 2009 and he has continued studying the structure of the chromosome ever since.

Erez Lieberman Aiden is currently an Assistant Professor in both the Department of Genetics at the Baylor College of Medicine, where he directs the newly-established Center for Genome Architecture, and in the Department of Computer Science and Computational and Applied Mathematics at Rice University across the street.

In this interview, we discuss the road that Erez Lieberman Aiden went down to optimize the Hi-C protocol, the hurdles he had to overcome, and how Hi-C made it possible to probe the three-dimensional structure of the genome.

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Chromatin Structure and Dynamics at Ribosomal RNA Genes (Tom Moss)24 Mar 202000:33:07

In this episode of the Epigenetics Podcast, we caught up with Professor Tom Moss from Université Laval in Québec City, Canada to talk about his work on the chromatin structure and dynamics at ribosomal RNA genes.

Dr. Tom Moss has been a member of the Department of Molecular Biology, Medical Biochemistry, and Pathology at the Laval University School of Medicine since he was recruited from the University of Portsmouth in the United Kingdom in 1986.

Since then he focused on the ribosomal transcription factor Upstream Binding Factor (UBF) and how it regulates the chromatin structure at ribosomal RNA genes (rDNA). UBF binds to the rDNA as a dimer where it leads to six in-phase bends and induces the formation of the ribosomal enhanceosome. This enhanceosome is required for the initial step in formation of an RNA polymerase I initiation complex, and therefore plays an important role in regulating the expression of ribosomal RNA genes.

In this Interview, we discuss the function of UBF on the rDNA, how UBF impacts the chromatin landscape at rRNA genes, the role of DNA methylation in this process, and how UBF influences the structure of the nucleolus.

References

  • D. Bachvarov, T. Moss (1991) The RNA polymerase I transcription factor xUBF contains 5 tandemly repeated HMG homology boxes (Nucleic Acids Research) DOI: 10.1093/nar/19.9.2331
  • V. Y. Stefanovsky, D. P. Bazett-Jones, … T. Moss (1996) The DNA supercoiling architecture induced by the transcription factor xUBF requires three of its five HMG-boxes (Nucleic Acids Research) DOI: 10.1093/nar/24.16.3208
  • V. Y. Stefanovsky, G. Pelletier, … T. Moss (2001) DNA looping in the RNA polymerase I enhancesome is the result of non-cooperative in-phase bending by two UBF molecules (Nucleic Acids Research) DOI: 10.1093/nar/29.15.3241
  • Elaine Sanij, Jeannine Diesch, … Ross D. Hannan (2015) A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes (Genome Research) DOI: 10.1101/gr.176115.114
  • Tom Moss, Jean-Clement Mars, … Marianne Sabourin-Felix (2019) The chromatin landscape of the ribosomal RNA genes in mouse and human (Chromosome Research) DOI: 10.1007/s10577-018-09603-9

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Epigenetic Origins Of Heterogeneity And Disease (Andrew Pospisilik)19 Feb 202000:33:10

In this episode of the Epigenetics Podcast, we caught up with Dr. Andrew Pospisilik from the Van Andel Institute in Grand Rapids, Michigan to talk about his work on the epigenetic origins of heterogeneity and disease.

Dr. Andrew Pospisilik worked at the Max-Planck Institute of Immunobiology and Epigenetics in Freiburg for 8 years and in 2018 he joined the Van Andel Institute as the director of its Center for Epigenetics. At the Van Andel Institute his research focuses on diabetes, neurodegenerative diseases, cancer, and obesity. The goal of the Pospisilik laboratory is to better understand epigenetic mechanisms of these diseases and the roles of epigenetics in disease susceptibility and heterogeneity.

 

These areas of medicine are among the most important public health challenges, with the latest estimates suggesting that they impact more than 1 billion people worldwide. Although these diverse conditions are all very different, they are now thought to be caused, at least partially, from alterations in the epigenetic mechanisms that regulate gene expression and metabolism. This interview covers recent work from the Pospisilik lab on the epigenetics of these complex diseases. 

 

References

 

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PIXUL: On the Leading Edge of Chromatin Shearing (Karol Bomsztyk and Tom Matula)28 Jan 202000:45:08

In this episode of the Epigenetics Podcast, we caught up with Karol Bomsztyk M.D. and Tom Matula, Ph.D. from the University of Washington and Matchstick Technologies, to talk about their work on DNA and chromatin sonication.

During his career, Karol's research has focused on improving ChIP protocols to make them faster, easier and higher throughput. First, to make ChIP assays faster, Karol and his lab developed "Fast-ChIP". More recently, he adjusted this protocol to improve throughput and "Matrix-ChIP" was born. Tom is an expert in the field of ultrasound and cavitation and the Director of the Center for Industrial and Medical Ultrasound at the University of Washington.

To further improve and speed up the 96-well "Matrix-ChIP" protocol, Karol and Tom teamed up to found Matchstick Technologies and develop a sonication device that would be able to processes each and every well of a 96-well microplate consistently and quickly. The result of this cooperation is the PIXUL Multi-Sample Sonicator that is now available for order from Active Motif.

PIXUL is an ultrasound-based sample preparation platform that was designed completely from the ground up to provide researchers with an easy-to-use tool that is simple to set up, simple to use, and generates consistent results day in and day out. No other sample preparation platform out there can match the power and convenience of PIXUL.

PIXUL was conceived by an epigenetics researcher, and designed and built by ultrasound engineers to take the guesswork out of sample preparation. With PIXUL, sample preparation is no longer an art form, but instead a simple and predictable part of experiments that work every single time.

This interview goes into the mechanism behind sonication-based shearing of DNA and chromatin and highlights how PIXUL is different from existing sonication instruments.

 

References

  

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Influence of Histone Variants on Chromatin Structure and Metabolism (Markus Buschbeck)16 Dec 201900:31:42

In this episode of the Epigenetics Podcast, we sat down with Marcus Buschbeck, Group Leader at the Josep Carreras Leukaemia Research Institute in Barcelona, to talk about his work on the histone variant macroH2A, its role in metabolism and how it contributes to the regulation of chromatin structure.

