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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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.

 

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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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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.

 

 

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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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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.

 

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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.

 

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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.

 

 

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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.

 

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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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