Epigenetic Control of Regulatory T Cells

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New research published this week in PLoS Biology shows the importance of epigenetic modifications in regulatory T cells.

Regulatory T cells play a pivotal role in the maintenance of self-tolerance within the immune system by preventing autoimmunity or excessive activation of the T cells that respond to pathogens (naïve and effector T cells). They differentiate within the thymus, but can also be de novo induced in the rest of the body. Mechanisms determining development of a stable regulatory T cell lineage are unknown. Our study provides evidence for a critical role of epigenetic modifications in the locus coding for the forkhead transcription factor Foxp3, which acts as a master switch controlling regulatory T cell development and function: An evolutionarily conserved region within the non-coding part of the gene contains CpG motifs, which are completely demethylated in regulatory T cells, but methylated in naïve and effector T cells, whereas we observed an inverse occurrence of acetylated histones, another epigenetic chromatin modification. Regulatory T cells induced in vitro—which, in contrast to natural regulatory T cells, do not display a stable regulatory T cell phenotype—display only incomplete DNA demethylation despite high Foxp3 expression. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to result in a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of regulatory T cells and for the understanding of long-term cell lineage decisions.


How I Found the Greally Lab

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The Greally lab was really easy to find. They linked to me. I have access to a nice stats package through my Web host that shows every referrer to Epigenetics News. So if any Web site links to any page of this site, I’ll eventually see it. Eventually, because there are now hundreds (if not thousands) of sites that link to Epigenetics News. And Dr. Greally, or presumably the person that updates their lab’s web page, decided to add a nice link to “Trevor Covert’s Epigenetics News site, a really valuable blog of all things current in the world of epigenetics.”

So, why should anyone care about the Greally lab? Well, as it turns out, they’re doing some fantastic epigenetics research. Based at the Albert Einstein College of Medicine in Bronx, New York, Dr. John M. Greally “has a long-standing interest in gene regulatory processes that extend over large regions of the genome and give rise to human diseases.”

Our major projects are centred on the discovery of DNA sequence characteristics that discriminate genes undergoing genomic imprinting, using these to find new imprinted genes that are candidates for causing human disease.

The technologies required for this research include innovative molecular assays and bioinformatics techniques. This combination provided the foundation for our recent new avenue of study into cytosine methylation patterns in large regions of the genome.

We use these techniques to learn the rules of normal epigenetic gene regulation through cytosine methylation, creating the foundation for understanding how it is disrupted in disease.

The disease-relevance of epigenetics is now being appreciated. The core dogma of medical genetics is that genes cause disease through mutations. However, this assumes that the gene is switched on appropriately to start with. In the field of cancer research in particular, it is now appreciated that inappropriate silencing of tumour-suppressor genes or activation of oncogenes through epigenetic dysregulation is a major contributor to neoplasia.

We study how the epigenome is altered in cancer, type 2 diabetes mellitus, aging, and as a response to diet and other influences. It is our belief that epigenetic dysregulation will prove to be a much more common cause of complex human diseases than DNA mutations.

I’d like to thank the Greally lab for their ongoing research because, without it, epigenetics would not be where it is today. Greally research articles Link

First Look at Cold Spring’s Epigenetics

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When Cold Spring Harbor Laboratory Press announced the release of the new epigenetics textbook, I knew that I had to get my hands on it. After receiving it earlier this month and getting a chance to read specific portions, I am going to offer some initial, “first look” comments on this highly specialized textbook.

For starters, the textbook is about the same size as your average genetics textbook: 24 chapters, 502 pages. While the book has its fair share of diagrams and illustrations, it is fair to say that the book is dominated by text. Perhaps the best way to describe much of the book would be to call it a fantastic compilation of reviews in every specialized area of epigenetics.

The book’s contributors are largely the foremost experts in their various fields. Cancer, small and interfering RNAs, epigenetics research specialized for various model organisms — these topics are all covered in CSHL’s Epigenetics. It is clear that the editors did a fantastic job of recruiting the best and the brightest to bring their expertise to a wide audience of researchers and students.