 

Histone variants equip chromatin with unique properties and show a specific genomic distribution. The histone variant macroH2A is unique in having a tripartite structure consisting of a N-terminal histone-fold, an intrinsically unstructured linker domain and a C-terminal macro domain. Recent discoveries show that macroH2A proteins have a major role in the nuclear organization which has the potential to explain how these proteins can act as tumor suppressors, promoters of differentiation and barriers to somatic cell reprogramming.

 

We discuss these topics, the mission of the Josep Carreras Leukaemia Research Institute, and much more in this episode.

  

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Epigenetic Mechanisms of Aging and Longevity (Shelley Berger)21 Nov 201900:38:47

In this Episode we sat down with Shelley Berger, Keynote Speaker at the "EMBO | EMBL Symposium: Metabolism Meets Epigenetics" to talk about her work on Epigenetic Mechanisms of Aging and Longevity. On how cytoplasmic chromatin fragments are involved in these processes, how alcohol has an effect on Histone PTMs in the brain and last but not least how Ants became her favorite Model Organism.

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Epigenetics & Glioblastoma: New Approaches to Treat Brain Cancer (Lucy Stead)15 Oct 201900:43:46

In this Episode of the Epigenetics Podcast our guest Lucy Stead from the University of Leeds provides insight into her work on intratumor heterogeneity in Glioblastoma. In order to tackle this area she uses an holistic approach including Computational Genomics, In silico Modeling and Functional Genomics in order to test whether treatment-resistant subclones emerge in recurrent tumors, and characterize them in clinically relevant ways in multiple patients. And this is just a glimpse of what is discussed in this Episode.

 

References 

  • Lucy F. Stead, Helene Thygesen, … Pamela Rabbitts (2015) Using common variants to indicate cancer genes (International Journal of Cancer) DOI: 10.1002/ijc.28951 
  • Caroline Conway, Jennifer L. Graham, … Lucy F. Stead (2015) Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq (Oncotarget) DOI: 10.18632/oncotarget.5529 
  • Alastair Droop, Alexander Bruns, … Lucy F. Stead (2018) How to analyse the spatiotemporal tumour samples needed to investigate cancer evolution: A case study using paired primary and recurrent glioblastoma (International Journal of Cancer) DOI: 10.1002/ijc.31184 
  • Georgette Tanner, David R. Westhead, … Lucy F. Stead (2019) Simulation of heterogeneous tumour genomes with HeteroGenesis and in silico whole exome sequencing (Bioinformatics (Oxford, England)) DOI: 10.1093/bioinformatics/bty1063 
  • Nora Rippaus, Alexander F-Bruns, … Lucy F. Stead (2019) JARID2 facilitates transcriptional reprogramming in glioblastoma in response to standard treatment (bioRxiv) DOI: 10.1101/649400

 

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The Impact of Paternal Diet on Offspring Metabolism (Upasna Sharma)21 Mar 202400:36:38

In this episode of the Epigenetics Podcast, we talked with Upasna Sharma from UC Santa Cruz about her work on a number of interesting projects on H2A.Z and telomeres, the impact of paternal diet on offspring metabolism, and the role of small RNAs in sperm.

In this interview Upasna Sharma discusses her work on the study of the paternal diet's impact on offspring metabolism. She reveals the discovery of small non-coding RNAs, particularly tRNA fragments, in mature mammalian sperm that may carry epigenetic information to the next generation. She explains the specific alterations in tRNA fragment levels in response to a low-protein diet and the connections found between tRNA fragments and metabolic status.

Dr. Sharma further explains the degradation and stabilization of tRNA fragments in cells and the processes involved in their regulation. She shares their observation of tRNA fragment abundance in epididymal sperm, despite the sperm being transcriptionally silent at that time. This leads to a discussion on the role of the epididymis in the reprogramming of small RNA profiles and the transportation of tRNA fragments through extracellular vesicles.

The conversation then shifts towards the potential mechanism of how environmental information could be transmitted to sperm and the observed changes in small RNAs in response to a low-protein diet. Dr. Sharma discusses the manipulation of small RNAs in embryos and mouse embryonic stem cells, revealing their role in regulating specific sets of genes during early development. However, the exact mechanisms that link these early changes to metabolic phenotypes are still being explored.

References

  • Sharma, U., Conine, C. C., Shea, J. M., Boskovic, A., Derr, A. G., Bing, X. Y., Belleannee, C., Kucukural, A., Serra, R. W., Sun, F., Song, L., Carone, B. R., Ricci, E. P., Li, X. Z., Fauquier, L., Moore, M. J., Sullivan, R., Mello, C. C., Garber, M., & Rando, O. J. (2016). Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science (New York, N.Y.), 351(6271), 391–396. https://doi.org/10.1126/science.aad6780

  • Sharma, U., Sun, F., Conine, C. C., Reichholf, B., Kukreja, S., Herzog, V. A., Ameres, S. L., & Rando, O. J. (2018). Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm. Developmental cell, 46(4), 481–494.e6. https://doi.org/10.1016/j.devcel.2018.06.023

  • Rinaldi, V. D., Donnard, E., Gellatly, K., Rasmussen, M., Kucukural, A., Yukselen, O., Garber, M., Sharma, U., & Rando, O. J. (2020). An atlas of cell types in the mouse epididymis and vas deferens. eLife, 9, e55474. https://doi.org/10.7554/eLife.55474

 

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The Past, Present, and Future of Epigenetics (Joe Fernandez, founder of Active Motif)05 Sep 201900:23:43

Joe Fernandez, the founder of Active Motif, has played a significant role in the evolution of the biotechnology industry. He’s seen where the industry has been, and he has a good idea where it’s going. 

Prior to founding Active Motif in 1999, Joe was a co-founder of Invitrogen where he helped revolutionize molecular cloning with the TOPO TA kit. Joe’s passion for disrupting established workflows by making them easier and more efficient didn’t stop there. With Active Motif, he launched the first ever ChIP kit in 2003, and the company now offers the most complete portfolio of ChIP kits for different workflows and sample types, the highest quality ChIP-validated antibodies, and the most comprehensive and most cited end-to-end Epigenetic Services. 

