Epigenomic findings illuminate veiled variants

March 23, 2011

Genes make up only a tiny percentage of the human genome. The rest, which has remained measurable but mysterious, may hold vital clues about the genetic origins of disease. Using a new mapping strategy, a collaborative team led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and MIT has begun to assign meaning to the regions beyond our genes and has revealed how minute changes in these regions might be connected to common diseases. The researchers' findings appear in the March 23 advance online issue of Nature.

The results have implications for interpreting genome-wide association studies – large-scale studies of hundreds or thousands of people in which scientists look across the for single "letter" changes or SNPs (single nucleotide polymorphisms) that influence the risk of developing a particular disease. The majority of SNPs associated with disease reside outside of and until now, very little was known about the functions of most of them.

"Our ultimate goal is to figure out how our genome dictates our biology," said co-senior author Manolis Kellis, a Broad associate member and associate professor of computer science at MIT. "But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation."

The term "epigenome" refers to a layer of chemical information on top of the genetic code, which helps determine when and where (and in what types of cells) genes will be active. This layer of information consists of chemical modifications, or "chromatin marks," that appear across the genetic landscape of every cell, and can differ dramatically between cell types.

In a previous study, the authors showed that specific combinations of these chromatin marks (known as "chromatin states") can be used to annotate parts of the genome – namely to attach biological meaning to the stretches of As, Cs, Ts, and Gs that compose our DNA. However, many questions remained about how these annotations differ between cell types, and what these differences can reveal about human biology.

In the current study, the researchers mapped chromatin marks in nine different kinds of cells, including blood cells, liver cancer cells, skin cells, and embryonic cells. By looking at the chemical marks, the researchers were able to create maps showing the locations of key control elements in each cell type. The researchers then asked how chromatin marks change across cell types, and looked for matching patterns of activity between controlling elements and the expression of neighboring genes.

"We first annotated the elements and figured out which cell types they are active in," said co-senior author Bradley Bernstein, a Broad senior associate member and Harvard Medical School (HMS) associate professor at Massachusetts General Hospital (MGH). "We could then begin to link the elements and put together a regulatory network."

Having pieced together these networks connecting non-coding regions of the genome to the genes they control, the researchers could begin to interpret data from disease studies. The team studied a large compendium of genome-wide association studies (GWAS), looking to characterize non-coding SNPs associated with control regions in specific cell types.

"Across 10 association studies of various human diseases, we found a striking overlap between previously uncharacterized SNPs and the control region annotations in specific cell types," said Kellis. "This suggests that these DNA changes are disrupting important regulatory elements and thus play a role in disease biology."

The researchers confirmed the reliability of their approach by showing that SNPs were associated with the appropriate cell types. For example, SNPs from autoimmune diseases such as rheumatoid arthritis and lupus sit in regions that are only active in immune cells, and SNPs associated with cholesterol and metabolic disease sit in regions active in liver cells. While more in-depth, follow-up studies will be needed to confirm the biological significance of these connections, the current study can help guide the direction of these investigations.

"GWAS has identified hundreds of non-coding regions of the genome that influence human disease, but a major barrier to progress is that we remain quite ignorant of the functions of these non-coding regions," said David Altshuler, deputy director at the Broad and an HMS professor at MGH, who was not involved in the study. "This remarkable and much-needed resource is a major step forward in helping researchers address that challenge."

SNPs in the non-coding regions of the genome may have subtler biological effects than their counterparts that arise in genes because they can influence how much protein is produced. The researchers mainly focused on SNPs in enhancer regions, which help boost a gene's expression, and their network connections to regulators that control them and genes that they target. Follow-up efforts can then focus on specific pieces of this network that could be targeted with drugs.

The team involved in this study hopes to expand its analysis to include many other and map additional marks to expand their networks beyond enhancer regions. In the meantime, researchers involved in genome-wide association studies will be able to use the maps from this project to analyze non-coding SNPs in a new light.

"These maps can be used to come up with hypotheses about how the variants themselves are working and which ones are causal," said Bernstein. "This resource now goes back to the GWAS community, which can use the maps to form and test new functional models."

More information: Ernst J et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. doi:10.1038/nature09906

Related Stories

Recommended for you

New gene editing approach for alpha-1 antitrypsin deficiency shows promise

October 20, 2017
A new study by scientists at UMass Medical School shows that using a technique called "nuclease-free" gene editing to correct cells with the mutation that causes a rare liver disease leads to repopulation of the diseased ...

Maternal diet may program child for disease risk, but better nutrition later can change that

October 20, 2017
Research has shown that a mother's diet during pregnancy, particularly one that is high-fat, may program her baby for future risk of certain diseases such as diabetes. A new study from nutrition researchers at the University ...

Researchers find evidence of DNA damage in veterans with Gulf War illness

October 19, 2017
Researchers say they have found the "first direct biological evidence" of damage in veterans with Gulf War illness to DNA within cellular structures that produce energy in the body.

Researchers drill down into gene behind frontotemporal lobar degeneration

October 19, 2017
Seven years ago, Penn Medicine researchers showed that mutations in the TMEM106B gene significantly increased a person's risk of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in those ...

New clues to treat Alagille syndrome from zebrafish

October 18, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies potential new therapeutic avenues for patients with Alagille syndrome. The discovery, published in Nature Communications, ...

Genetic variants associated with obsessive-compulsive disorder identified

October 18, 2017
(Medical Xpress)—An international team of researchers has found evidence of four genes that can be linked to obsessive-compulsive disorder (OCD). In their paper published in the journal Nature Communications, the group ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Mar 23, 2011
What epigenetic changes are they talking about? DNA SNP changes in different cells of the same body?! Or methylation, etc.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.