Even better, the text is still very approachable for even the novice undergraduate. The authors do an admirable job of educating the reader about important background information necessary to understanding the concepts presented. And the book has already attracted attention from postdocs and other researchers in my lab, who are intrigued by all of the specialized areas of epigenetics that fall outside their own knowledge of this rapidly expanding field.

With that said, I plan to share additional thoughts on the book as I am able to read more of its contents. Until then, I would highly recommend that anyone interested in the field of epigenetics grab the new “must-have” for your reference book shelf. Link

Cause For Concern in Microarray-Based Studies

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New research published in the Journal of the National Cancer Institute shows that many microarray-based cancer studies have critical flaws in their analyses or conclusions.

In the study, Simon and his NCI colleague Dr. Alain Dupuy looked at 90 studies published through the end of 2004 that compared microarray profiling with medical results. The most frequently studied cancers were blood malignancies (24 studies), lung tumors (12 studies), and breast cancer (12 studies).

Simon and Dupuy then specifically looked at the statistical methods and reporting in 42 studies published in 2004. Half of these efforts had at least one basic error. In the 23 studies with an outcome-related gene finding, nine involved inadequate, confusing, or unstated methods to account for false-positive results, Simon and Dupuy found.

In 13 studies, there were unsupported claims of meaningful classifications of results, where the authors did not do adequate analyses to reach their conclusions. In addition, in the 28 studies that predicted outcomes, 12 used biased estimates of the accuracy of their predictions, according to Simon and Dupuy.


Monday Morning Carnivals and Links

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There are a number of recent science blog carnivals and other reading material that I’d like to highlight:

Shirley Tilghman Wins GSA Medal

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Princeton University President Shirley M. Tilghman has been awarded the Genetics Society of America Medal, which recognizes a scientist’s outstanding contributions to genetics over the past 15 years.

Tilghman was nominated for her pioneering work in epigenetics and imprinting, which has expanded the knowledge base about embryo development in mammals.

Tilghman published many papers characterizing the imprinted H19 and IGF2 genes, many of which can be seen here.

Jane Gitschier interviewed Shirley Tilghman last year in an article for PLoS Genetics. Link

A Quick January Update

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There have been a few changes to the site that I’ve made over the past couple months that I wanted to make everyone aware of. For starters, if you haven’t noticed lately, I have set up the RSS feed to be handled exclusively by FeedBurner. This allows me to keep an eye on how many of you are reading about epigenetics through an RSS reader. I read this and many other sites through my preferred RSS reader, NetNewsWire Lite for Mac OS X. More importantly, the RSS feed is now a full feed, so if you were annoyed by the summaries I used in the past, the full content is now available through the feed. I hope that is helpful.

Also, you may have noticed that the site has picked up some more sponsorships and advertisers. For instance, we are a sponsoring publication of Cambridge Healthtech Institute’s Epigenomics conference, and we are prominently advertising the conference through March. In addition, there are sponsored text links in the sidebar from CalculateMe.com, Medical Software Associates, Health Insurance Choice, and Red Apple Living.
As the site has grown tremendously since its inception in March 2006, there is a likely possibility that we will have to move to a new server in the near future to accommodate the extra bandwidth requirements. These sponsorships will make that transition possible.


In addition, I have moved the list of epigenetics labs (that is still in its infancy) from the sidebar to a separate page. This was done in order to reduce the load time for pages across the site. I am still working on adding labs as I come across them; if you have any additions, please drop me a line.

I decided last month to add a short profile and picture of myself to the sidebar in order to help readers easily see who the author is and hopefully will encourage readers to discover more about how the content is prepared and selected. I attempted to clarify this in this post, but figured a more prominent display would be more effective. Plus, if there was any confusion about whether this was a blog or a news site that could potentially be a blog, that should clear things up.

As far as posting frequency, I have tried to be more consistent with the number of posts each week. I hope that you will bear with the occasional quiet days as I attempt to keep up with courses this semester and continue work on writing a research paper. But, rest assured, that we will try to keep up with all of the major developments in epigenetics. In fact, there have been some big papers that have not gotten their due attention here, but Mr. Rekow and I are preparing to review several of them in full as part of the upcoming Just Science week.