In this interview, we sat down with Joe to learn how he got started in science, what he’s currently excited about, and what he thinks will be the next big thing in epigenetics research.  

 

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The Interchromatin Network Model (Ana Pombo)12 Aug 201900:29:47

In this Episode of the Epigenetics Podcast our guest Ana Pombo from the Max-Delbrück-Center in Berlin provides insight in her work on the interplay between gene regulation and genome architecture. To do so she and her team use different state of the art methods, including cryo-sectioning to unravel this regulatory network. In 2006, they proposed the Interchromatin Network Model of chromosome organization which postulates that chromosome folding is driven by contacts between different genomic regions and between chromatin and nuclear landmarks, such as the nuclear lamina. And later on they used polymer physics modeling to study those mechanisms, which lead to the development of the Strings & Binders Switch (SBS) model. And this is just a glimpse of the topics that are discussed in this Episode.

 

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Dosage Compensation in Drosophila (Asifa Akhtar)16 Jul 201900:36:23

Dosage compensation is an essential process to regulate the gene expression of the X-chromosome in female and male flies. Thereby the mechanism of regulation in humans and in drosophila is different. In humans one X-chromosome is randomly shut down in females compared to men, whereas in drosophila equilibrium is achieved by overexpression of the single X-chromosome in males. In this Episode our guest Dr. Asifa Akhtar provides information on her work on dosage compensation in drosophila melanogaster and how the MSL-complex, the Histone-acetyltransferase MOF work together in this process. Furthermore, she also talks about potential functions of those Proteins in the human system.

 

References 

 

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Spatial Organization of the Human Genome (Wendy Bickmore)11 Jun 201900:31:38

In recent years it has become more and more evident, that genome folding and chromatin packaging into the nucleus plays a pivotal role in the regulation of gene expression. In this Episode of our Podcast our host Dr. Stefan Dillinger spoke with Professor Wendy Bickmore about her work on the spatial organization of the human genome. Prof. Bickmore and her team mainly use visual methods like fluorescence in situ hybridisation (FISH) to study the organization of chromosomes in human and murine cells and how they contribute to transcriptional regulation and how this organization changes during ageing, development or disease.

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Heterochromatin and Phase Separation (Gary Karpen)09 May 201900:34:07

Heterochromatin plays a pivotal role in organizing our genome in the nucleus and separating active from inactive genomic regions. In this Podcast Episode our Guest Gary Karpen from UC Berkeley sits down with our Host Stefan Dillinger to talk about the regulation of this chromatin structure and how DNA repair mechanisms function in this densely packed nuclear compartment. Furthermore, they also discuss how phase separation might be an important part in how heterochromatin domains are formed.

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Diabetes and Epigenetics (Jean-Sébastien Annicotte)04 Apr 201900:18:58

Type 2 Diabetes (T2D) is a chronic metabolic disease, which is caused by the failure of beta-cells in the pancreas and insulin resistance in peripheral tissue and characterized by high glucose levels in the blood. World-wide 382 Million people suffer from Diabetes which makes up 8,3% of the population. Due to this high proportion it is of high interest to find a cure for this disease.

The restoration of β-cell mass and function has therefore become a field of intensive research seeking for the next generation of anti-diabetic drugs. Tremendous efforts have been made on deciphering epigenetic regulations that control metabolic tissue function. For several years, the team led by Dr. Jean-Sebastien Annicotte has dissected the molecular links between insulin producing cells, insulin target tissues and T2D/obesity development. Especially, the team research has been focused on the role of cell cycle regulators and their transcriptional co-regulators in the control of metabolic homeostasis, T2D and obesity.

 

References

 

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Epigenetics and X-inactivation (Edith Heard)21 Nov 201800:35:06

In the seventh Episode of Active Motif's Epigenetics Podcast our host Dr. Stefan Dillinger sat down with Prof. Edith Heard, designated Director General of the European Molecular Biology Laboratory (EMBL), to talk about the challenges and goals of her new position as Director General of the EMBL. Furthermore, they also talk about her research on X-inactivation and dosage compensation.

 

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Chromatin Organization (Susan Gasser)15 Oct 201800:33:23

In the sixth Episode of Active Motif's Epigenetics Podcast our host Dr. Stefan Dillinger sits down with Prof. Susan Gasser, director of the Friedrich Miescher Institute in Basel, to talk about her research on heterochromatin, its localization in the nucleus and factors that are involved in the anchoring genomic regions at the nuclear periphery.

 

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Epigenomics (Henk Stunnenberg)12 Sep 201800:33:34

In the fifth Episode of the Epigenetics Podcast of Active Motif our host Dr. Stefan Dillinger sits down with Prof. Henk Stunnenberg, full professor and head of the Department of Molecular Biology at the Radboud University in Nijmegen, to talk about his research in Epigenetics and his contributions to the BLUEPRINT and Human Cell Atlas consortia.

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Aging and Epigenetics (Peter Tessarz)03 Jan 201800:30:52

The aging population and challenges that arise from aging are one of the great scientific challenges of this time. In the fourth episode of the Epigenetics Podcast from Active Motif, our host Dr. Stefan Dillinger talks with Dr. Peter Tessarz from the Max Planck Institute for Biology of Ageing about his contributions to the field of aging and also, which epigenetic factors play a role in this process.

References for this episode: Active Motif Contact Details
H3K36me3, H4K16ac and Cryptic Transcription in Ageing (Weiwei Dang)07 Mar 202400:56:15

In this episode of the Epigenetics Podcast, we talked with Weiwei Dang from Baylor College of Medicine about his work on molecular mechanisms of aging and the role of H3K36me3 and cryptic transcription in cellular aging.

The team in the Weiwei Dang lab explored the connection between histone marks, specifically H4K16 acetylation and H3K36 methylation, and aging. Dr. Dang describes how the lab conducted experiments by mutating H4K16 to determine its effect on lifespan. They observed that the mutation to glutamine accelerated the aging process and shortened lifespan, providing causal evidence for the relationship between H4K16 and lifespan. They also discovered that mutations in acetyltransferase and demethylase enzymes had opposite effects on lifespan, further supporting a causal relationship.

