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Environmental Factor, February 2012

Minisymposium brings epigenetic experts to NIEHS

By Ashley Godfrey

Sponsored by the Division of Extramural Research and Training (DERT), a minisymposium Jan. 10 at NIEHS showcased scientific presentations by many leaders in the field of epigenetics, chromatin biology, development, and disease. Speakers from the NIEHS intramural and extramural communities were on hand to discuss findings from their latest research (see text box).

The daylong symposium was part of the DERT Keystone Science Lecture Seminar Series. DERT scientists Astrid Haugen, Lisa Chadwick, Ph.D., and Frederick Tyson, Ph.D., hosted the event’s 10 scientific presentations.

“NIEHS has made a commitment to translating basic fundamental research and really putting it to work for the benefit of public health and disease prevention,” said Deputy Director Rick Woychik, Ph.D., in his welcoming remarks.

Woychik explained the significance of epigenetic research in relation to the Institute’s mission. Environmental exposure is increasingly linked to changes in epigenetic profiles and subsequently with disease. “One area we are very interested in is better understanding why it is that, when you take two different individuals and you expose them to exactly the same environment, there are different phenotypic outcomes or health outcomes,” Woychik told the near-capacity audience.

Watch as Woychik describes the NIEHS commitment to epigenetics research (10:29)

 

Epigenetics an emerging frontier in science

Epigenetics refers to heritable changes in the regulation of gene activity and expression that are independent of any change in the gene sequence itself. Epigenetic mechanisms, such as DNA methylation and histone tail modifications, can serve as the interface between the genome and the environment. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to a more global analysis of epigenetic changes across the entire genome.

The day before the symposium, several of the speakers participated in a steering committee advisory meeting for the NIH Roadmap Epigenomics Mapping Consortium. (http://www.roadmapepigenomics.org/)  NIEHS and the National Institute on Drug Abuse are administrative leads for the NIH Common Fund effort. The goal of the consortium is to produce a public resource of human epigenomic data to help jumpstart basic biology and disease-oriented research. The consortium plans to continue to build a publically accessible collection of reference epigenomes, from a wide range of species and human tissue types, which will provide the framework for a broad array of future studies.

“The steering committee actually met yesterday and they reported that there are now 39 different reference genomes that are completed,” reported Woychik, referring to data now posted online. (http://www.roadmapepigenomics.org/) 

Bringing together diverse epigenetic research interests

The symposium was divided into three sessions, each with a different focus on epigenetic research. The first focused on epigenomics and disease. The three speakers demonstrated how epigenomics can be used to understand the epigenetic mechanisms that contribute to cell type specificity and also to human disease.

In the second session, the emphasis was on chromatin and transcription. The four speakers sought to answer the question of how epigenetic modifications work in combination, both with each other and with transcription factors and other proteins to direct gene expression.

Finally, the third session explored the role of epigenetic mechanisms in development and disease. The three speakers showcased examples of the critical role epigenetics plays in normal mammalian development through different processes, including maintaining stem cell pluripotency, genomic imprinting, and B cell activation and differentiation.

Translating research into treatment and prevention

In her closing comments, Gwen Collman, Ph.D., DERT director, focused on the enormous opportunity epigenetics research offers as a protective and preventive strategy. Collman emphasized that this research could be used not only to understand the causes of human disease, but also to create strategies and interventions that will help keep populations and individuals healthy and strong.  

“There is a lot to do in this field of epigenetics, and we are only at the beginning,” concluded Collman. “I hope the take-home message is to stay the course and help us use the tools and technology and knowledge we have now, to be able to protect our health in the future.”

(Ashley Godfrey, Ph.D., is a postdoctoral fellow in the Molecular and Genetic Epidemiology Group in the NIEHS Laboratory of Molecular Carcinogenesis.)


Jack Taylor, M.D., Ph.D. sitting in the audience

Jack Taylor, M.D., Ph.D., head of the NIEHS Molecular and Genetic Epidemiology Group diligently takes notes during the first session. Taylor said he was interested in the data Stamatoyannopoulos presented, showing that most of the common disease associated variants in the human gene sequence are concentrated in DNA regulatory regions. (Photo courtesy of Steve McCaw)


Karen Adelman, Ph.D. waiting in the audience to present her groups research

Adelman, right, waited for her chance to describe her group’s research on paused polymerase and chromatin architecture. (Photo courtesy of Steve McCaw)


left to right: Hrisavgi Kondilis-Mangum, Ph.D., and Lai.

Members of the Wade lab were on hand, as many of the leaders in the field of epigenetics, including their own group leader, presented their work. Shown, left to right, are Hrisavgi Kondilis-Mangum, Ph.D., and Lai. (Photo courtesy of Steve McCaw)


Marisa S. Bartolomei, Ph.D. presenting

Bartolomei began her presentation by saying how much she enjoyed being part of the NIH Roadmap Epigenomics Mapping Consortium External Scientific Panel. (Photo courtesy of Steve McCaw)


Paul Wade, Ph.D. giving his presentation.

