Epigenetics Podcast

How to Publish in Nature: Lessons from the ENCODE Consortium (Michelle Trenkmann, Senior Editor at Nature)

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
 
Immersive ENCODE Website
Perspectives on ENCODE
 
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The Role of Non-Histone Proteins in Chromosome Structure and Function During Mitosis (Bill Earnshaw)

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
 
Johan H. Gibcus, Kumiko Samejima, … Job Dekker (2018) A pathway for mitotic chromosome formation (Science (New York, N.Y.)) DOI: 10.1126/science.aao6135
A. F. Pluta, A. M. Mackay, … W. C. Earnshaw (1995) The Centromere: Hub of Chromosomal Activities (Science) DOI: 10.1126/science.270.5242.1591
Nuno M. C. Martins, Jan H. Bergmann, … William C. Earnshaw (2016) Epigenetic engineering shows that a human centromere resists silencing mediated by H3K27me3/K9me3 (Molecular Biology of the Cell) DOI: 10.1091/mbc.E15-08-0605
Oscar Molina, Giulia Vargiu, … William C. Earnshaw (2016) Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance (Nature Communications) DOI: 10.1038/ncomms13334
Jan G Ruppert, Kumiko Samejima, … William C Earnshaw (2018) HP 1α targets the chromosomal passenger complex for activation at heterochromatin before mitotic entry (The EMBO Journal) DOI: 10.15252/embj.201797677
 
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Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)

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
Tuncay Baubec, Daniele F. Colombo, … Dirk Schübeler (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation (Nature) DOI: 10.1038/nature14176 
Paul Adrian Ginno, Lukas Burger, … Dirk Schübeler (2018) Cell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape (Nature Communications) DOI: 10.1038/s41467-018-06007-5 
Michael B. Stadler, Rabih Murr, … Dirk Schübeler (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions (Nature) DOI: 10.1038/nature10716 
Silvia Domcke, Anaïs Flore Bardet, … Dirk Schübeler (2015) Competition between DNA methylation and transcription factors determines binding of NRF1 (Nature) DOI: 10.1038/nature16462 
Florian Lienert, Christiane Wirbelauer, … Dirk Schübeler (2011) Identification of genetic elements that autonomously determine DNA methylation states (Nature Genetics) DOI: 10.1038/ng.946
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CpG Islands, DNA Methylation, and Disease (Adrian Bird)

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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Biophysical Modeling of 3-D Genome Organization (Leonid Mirny)

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. 
 
References
Grigory Kolesov, Zeba Wunderlich, … Leonid A. Mirny (2007) How gene order is influenced by the biophysics of transcription regulation (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.0700672104 
Erez Lieberman-Aiden, Nynke L. van Berkum, … Job Dekker (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome (Science (New York, N.Y.)) DOI: 10.1126/science.1181369 
Geoffrey Fudenberg, Maxim Imakaev, … Leonid A. Mirny (2016) Formation of Chromosomal Domains by Loop Extrusion (Cell Reports) DOI: 10.1016/j.celrep.2016.04.085 
Johannes Nuebler, Geoffrey Fudenberg, … Leonid A. Mirny (2018) Chromatin organization by an interplay of loop extrusion and compartmental segregation (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.1717730115 
Martin Falk, Yana Feodorova, … Leonid A. Mirny (2019) Heterochromatin drives compartmentalization of inverted and conventional nuclei (Nature) DOI: 10.1038/s41586-019-1275-3
 
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From Nucleosome Structure to Function (Karolin Luger)

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)

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).
 
References
The ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project (Science) DOI: 10.1126/science.1105136 
Yin Shen, Feng Yue, … Bing Ren (2012) A map of the cis -regulatory sequences in the mouse genome (Nature) DOI: 10.1038/nature11243 
Tae Hoon Kim, Leah O. Barrera, … Bing Ren (2005) A high-resolution map of active promoters in the human genome (Nature) DOI: 10.1038/nature03877 
Tae Hoon Kim, Ziedulla K. Abdullaev, … Bing Ren (2007) Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome (Cell) DOI: 10.1016/j.cell.2006.12.048 
R. David Hawkins, Gary C. Hon, … Bing Ren (2010) Distinct Epigenomic Landscapes of Pluripotent and Lineage-Committed Human Cells (Cell Stem Cell) DOI: 10.1016/j.stem.2010.03.018 
Jesse R. Dixon, Siddarth Selvaraj, … Bing Ren (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions (Nature) DOI: 10.1038/nature11082 
Fulai Jin, Yan Li, … Bing Ren (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells (Nature) DOI: 10.1038/nature12644
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Hi-C and Three-Dimensional Genome Sequencing (Erez Lieberman Aiden)

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.
References 
Erez Lieberman-Aiden, Nynke L. van Berkum, … Job Dekker (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome (Science (New York, N.Y.)) DOI: 10.1126/science.1181369 
Suhas S. P. Rao, Miriam H. Huntley, … Erez Lieberman Aiden (2014) A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping (Cell) DOI: 10.1016/j.cell.2014.11.021 
Adrian L. Sanborn, Suhas S. P. Rao, … Erez Lieberman Aiden (2015) Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes (Proceedings of the National Academy of Sciences) DOI: 10.1073/pnas.1518552112 
Suhas S.P. Rao, Su-Chen Huang, … Erez Lieberman Aiden (2017) Cohesin Loss Eliminates All Loop Domains (Cell) DOI: 10.1016/j.cell.2017.09.026
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