Weiwei Dang then discusses their expanded research on aging, conducting high-throughput screens to identify other histone residues and mutants in yeast that regulate aging. They found that most mutations at K36 shortened lifespan, and so they decided to follow up on a site that is known to be methylated and play a role in gene function. They discovered that H3K36 methylation helps suppress cryptic transcription, which is transcription that initiates from within the gene rather than at the promoter. Mutants lacking K36 methylation showed an aging phenotype. They also found evidence of cryptic transcription in various datasets related to aging and senescence, including C. elegans and mammalian cells.

References

  • Dang, W., Steffen, K., Perry, R. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009). https://doi.org/10.1038/nature08085

  • Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, J. Y., Wasko, B. M., Carr, D. T., He, C., Robison, B., Wagner, J., Gregory, B. D., Kaeberlein, M., Kennedy, B. K., Boeke, J. D., & Berger, S. L. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes & development, 29(13), 1362–1376. https://doi.org/10.1101/gad.263707.115

  • Yu, R., Cao, X., Sun, L. et al. Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism. Nat Commun 12, 1981 (2021). https://doi.org/10.1038/s41467-021-22257-2

  • McCauley, B.S., Sun, L., Yu, R. et al. Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat Aging 1, 684–697 (2021). https://doi.org/10.1038/s43587-021-00091-x

     

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Cancer and Epigenetics (David Jones)31 Oct 201700:32:44

Cancer has become one of the most dangerous diseases of the aging population of industrialized countries. Finding tools to fight cancer is hard, because Cancer presents itself as highly heterogeneous, with over 100 types of cancers described. Not only does Cancer affect aged humans, it has been observed in children in the form of e.g. Medulloblastoma. In the third episode of Active Motif's Epigenetics Podcast, our host Dr. Stefan Dillinger sits down with Dr. David Jones, group leader at the German Cancer Research Center in Heidelberg, to talk about his research on Medulloblastoma and also the emerging role of epigenetic factors in Cancer.

References for this episode Active Motif Contact Details
The Nucleosome (Ada and Don Olins)11 Sep 201700:34:20

The Nucleosome is the basic building unit of chromatin. It consists out of 147 base pairs of double stranded DNA wrapped around the Histone core octamer that consists out of 2 copies of each dimer of H2A/H2B, and H3/H4. Nucleosomes are organized like "beads on a string" to form a modifiable regulatory basis for higher order structures of chromatin. The first images of the nucleosome as a particle was published by our guests Ada and Don Olins from the University of New England in 1974 (Olins, A. L. & Olins, D. E. Spheroid Chromatin Units (ν Bodies). Science 183, 330–332 (1974).). This observation lead the way to numerous discoveries around chromatin which ultimately culminated in the discovery of the 2.8 Angstrom high-resolution crystal structure 20 years ago in the year 1997 (Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).)

References for this episode Active Motif Contact Details
Multiple Challenges in ChIP (Adam Blattler)09 Jun 201700:35:48

Chromatin Immunoprecipitation (ChIP) was first developed in Drosophila, where interactions of RNA Pol II with genes were investigated (Mol. Cell. Biol. August 1985 vol. 5 no. 8 2009-2018). Then, in a 1993 publication, (Genes & Dev. 1993 7:592-604), the group of James Broach described the association of histone acetylation state with transcriptional gene silencing in yeast. The technique was first used successfully in mammalian cells by Richard Treisman's group, published in 1998 (Cell (1998) 92:475-87). Chromatin Immunoprecipitation is used to link specific states of chromatin to individual loci in a cell, to understand how genes are regulated, and to decipher the Histone Code. In this Episode, we discuss the multiple challenges of ChIP experiments and the difficulties that can arise during different steps of the process.

References for this episode

Epigenetics News:

Multiple Challenges in ChIP

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Split-Pool Recognition of Interactions by Tag Extension (SPRITE) (Mitch Guttman)22 Feb 202400:54:22

In this episode of the Epigenetics Podcast, we talked with Mitch Guttman from California Institute of Technology about his work on characterising the 3D interactions of the genome using Split-Pool Recognition of Interactions by Tag Extension (SPRITE).

Mitch Guttman discusses his exploration of the long non-coding RNA Xist, which plays a crucial role in X chromosome inactivation. He explains how they discovered that Xist is present everywhere in the nucleus, not just in specific locations on the X chromosome. Through their research, they identified critical proteins like SHARP that are involved in X chromosome silencing.

The discussion then shifts to SPRITE, a method they developed to map multi-way contacts and generalize beyond DNA to include RNA and proteins. They compare SPRITE to classical proximity ligation methods like Hi-C and discuss how cluster sizes in SPRITE can estimate 3D distances between molecules. The conversation also touches upon the potential of applying SPRITE to single-cell experiments, allowing for the mapping of higher order nucleic acid interactions and tracking the connectivity of DNA fragments in individual cells.

 

References

  • Jesse M. Engreitz et al., The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science 341,1237973(2013). DOI:10.1126/science.1237973

  • Chun-Kan Chen et al., Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354, 468-472(2016). DOI: 10.1126/science.aae0047

  • Quinodoz, S. A., Ollikainen, N., Tabak, B., Palla, A., Schmidt, J. M., Detmar, E., Lai, M. M., Shishkin, A. A., Bhat, P., Takei, Y., Trinh, V., Aznauryan, E., Russell, P., Cheng, C., Jovanovic, M., Chow, A., Cai, L., McDonel, P., Garber, M., & Guttman, M. (2018). Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus. Cell, 174(3), 744-757.e24. https://doi.org/10.1016/j.cell.2018.05.024

  • Goronzy, I. N., Quinodoz, S. A., Jachowicz, J. W., Ollikainen, N., Bhat, P., & Guttman, M. (2022). Simultaneous mapping of 3D structure and nascent RNAs argues against nuclear compartments that preclude transcription. Cell Reports, 41(9), 111730. https://doi.org/10.1016/j.celrep.2022.111730

  • Perez, A. A., Goronzy, I. N., Blanco, M. R., Guo, J. K., & Guttman, M. (2023). ChIP-DIP: A multiplexed method for mapping hundreds of proteins to DNA uncovers diverse regulatory elements controlling gene expression [Preprint]. Genomics. https://doi.org/10.1101/2023.12.14.571730

 

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MLL Proteins in Mixed-Lineage Leukemia (Yali Dou)08 Feb 202400:36:03

In this episode of the Epigenetics Podcast, we talked with Yali Dou from Keck School of Medicine of USC about her work on MLL Proteins in Mixed-Lineage Leukemia.