Finally, I decided to experiment with a syndicated feed of links gathered by Environmental Health Sciences. The feed, available in the sidebar on the right, is currently set to grab articles related to gene expression, which can also include areas of epigenetics. I’m monitoring the quality of the links in terms of relevancy for our audience. But you may be interested by some of the articles available there, even if they’re not directly related to epigenetics research and discoveries.

With that said, please feel free to leave any feedback, suggestions, complaints, etc. in the comments. I’m listening.

Tumor-Free Breast Tissue Can Have Increased Methylation

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New research from a team at the Ohio State University Comprehensive Cancer Center shows that normal breast tissue as much as 4 cm away from a cancerous breast tissue can have increased methylation in the RASSF1A gene promoter.

During this study, the researchers measured the degrees of methylation in tissue removed from 47 patients who had undergone mastectomies for a form of breast cancer called invasive ductal carcinoma. This tissue was compared with 69 samples of normal tissue taken up to four centimeters (almost two inches) from the tumor’s visible edge and with control tissues removed during breast-reduction surgery.

The study also included two double-mastectomy cases in which both breasts had been removed to prevent cancer recurrence. For these, the researchers also tested tissue from four locations on the breast that had no visible tumor.

The researchers used microdissection techniques to isolate tiny milk ducts in each sample. They then measured methylation levels in the RASSF1A gene in epithelial cells that lined the ducts. These cells were the sources of the initial tumor.

As expected, tumor cells showed the highest methylation levels. But the researchers found significant methylation levels in normal tissue adjacent to the tumors in 29 patients. The degree of methylation was lower than in the tumor cells, but it was 1.75 times higher than in control cells.

“In both double-mastectomy cases, we were surprised to find high methylation levels in the tumor-free breast,” says Yan.

In addition, the researchers identified three other genes (called CYP26A1, KCNAB1 and SNCA) that were highly methylated in about one-third to nearly one-half of the breast tumors.

“Again to our surprise, we found that in 70 percent of cases, when these genes were highly methylated in tumor cells, they were also highly methylated in the adjacent normal tissue,” says Yan.

“This suggests that the presence of DNA methylation in normal tissue adjacent to tumors is more prevalent that previously thought.”


The Just Science Challenge: We Accept

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There is a movement afoot, known as the Just Science Challenge, that aims to have science bloggers post only about science for the week beginning Monday, February 2 and ending Sunday, February 8.

During that time each blogger should post about science only, with at least one post per day. Furthermore, issues which are favored by anti-scientific groups (creationism, global warming, etc.) should be either avoided, or discussed without reference to anti-scientific positions.

Since the challenge calls for at least one post per day and this site’s curator is a full-time student, half-time researcher, full-time husband and father, I have asked Stephen Rekow (aka Shane) to assist with the week-long event. (I just realized that Mr. Rekow has all of those same responsibilities, plus his son is much younger than my 13-year-old. Good thinking, Trevor.) Shane is also an undergraduate researcher at WSU, and has been working at the lab and on our project for much longer than I have. You should go ahead and jot down his name if you’re a researcher looking for molecular biology grad students. His publications, oral presentations of research, and awards/scholarships as an undergrad are nearly unheard of, and he will most likely teach your postdocs a few things about good wet lab work.

With that said, we plan on covering some of the latest epigenetics research articles, and will most likely traverse some terrain that this site has never been across before (such as the wide world of epigenetics research in plants). Hopefully these posts will be informative and educational for both the students (that would be us) and the readers (that would be you).

If you write a science blog, I would encourage you to accept the challenge. So far, it looks like the following blogs have also accepted the challenge:


Nygaard Named New CEO of Epigenomics AG

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Epigenomics AG (Frankfurt: ECX) has appointed its new CEO: Geert Walther Nygaard, formerly managing director and member of the management board of pharmaceutical and diagnostics company Abbott GmbH & Co. KG.

    Nygaard started his career in Denmark, working for Diagnostics companies Beckman Instruments and Dako A/S in national and international positions. He joined Abbott in 1999 as the company’s Country Manager in Denmark from a position as Managing Director of Dako AG in Switzerland. He then moved on into positions with increasing responsibilities, including business development and marketing for Abbott Diagnostics in Europe.