Wade rounded out the minisymposium with the last presentation of the day. Research from his group has shown that two different types of B cells, naive and memory, have closely related gene expression profiles, but have distinct DNA methylation signatures. (Photo courtesy of Steve McCaw)


Rick Woychik, Ph.D. speaking at the podium

Woychik gave the welcome remarks and introduction for the symposium. He ended by emphasizing, “The epigenome serves as an interface between the genome and the environment in complex human disease.” (Photo courtesy of Steve McCaw)


Bing Ren, Ph.D. presenting his groups findings

Ren and his group used genome-wide mapping of parent of origin specific DNA methylation in mouse strains to discover 24 novel methylated regions, with 9 of those outside of any previously known imprinted regions in the genome. (Photo courtesy of Steve McCaw)


Manolis Kellis, Ph.D. and Marisa S. Bartolomei, Ph.D. sitting in the audience

Shown, left to right, Tyson joined Kellis and Bartolomei in the audience. Kellis presented his group’s work on the interpretation of the genomics and epigenomics of human disease variants during the morning session, while Bartolomei presented her group’s work on the epigenetic regulation of genomic imprinting during the last session in the afternoon. (Photo courtesy of Steve McCaw)


Trevor Archer, Ph.D. speaking at the podium

Archer presented data from his lab on the molecular mechanisms of hormone-mediated chromatin remodeling. He explained that most of this work was done by Kevin Trotter, a biologist in his group. (Photo courtesy of Steve McCaw)


Raja Jothi, Ph.D. on hand at the symposia

Biostatistician Raja Jothi, Ph.D., head of the NIEHS Systems Biology Group, was on hand for the symposia. Jothi’s group is also interested in understanding how transcription regulators and epigenetic modifications control gene expression programs during cellular development and differentiation. (Photo courtesy of Steve McCaw)


Epigenetics research highlighted by the keystone minisymposium

Session I — Epigenomics and Disease

  • “Epigenomic contributions to cell identity in the human breast,” by Martin Hirst, Ph.D., (http://www.chibi.ubc.ca/faculty/hirst)  of the University of British Columbia. Working closely with collaborators within the NIH Roadmap Epigenomics project, Hirst and his team have undertaken a comprehensive study of sequencing based methodologies for DNA methylation profiling of normal human mammary epithelial cells.
  • “Widespread variation in regulatory DNA associated with common human disease,” by John Stamatoyannopoulos, M.D., (http://www.gs.washington.edu/faculty/stamj.htm)  of the University of Washington. Stamatoyannopoulos and his research team have used the application of novel molecular and computational technologies to read eukaryotic regulatory genomes and epigenomes, with the goal of predicting the functional consequences of non-coding human genetic variation, especially in relation to common human disease.
  • “Comparative and epigenomic signatures for interpreting disease variants,” by Manolis Kellis, Ph.D., (http://web.mit.edu/manoli/www/research.html)  of the Massachusetts Institute of Technology. Kellis and his group have developed new algorithms and machine learning techniques that can help researchers with the interpretation of the genomics and epigenomics of human disease variants.

Session II — Chromatin and Transcription

  • “Decoding the genome’s second code,” by Bing Ren, Ph.D., (http://igm.ucsd.edu/faculty/profiles/bing-ren.shtml)  of the University of California, San Diego. Ren and his lab have developed a high throughput method for genome-wide mapping of parent of origin specific DNA methylation, and have also used this method to characterize the epigenomic landscape of human embryonic stem cell differentiation.
  • “Potentiating signal-responsive transcription: a dynamic dance between paused polymerase and chromatin,” by Karen Adelman, Ph.D., head of the NIEHS Transcriptional Responses to the Environment Group. Adelman and her research group have used cutting-edge genomic techniques to determine the global distribution of promoter-proximally paused polymerase and have found that Pol II pausing plays a critical role in establishing an accessible chromatin architecture around gene promoters that facilitates further or future gene activation.
  • “Nuclear receptors modulate chromatin to regulate transcription,” by Trevor Archer, Ph.D., chief of the NIEHS Laboratory of Molecular Carcinogenesis. Archer and his group are using cancer cell culture models and biochemical assays to understand the molecular mechanisms of hormone-mediated chromatin remodeling to allow gene transcription.
  • “Chromatin and transcription factor dynamics in development and disease,” by Jason Lieb, Ph.D., (http://bio.unc.edu/people/faculty/lieb/)  of the University of North Carolina at Chapel Hill. Lieb and a postdoctoral student, Dan McKay, Ph.D., are using the model organism Drosophila and a technique developed in his lab to map where transcription regulatory elements are in the genome during early development and also during the formation of different body structures.

Session III — Epigenetics and Development

  • “DNA methylation dynamics in development,” by Alex Meissner, Ph.D., (http://www.hsci.harvard.edu/people/alex-meissner-phd)  of Harvard University and the Broad Institute. Meissner and his research group have developed a high-throughput bisulfite sequencing technology for DNA methylation analysis and have used this to address questions about the transmission of epigenetic marks and also to identify epigenetic changes involved in reprogramming and maintaining cellular states.
  • “Epigenetic regulation of genomic imprinting,” by Marisa S. Bartolomei, Ph.D., (http://www.med.upenn.edu/apps/faculty/index.php/g20000320/p13534)  of the University of Pennsylvania. Bartolomei and her lab are using a mouse model system to understand the biology behind the epigenetic regulation of genomic imprinting and have further translated those findings to a human disease model possibly regulated by similar epigenetic mechanisms.
  • “Epigenetic reprogramming during B lymphocyte activation and differentiation,” by Paul Wade, Ph.D., head of the NIEHS Eukaryotic Transcriptional Regulation Group. Wade and a postdoctoral fellow in his lab, Anne Lai, Ph.D., have been using surgically removed tonsil cells to study DNA methylation in four different populations of B cells and are using this model to study the pathway of activation and ultimate differentiation of these cells.


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