To start off this Interview Yali describes her early work on MLL1 and its function in transcription, particularly its involvement in histone modification. She explains her successful purification of the MLL complex and the discovery of MOF as one of the proteins involved.

Next, the interview focuses on her work in reconstituting the MLL core complex and the insights gained from this process. She shares her experience of reconstituting the MLL complex and discusses her focus on the crosstalk of H3K4 and H3K79 methylation, regulated by H2BK34 ubiquitination.

The podcast then delves into the therapeutic potential of MLL1, leading to the discovery of a small molecule inhibitor. Finally, we talk about the importance of the protein WDR5 in the assembly of MLL complexes and how targeting the WDR5-ML interaction can inhibit MLL activity.

 

References

  • Dou, Y., Milne, T., Ruthenburg, A. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 13, 713–719 (2006). https://doi.org/10.1038/nsmb1128

  • Wu, L., Zee, B. M., Wang, Y., Garcia, B. A., & Dou, Y. (2011). The RING Finger Protein MSL2 in the MOF Complex Is an E3 Ubiquitin Ligase for H2B K34 and Is Involved in Crosstalk with H3 K4 and K79 Methylation. Molecular Cell, 43(1), 132–144. https://doi.org/10.1016/j.molcel.2011.05.015

  • Cao, F., Townsend, E. C., Karatas, H., Xu, J., Li, L., Lee, S., Liu, L., Chen, Y., Ouillette, P., Zhu, J., Hess, J. L., Atadja, P., Lei, M., Qin, Z. S., Malek, S., Wang, S., & Dou, Y. (2014). Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia. Molecular Cell, 53(2), 247–261. https://doi.org/10.1016/j.molcel.2013.12.001

  • Park, S.H., Ayoub, A., Lee, YT. et al. Cryo-EM structure of the human MLL1 core complex bound to the nucleosome. Nat Commun 10, 5540 (2019). https://doi.org/10.1038/s41467-019-13550-2

 

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Sex-biased Imprinting and DNA Regulatory Landscapes During Reprogramming (Sam Buckberry)25 Jan 202400:38:30

In this episode of the Epigenetics Podcast, we talked with Sam Buckberry from the Telethon Kids Institute about his work on gene imprinting, sex-biased gene expression, DNA regulatory landscapes, and genomics in the indigenous population of Australia.

Sam Buckberry's research career started with working on the imprinting of H19, IGF2, and IGF2R genes in the placenta. We talk about the controversy surrounding the imprinting of IGF2R and how his study used pyrosequencing to quantify gene expression. We also discuss Sam's work on sex-biased gene expression in the placenta and the identification of a cluster of genes related to placental development and pregnancy.

In addition, we talk about Sam's research on reprogramming and the characterization of DNA regulatory landscapes during the process. We discuss the challenges of working with sequencing data, the discovery of epigenetic memories, and erasing them during reprogramming. Towards the end of the conversation, Sam mentions his current work in setting up an epigenetics group focused on indigenous genomics. They are conducting a large-scale, multi-omics study on cardiometabolic conditions in samples from indigenous Australian communities, with the goal of identifying biomarkers and better understanding the molecular basis of these conditions.

 

References

  • Buckberry, S., Liu, X., Poppe, D. et al. Transient naive reprogramming corrects hiPS cells functionally and epigenetically. Nature 620, 863–872 (2023). https://doi.org/10.1038/s41586-023-06424-7

  • Knaupp AS1, Buckberry S1, Pflueger J, Lim SM, Ford E, Larcombe MR, Rossello FJ, de Mendoza A, Alaei S, Firas J, Holmes ML, Nair SS, Clark SJ, Nefzger CM, Lister R and Polo JM (2017). Transient and permanent reconfiguration of chromatin and transcription factor occupancy drive reprogramming. Cell Stem Cell 21, 1-12 1 Co-first author

 

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BET Proteins and Their Role in Chromosome Folding and Compartmentalization (Kyle Eagen)11 Jan 202400:30:53

In this episode of the Epigenetics Podcast, we talked with Kyle Eagen from Baylor College of Medicine about his work on BET Proteins and their role in chromosome folding and compartmentalization.

In the early days of his research career Dr. Eagen made use of genomics and microscopy to study chromosomes, particularly polytene chromosomes in Drosophila. The correlation between the folding patterns detected by Hi-C and polytene bands highlights the similarities between the two, bridging traditional cytology with modern NGS methods. This work formed the basis of Kyle's thesis and sparked his interest in nuclear organization and chromosome 3D structure.

In his independent lab Kyle then studied compartments in chromatin structure and focused on the relationship between histone modifications and the 3D structure of chromosomes. The discovery of BRD4-NUT, a fusion oncoprotein that reprograms chromosome 3D structure, is highlighted as a significant step forward in understanding chromatin structure.

The conversation then shifts to the use of a tool to test hypotheses about the involvement of BRD4 in a specific process, leading to consistent results and considerations for manipulating chromosome organization for therapeutic purposes. The role of BET proteins in genome folding and the need for further research on other factors involved in 3D genome structure are discussed.