The Science Blogging Anthology 2006

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Bora Zivkovic of A Blog Around the Clock has announced the release of The Open Laboratory: The Best Writing on Science Blogs 2006. The inaugural anthology hopes to capture the best that the science blogosphere offered in 2006, and the results are pretty impressive. Even more impressive is the fact that Bora had only three weeks from conception to print. It’s no surprise that most are calling for him to edit the anthology’s second edition.

Some of my favorites from the book include It’s not just the genes, it’s the links between them (Pharyngula) and the best and worst parts of scientific life (The Daily Transcript).

The Open Laboratory
The book is available through Lulu.com as a paperback (US$19.99) or downloadable PDF (US$8.69). The list of links to the 50 science blog posts that are included in the book are available here. Link

Martin Luther King, Jr. Day 2007

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Today is a day of remembrance. Here is a video of Martin Luther King, Jr.’s “I Have a Dream” speech. Enjoy.

Epigenetics in the Card Catalog

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Before I decided to pursue a degree at WSU, I had just moved to the Pullman area and was in desperate need of a job during one of the worst possible times for a college town: summer. Since the university is Pullman’s largest employer (by far), and has their own need for people to do the lousy jobs during the summer, I actually got one of the better ones that involved time in an air-conditioned building.

The downside? The building was Holland Library, and I was one of eight people hired to expend extra budget money by, among other things, assisting in the ongoing effort to move card catalogs to the electronic catalog system. Since I was old enough to have learned the Dewey decimal system in elementary school, and had experience as an editor (for spotting spelling and grammar mistakes on the cards), I was hired to review hundreds of the cards before they were hand-typed into the computer.

So, needless to say, this brings back some bad memories:

EN Card Catalog
You can make your own at blyberg.net. (Hat tip: Genetics and Health)

Epigenetics Gordon Conference in August 2007

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The 2007 Epigenetics Gordon Conference, held every odd year at the Holderness School in Plymouth, NH, is set for August 5-10, 2007. This year’s conference will be chaired by Dr. Anne-Ferguson Smith of the University of Cambridge and Dr. Steven E. Jacobsen of the University of California, Los Angeles (UCLA). The list of confirmed speakers and chairs:

Histone modifications and variants
Chair: Sarah Elgin
Speakers: Steve Henikoff, Hiten Madhani, Karolin Luger, Terry Magnuson, Justin Goodrich

The dynamic nucleus
Chair: Jasper Rine
Speakers: David Spector, Edith Heard, Peter Fraser, En Li, Vincenzo Pirotta, Ting Wu

Chair: Steve Jacobsen
Speakers: Bradley Bernstein, Ian Dunham, Rob Martienssen, Peter Jones

The roles of RNA I & II
Chair: Bill Kelly
Speakers: Marjori Matzke, David Baulcombe, Phillip Zamore, Bob Kingston, Vikki Chandler, Craig Pikaard, Shiv Grewal, Denise Barlow

DNA methylation
Chair: Jörn Walter
Speakers: Eric Selker, Tim Bestor, Hiro Sasaki, Judy Bender, Xiaodong Cheng

Imprinting, dosage compensation and chromosomal mechanisms
Chair: Emma Whitelaw
Speakers: Ueli Grossniklaus, Marisa Bartolomei, Jeannie Lee, Barbara Meyer, Jim Birchler

Epigenetics in developmental processes
Chair: Tomoko Kaneko-Ishino
Speakers: Renato Paro, Rudolph Jaenisch, Laura O’Neill, Azim Surani, Wolf Reik

Epigenetics and disease
Chair: Amar Klar
Speakers: Olivier Voinnet, Asifa Akhtar, Steve Baylin, Mike Higgins

Epigenetics, environment and evolution
Chair: Jean Finnegan
Speakers: Phil Avner, Eric Richards, Rick Amasino

Applications for the conference must be submitted by July 15, 2007. Applicants are encouraged to apply early as the selection of participants and short talks will commence in March 2007. Link

Late Fall Issue of Journal of Epigenetics Available

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The October/November/December 2006 issue of the journal Epigenetics is now available and contains four research papers covering topics related to breast cancer, autism, and prostate cancer.