Exploring the Epigenome

A National Institutes of Health-funded consortium publishes 111 reference maps of DNA and histone marks.

By | February 18, 2015

PIXABAY, PUBLICDOMAINPICTURESIn a culmination of a multiyear project to identify the chemical modifications of DNA and its associated proteins that regulate gene expression, members of the Roadmap Epigenome Consortium today (February 18) published their analysis of 111 different human epigenomes in Nature. The National Institutes of Health (NIH)-funded team’s analysis—comparing histone and DNA methylation, DNA availability, and other marks such as histone acetylation among the 111 genomes as well as 16 previously released annotated epigenomes from the Encyclopedia of DNA Elements (ENCODE) project—was accompanied by articles examining the patterns of chemical markers and chromatin structure in stem cells, Alzheimer’s disease, and cancer.

“It is definitely a milestone,” said Kristian Helin of the University of Copenhagen, who was not involved in the research. “It should mostly be credited for the enormous amount of work . . . that hopefully will serve as a very good guide for epigenome studies in the future.”

“The human epigenome is this collection of . . . chemical modifications on the DNA itself and on the packaging that holds DNA together,” explained study coauthor Manolis Kellis of MIT during a press conference. “All our cells have a copy of the same book, but they’re all reading different chapters, bookmarking different pages, and highlighting different paragraphs and words.” These chemical bookmarks, such as methylation and acetylation, help control which genes are transcribed into RNA and expressed in a given cell type, thus aiding the maintenance of a particular cell’s identity.

Although members of the ENCODE project had already performed some epigenome mapping as part of their effort to annotate the human genome, the Roadmap group has expanded this work into previously uncharted tissues in organs such as the brain and the heart. Much of the data collected—from more than 2,800 experiments that examined 150 billion genome fragments—was already publicly available; now, the analyzed and annotated versions of the data will also be accessible through an online database.

“At times, we need a control or reference, a baseline, and now we can just go here and download this data, and use that as a baseline for our experiments, and that’s important,” said Manel Esteller of the Bellvitge Biomedical Research Institute in Spain who was not involved in the study.

Each of the Roadmap reference epigenomes annotated the placement of a core set of marks associated with particular functions, such as modifications indicative of gene promoter regions, actively expressed genes, repressed genes, and inactive heterochromatin regions. Many epigenomes also contain additional information, such as RNA transcript sequences, to highlight genes that are actively expressed in a given cell type.

By comparing the annotated epigenomes, the researchers were able to begin to “compare different tissues and cell types to each other at the molecular level and to understand what makes them different,” said Kellis. This allowed them to determine, for example, that the epigenomes of cells derived from embryonic stem cells more closely resembled those of their cells of origin than those of the mature tissues they became.  Additionally, the epigenetic marks in the gene enhancer regions of the neurons of Alzheimer’s patients more closely matched immune system enhancer patterns than typical neural patterns.

While the NIH-led Roadmap group does not plan to produce more epigenomic data, the studies published today represent the first major contribution to the International Human Epigenome Consortium’s eventual goal of generating 1,000 reference genomes. “They will continue to add new cell types, new marks, and deposit that type of data in public databases,” said study coauthor Lisa Chadwick of NIH’s National Institute for Environmental Health Sciences. Already, Esteller said he looks forward to updated reference epigenomes with annotations for new marks and correlations with non-coding RNA, while Helin noted that technological advances toward single-cell epigenome mapping could provide a greater degree of precision.

In the meantime, Kellis and his colleagues have unlocked the predictive power of their data set by applying it to related unmapped tissues. “As new marks are profiled, their correlation structure with existing marks, and the relationship between closely related cell types to each other, will allow us to actually predict the missing marks,” Kellis told reporters. “There’s a phase transition that happens when you have such a large number of data sets that are already mapped.”

 

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Avatar of: James V. Kohl

James V. Kohl

Posts: 350

February 18, 2015

Study coauthor Manolis Kellis may be the first to explain nutrient-dependent RNA-directed DNA methylation and cell type differentiation in terms that non-scientists can understand.

It would help if others also understood  how 'chemical bookmarks' linked to mutations may lead to the failure of particular cell types to maintain their RNA-mediated identity.

For example, others have engineered genetically modified E. coli with a synthesized amino acid substitution that probably ensures the stability of DNA in its organized genome. See: Biocontainment of genetically modified organisms by synthetic protein design

Can anyone else help to explain how RNA-directed DNA methylation and RNA-mediated amino acid substitutions link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man?

That explanation would help to rid serious scientists of claims that mutations somehow lead from entropic elasticity to anti-entropic stability. The stability is obviously due to the fixation of the amino acid substitutions in the context of the physiology of nutrient-dependent species-specific reproduction. That explanation of anti-entropic stability might also help alleviate fears that genetically modified organisms could lead to the death of us all.

The alternative is to change Gregor Mendel's century-old "law of segregation" and/or add more laws to the second law of thermodynamics in attempts to explain  transmission ratio distortion (TRD). 

Distortion links nutrient-dependent fixation of favored alleles from plants to animals via the biophysically constrained chemistry of RNA-mediated protein folding and the physiology of reproduction.

TRD could be compared to theories about the role constraint-breaking mutations play in the evolution of biodiversity. See for example: Mutation-Driven Evolution "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world." (p. 199)

Avatar of: PastToTheFuture

PastToTheFuture

Posts: 69

February 18, 2015

Couyld someone clarify something for me please. I mostly study evolutionary biology and I understand the developmental aspects of epigentics (somewhat), but are there any known cases of environmentally induced epigentic change with survival advantage or one that can both switch on and off based on environmental factors?

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