 

References

  • Rosencrance, C. D., Ammouri, H. N., Yu, Q., Ge, T., Rendleman, E. J., Marshall, S. A., & Eagen, K. P. (2020). Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment. Molecular Cell, 78(1), 112-126.e12. https://doi.org/10.1016/j.molcel.2020.03.018

  • Huang, Y., Durall, R. T., Luong, N. M., Hertzler, H. J., Huang, J., Gokhale, P. C., Leeper, B. A., Persky, N. S., Root, D. E., Anekal, P. V., Montero Llopis, P. D. L. M., David, C. N., Kutok, J. L., Raimondi, A., Saluja, K., Luo, J., Zahnow, C. A., Adane, B., Stegmaier, K., … French, C. A. (2023). EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes. Cancer Research, 83(23), 3956–3973. https://doi.org/10.1158/0008-5472.CAN-23-1475

 

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Epigenetic Underpinnings of Human Addiction (Francesca Telese & Jessica Zhou)21 Dec 202300:59:33

In this episode of the Epigenetics Podcast, we talked with Francesca Telese from UC San Diego and Jessica Zhou from Cold Spring Harbour about their work on the molecular underpinnings of human addiction.

Francesca Telese worked on neuronal enhancers and their pivotal role in governing gene activity. She sheds light on her remarkable findings concerning the epigenetic signature of neuronal enhancers that are intricately involved in synaptic plasticity.

Jessica Zhou joined Francesca Telese's lab as a PhD student where she worked on elucidating the effects of chronic cannabis use on memory and behavior in mice. She takes us through the fascinating correlation between THC and gene co-expression networks. Francesca and Jessicathen discuss the utilization of genetically diverse outbred rats in their research, along with the crucial exploration of cell type specificity in gene expression studies. They then delve into the long-term changes that occur in the brain after drug exposure and the profound implications for relapse. Additionally, they touch upon the challenges they face in analyzing single-cell data.

 

References

  • Zhou, J. L., de Guglielmo, G., Ho, A. J., Kallupi, M., Pokhrel, N., Li, H. R., Chitre, A. S., Munro, D., Mohammadi, P., Carrette, L. L. G., George, O., Palmer, A. A., McVicker, G., & Telese, F. (2023). Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition. Nature neuroscience, https://doi.org/10.1038/s41593-023-01452-y

  • Wang, J., Telese, F., Tan, Y., Li, W., Jin, C., He, X., Basnet, H., Ma, Q., Merkurjev, D., Zhu, X., Liu, Z., Zhang, J., Ohgi, K., Taylor, H., White, R. R., Tazearslan, C., Suh, Y., Macfarlan, T. S., Pfaff, S. L., & Rosenfeld, M. G. (2015). LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nature neuroscience, 18(9), 1256–1264. https://doi.org/10.1038/nn.4069

 

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H3K79 Methylation, DOT1L, and FOXG1 in Neural Development (Tanja Vogel)30 Nov 202300:42:03

In this episode of the Epigenetics Podcast, we talked with Tanja Vogel from the University Clinics Freiburg about her work on epigenetic modifications in stem cells during central nervous system development.

During our discussion, Dr. Vogel shared that she and her team have investigated H3K79 methylation and its functional significance, which remains a topic of debate in the scientific community. They’ve also investigated the role of DOT1L in neural development and its implications for neuronal networks, as disrupting DOT1L can lead to conditions such as epilepsy and schizophrenia. They explored the function of the SOX2 enhancer in the presence or absence of DOT1L enzymatic inhibition.

The conversation then shifts to FoxG1, a vital player in forebrain development. The team uncovered its role in chromatin accessibility and its connection to microRNA processing. Their study, utilizing ChIP-Seq, reveals FoxG1's interactions with enhancer regions and other transcription factors, like NeuroD1.

 

### References

  • Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K. Y., Schwark, M., Gyorgy, A., Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnár, Z., & Tarabykin, V. (2008). Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron, 57(3), 378–392. https://doi.org/10.1016/j.neuron.2007.12.028

  • Büttner, N., Johnsen, S. A., Kügler, S., & Vogel, T. (2010). Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 7042–7047. https://doi.org/10.1073/pnas.0912041107

  • Franz, H., Villarreal, A., Heidrich, S., Videm, P., Kilpert, F., Mestres, I., Calegari, F., Backofen, R., Manke, T., & Vogel, T. (2019). DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic acids research, 47(1), 168–183. https://doi.org/10.1093/nar/gky953

  • Ferrari, F., Arrigoni, L., Franz, H., Izzo, A., Butenko, L., Trompouki, E., Vogel, T., & Manke, T. (2020). DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility. Nature communications, 11(1), 5200. https://doi.org/10.1038/s41467-020-19001-7

  • Akol, I., Izzo, A., Gather, F., Strack, S., Heidrich, S., Ó hAilín, D., Villarreal, A., Hacker, C., Rauleac, T., Bella, C., Fischer, A., Manke, T., & Vogel, T. (2023). Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2122467120. https://doi.org/10.1073/pnas.2122467120

     

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Stem Cell Transcriptional Regulation in Naive vs. Primed Pluripotency (Christa Buecker)08 Aug 202400:36:21

In this episode of the Epigenetics Podcast, we talked with Christa Buecker from the Max Perutz Laboratories in Vienna about her work on transcriptional regulation during early embryonic development. Dr. Buecker unravels the differences between naive and primed pluripotency states, showcasing how OCT4 relocalization and enhancer chromatin landscapes play pivotal roles during this transition. The conversation delves into the intricate interplay of transcription factors like OCT4 and OTX2, shedding light on their collaborative efforts in regulating gene expression during differentiation.

Dr. Buecker then shares insights from her study on enhancer elements controlling FGF5 expression and discusses the surprising revelation that individual enhancers show no intrinsic activity but work together in a super additive fashion. She also touches upon her research on IRF1's connection to the gene regulatory network and its role in protecting cells against viral infections.

The conversation shifts to Dr. Buecker's current research endeavors, focusing on exploring the strength of enhancers and their impact on gene expression at different distances from promoters. She shares her vision for future experiments and the integration of enhancers to decipher their impact on transcription regulation.

 

References

  • Buecker, C., Srinivasan, R., Wu, Z., Calo, E., Acampora, D., Faial, T., Simeone, A., Tan, M., Swigut, T., & Wysocka, J. (2014). Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell stem cell, 14(6), 838–853. https://doi.org/10.1016/j.stem.2014.04.003

  • Thomas, H. F., Kotova, E., Jayaram, S., Pilz, A., Romeike, M., Lackner, A., Penz, T., Bock, C., Leeb, M., Halbritter, F., Wysocka, J., & Buecker, C. (2021). Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements. Molecular cell, 81(5), 969–982.e13. https://doi.org/10.1016/j.molcel.2020.12.047

  • Romeike, M., Spach, S., Huber, M., Feng, S., Vainorius, G., Elling, U., Versteeg, G. A., & Buecker, C. (2022). Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection. EMBO reports, 23(9), e55375. https://doi.org/10.15252/embr.202255375

 

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Function of Insulators in 3D Genome Folding (Maria Gambetta)16 Nov 202300:43:35

In this episode of the Epigenetics Podcast, we talked with Maria Gambetta from the University of Lausanne about her work on the function of insulators in 3D genome folding.

Maria Gambetta focuses on investigating 3D contact dynamics between enhancers and promoters, providing insights into tissue-specific gene activation. The team used capture-C to analyze dynamic looping events, emphasizing the significance of accessible chromatin peaks in enhancer-promoter interactions. Furthermore, they focused on gene insulation and CTCF's role in forming topologically associating domains in Drosophila. Hi-C analysis on CTCF mutants revealed the conservation of TAD boundary mechanisms, identifying CP-190 as a potential binding protein.

Their findings on the loss of TAD boundaries in mutants and the role of transcription in TAD boundary formation are discussed as well as the function of CP190 and insulators in preventing interactions between promoters and enhancers. Their work challenges existing models of insulator function and seeks to understand their mechanisms better. The conversation concludes with insights into long-range regulatory associations in Drosophila, emphasizing the punctual interactions between transcription factor binding sites and their effect on neural gene transcription and genome folding.

 

References

  • Gambetta, M. C., Oktaba, K., & Müller, J. (2009). Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science (New York, N.Y.), 325(5936), 93–96. https://doi.org/10.1126/science.1169727

  • Kaushal, A., Mohana, G., Dorier, J., Özdemir, I., Omer, A., Cousin, P., Semenova, A., Taschner, M., Dergai, O., Marzetta, F., Iseli, C., Eliaz, Y., Weisz, D., Shamim, M. S., Guex, N., Lieberman Aiden, E., & Gambetta, M. C. (2021). CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions. Nature communications, 12(1), 1011. https://doi.org/10.1038/s41467-021-21366-2

  • Hoencamp, C., Dudchenko, O., Elbatsh, A. M. O., Brahmachari, S., Raaijmakers, J. A., van Schaik, T., Sedeño Cacciatore, Á., Contessoto, V. G., van Heesbeen, R. G. H. P., van den Broek, B., Mhaskar, A. N., Teunissen, H., St Hilaire, B. G., Weisz, D., Omer, A. D., Pham, M., Colaric, Z., Yang, Z., Rao, S. S. P., Mitra, N., … Rowland, B. D. (2021). 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science (New York, N.Y.), 372(6545), 984–989. https://doi.org/10.1126/science.abe2218

  • Mohana, G., Dorier, J., Li, X., Mouginot, M., Smith, R. C., Malek, H., Leleu, M., Rodriguez, D., Khadka, J., Rosa, P., Cousin, P., Iseli, C., Restrepo, S., Guex, N., McCabe, B. D., Jankowski, A., Levine, M. S., & Gambetta, M. C. (2023). Chromosome-level organization of the regulatory genome in the Drosophila nervous system. Cell, 186(18), 3826–3844.e26. https://doi.org/10.1016/j.cell.2023.07.008

     

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Contribution of the Estrogen Receptor to Breast Cancer Progression (Jason Carroll)02 Nov 202300:46:37

In this episode of the Epigenetics Podcast, we talked with Jason Carroll from the Cambridge Research Institute about his work on contribution of estrogen receptor to breast cancer progression.

The Podcast centers around the crucial role of the forkhead protein FOXA1 in breast cancer. FOXA1 acts as a pioneer transcription factor, facilitating gene regulation by recruiting nuclear receptors to chromatin, profoundly influencing gene expression in various breast cancer subtypes. The FOXA1-positive subtype of triple-negative breast cancer, despite being estrogen receptor-negative, shares gene expression profiles with estrogen receptor-positive breast cancer, shedding light on the importance of targeting the androgen receptor for treatment.

The challenges of studying transcription factor mappings from clinical samples are explored, with a focus on the ChIP-seq method's success in mapping estrogen receptor binding sites. Various techniques for transcription factor mapping, including CUT&RUN, CUT&Tag, and ChIP-exo, are discussed, as well as the potential of mass spec techniques like the RIME method in analyzing protein interactions. An intriguing experiment involving the purification of multiple proteins to identify interactions is highlighted.

 

References

  • Carroll, J. S., Meyer, C. A., Song, J., Li, W., Geistlinger, T. R., Eeckhoute, J., Brodsky, A. S., Keeton, E. K., Fertuck, K. C., Hall, G. F., Wang, Q., Bekiranov, S., Sementchenko, V., Fox, E. A., Silver, P. A., Gingeras, T. R., Liu, X. S., & Brown, M. (2006). Genome-wide analysis of estrogen receptor binding sites. Nature genetics, 38(11), 1289–1297. https://doi.org/10.1038/ng1901

  • Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., Jiang, J., Howat, W. J., Ali, S., & Carroll, J. S. (2008). Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature, 456(7222), 663–666. https://doi.org/10.1038/nature07483

  • Ross-Innes, C. S., Stark, R., Teschendorff, A. E., Holmes, K. A., Ali, H. R., Dunning, M. J., Brown, G. D., Gojis, O., Ellis, I. O., Green, A. R., Ali, S., Chin, S. F., Palmieri, C., Caldas, C., & Carroll, J. S. (2012). Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature, 481(7381), 389–393. https://doi.org/10.1038/nature10730

  • Mohammed, H., Russell, I. A., Stark, R., Rueda, O. M., Hickey, T. E., Tarulli, G. A., Serandour, A. A., Birrell, S. N., Bruna, A., Saadi, A., Menon, S., Hadfield, J., Pugh, M., Raj, G. V., Brown, G. D., D'Santos, C., Robinson, J. L., Silva, G., Launchbury, R., Perou, C. M., … Carroll, J. S. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313–317. https://doi.org/10.1038/nature14583

     

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Inheritance of Transcriptional Memory by Mitotic Bookmarking (Sheila Teves)19 Oct 202300:45:35

In this episode of the Epigenetics Podcast, we caught up with Sheila Teves from the University of British Columbia to talk about her work on the inheritance of transcriptional memory by mitotic bookmarking.

Early in her research career, Sheila Teves focused on the impact of nucleosomes on torsional stress and gene regulation. She also highlights the development of a genome-wide approach to measure torsional stress and its relationship to nucleosome dynamics and RNA polymerase regulation.

The conversation then shifts to her focus on transcriptional memory and mitotic bookmarking during her postdoc in the Tijan lab. She explores the concept of mitotic bookmarking, whereby certain transcription factors remain bound to their target sites during mitosis, facilitating efficient reactivation of transcription after cell division. She discusses her findings on the behavior of transcription factors on mitotic chromosomes, challenging the notion that they are excluded during mitosis. She also discusses the differences in binding behavior between the general transcription factor TBP and other transcription factors. Finally, the effect of formaldehyde fixation on the potential to find transcription factors bound to mitotic chromosomes is discussed.

 

References

  • Teves, S., Henikoff, S. Transcription-generated torsional stress destabilizes nucleosomes. Nat Struct Mol Biol 21, 88–94 (2014). https://doi.org/10.1038/nsmb.2723

  • Sheila S Teves, Luye An, Anders S Hansen, Liangqi Xie, Xavier Darzacq, Robert Tjian (2016) A dynamic mode of mitotic bookmarking by transcription factors eLife 5:e22280. https://doi.org/10.7554/eLife.22280

  • Sheila S Teves, Luye An, Aarohi Bhargava-Shah, Liangqi Xie, Xavier Darzacq, Robert Tjian (2018) A stable mode of bookmarking by TBP recruits RNA polymerase II to mitotic chromosomes eLife 7:e35621. https://doi.org/10.7554/eLife.35621

  • Kwan, J. Z. J., Nguyen, T. F., Uzozie, A. C., Budzynski, M. A., Cui, J., Lee, J. M. C., Van Petegem, F., Lange, P. F., & Teves, S. S. (2023). RNA Polymerase II transcription independent of TBP in murine embryonic stem cells. eLife, 12, e83810. https://doi.org/10.7554/eLife.83810

  • Price, R. M., Budzyński, M. A., Shen, J., Mitchell, J. E., Kwan, J. Z. J., & Teves, S. S. (2023). Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes. Nucleic acids research, 51(10), 5040–5055. https://doi.org/10.1093/nar/gkad304

     

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Differential Methylated Regions in Autism Spectrum Disorders (Janine La Salle)05 Oct 202300:40:39

In this episode of the Epigenetics Podcast, we talked with Janine La Salle from UC Davis about her work on differential methylated regions in autism spectrum disorders.

In our discussion, Janine LaSalle highlights her work on the placental epigenetic signature, which offers insights into the impact of fetal exposures and gene-environment interactions during the perinatal period. She emphasizes the placenta's value as a surrogate tissue for understanding human diseases. Her research on DNA methylation in the placenta across different mammalian species reveals consistent patterns in partially methylated and highly methylated domains. She explains the critical role of higher methylation levels in specific regions for gene expression and how this knowledge helps trace the placenta's developmental history.

The conversation then delves into Dr. LaSalle's research on the link between placental DNA methylation and autism. Through epigenome-wide association studies, she discovered a novel autism gene and explored the effects of prenatal exposures on DNA methylation profiles. Additionally, she discusses the impact of maternal obesity on offspring neurodevelopment. Ultimately, the goal of her research is to contribute to precision public health and preventative healthcare with epigenetic signatures offering high potential for predicting and preventing future health problems.

 

References

  • Schroeder, D. I., Blair, J. D., Lott, P., Yu, H. O., Hong, D., Crary, F., Ashwood, P., Walker, C., Korf, I., Robinson, W. P., & LaSalle, J. M. (2013). The human placenta methylome. Proceedings of the National Academy of Sciences of the United States of America, 110(15), 6037–6042. https://doi.org/10.1073/pnas.1215145110

  • Zhu, Y., Gomez, J. A., Laufer, B. I., Mordaunt, C. E., Mouat, J. S., Soto, D. C., Dennis, M. Y., Benke, K. S., Bakulski, K. M., Dou, J., Marathe, R., Jianu, J. M., Williams, L. A., Gutierrez Fugón, O. J., Walker, C. K., Ozonoff, S., Daniels, J., Grosvenor, L. P., Volk, H. E., Feinberg, J. I., … LaSalle, J. M. (2022). Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism. Genome biology, 23(1), 46. https://doi.org/10.1186/s13059-022-02613-1

  • Laufer, B. I., Hasegawa, Y., Zhang, Z., Hogrefe, C. E., Del Rosso, L. A., Haapanen, L., Hwang, H., Bauman, M. D., Van de Water, J., Taha, A. Y., Slupsky, C. M., Golub, M. S., Capitanio, J. P., VandeVoort, C. A., Walker, C. K., & LaSalle, J. M. (2022). Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models. Nature communications, 13(1), 5538. https://doi.org/10.1038/s41467-022-33162-7

  • Coulson, R. L., Yasui, D. H., Dunaway, K. W., Laufer, B. I., Vogel Ciernia, A., Zhu, Y., Mordaunt, C. E., Totah, T. S., & LaSalle, J. M. (2018). Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nature communications, 9(1), 1616. https://doi.org/10.1038/s41467-018-03676-0

  • Neier, K., Grant, T. E., Palmer, R. L., Chappell, D., Hakam, S. M., Yasui, K. M., Rolston, M., Settles, M. L., Hunter, S. S., Madany, A., Ashwood, P., Durbin-Johnson, B., LaSalle, J. M., & Yasui, D. H. (2021). Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome. Communications biology, 4(1), 1408. https://doi.org/10.1038/s42003-021-02915-3

     

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