Epigenomics Program Highlights
Researchers supported by the NIH Common Fund have discovered that genetic differences linked to a wide variety of diseases influence how genes are turned on, or expressed. Many genetic differences, or variants, that are associated with disease do not fall within genes themselves, but are in stretches of DNA between genes, called non-coding DNA. For many years, scientists were unsure whether or not non-coding DNA served any purpose in the cell, or what the purpose could be. It is now known that these non-coding regions have important roles in regulating gene expression, but linking genetic variation in these regions with disease risk has been challenging. Dr. John Stamatoyannopolous M.D., and colleagues, funded in part by the Common Fund’s Epigenomics program, report that the majority of genetic variants linked to risk for a number of common diseases are located in non-coding DNA regions that regulate gene expression, providing new insight into how, when, and why many diseases occur. Their findings are published in the Sept. 5 online issue of the journal Science.
Dr. Stamatoyannopolous and colleagues found that some of the genetic variants linked to adult-onset diseases lie in regions of DNA that regulate genes during the early stages of development, providing a potential mechanism to explain the observation that some environmental exposures in utero or during early childhood are known to increase risk of diseases that produce symptoms years or even decades later. The researchers were also able to link genetic variants in non-coding regions with the genes they regulate, which has been a major challenge in genetic studies because the genes are often located a great distance away. In addition, researchers were able to pinpoint which cell types are affected by different diseases. These results provide new insight into disease mechanisms, and suggest novel targets for therapeutics development and disease prevention strategies.
Epigenetic marks are chemical modifications to the genome that regulate which genes are active and which proteins are made in a cell. These marks are found on DNA as well as on the histone proteins that DNA is wrapped around. Epigenetic marks help regulate the expression of genes involved in cell development and function, and are also implicated in a growing number of diseases such as cancer, diabetes, autoimmune diseases, and mental illness (see “A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health”). Drs. Yingming Zhao and Bing Ren, supported in part by the Common Fund’s Epigenomics program, along with their colleagues, have expanded our understanding of epigenetics by identifying a wealth of novel histone modification sites, as well as histone modifications that have never been described before. Using a combination of approaches in the most thorough examination of histones to date, the researchers identified 67 new histone modifications, increasing the number of known histone marks by about 70%. Some of these newly discovered histone marks correspond to types of chemical modifications that had already been described in other regions of histone proteins, but others represent an entirely new type of chemical modification of histones. One such novel modification, lysine crotonylation or Kcr, was found to label regions of the genome that are actively making proteins. In particular, Kcr modifications were found associated with genes that are activated in the testes of male mice at a specific time during development, suggesting that Kcr may regulate genes that are important for aspects of sperm cell maturation and function. The discovery of these new histone modifications expands our understanding of epigenomics, and opens the door to further research into the epigenome that regulates health and disease.
Tan M, Luo H, Lee S, Jin F, Soo Yang J, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, and Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell, September 16, 2011. 146: 1016-28. PMID: 21925322.
New discoveries in stem cell biology are fueling the development of new cell-based therapies for diseases such as Parkinson’s and diabetes where tissues may become diseased or damaged. Before this potential can be reached, an important, yet unanswered question is whether adult cells that are “induced” to become like embryonic stem cells – so called induced pluripotent stem cells (iPS cells) -- are actually equivalent to embryonic stem cells and can be used in cell-based therapies. Researchers in the Common Fund’s Epigenomics program are tackling this question.
Stem cells offer enormous potential for repairing damaged tissue but historically they have been hard to obtain. Recent discoveries have shown that normal skin cells can be induced to form stem cells. This provides a readily available source of stem cells, but it’s not known if these “induced” stem cells are really equivalent to embryonic stem cells, or if the range of adult cell types made from them are normal and could be used for therapeutic purposes. An important step to answer these questions is the development of “fingerprints” of all cell types. Chemical modifications to DNA occur in different patterns in each type of cell. These modifications serve as one type of molecular fingerprint that defines what makes a liver cell a liver cell vs. a heart cell vs. a neuron vs. a “pluripotent” stem cell that has the potential to become any one of these cell types and more. To understand how an embryonic stem cell differentiates to become any type of cell in the body, we need to decipher its molecular fingerprint. We also need to know if induced stem cells have the same molecular fingerprint as embryonic stem cells.
Researchers in the Common Fund’s Epigenomics Program have taken the first step toward this goal. They have determined a high resolution fingerprint of one type of chemical group on the DNA of human embryonic stem cells and have compared it to what is found in fibroblasts, a type of cell found in many tissue types, including skin. They found that the fingerprints varied drastically between the two cell types. In addition, an analysis of limited regions of DNA from induced stem cells yielded a partial fingerprint that showed the same characteristics as in human embryonic stem cells. This discovery yields fundamental knowledge about stem cells and indicates that induced stem cells are molecularly similar to embryonic stem cells. It provides a method to identify cells as stem cells, and it is important for future work in which these cells will be used to regenerate adult tissues.
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009 Nov 19;462(7271):315-22. Epub 2009 Oct 14.PMID: 19829295. Link: http://www.nature.com/nature/journal/v462/n7271/full/nature08514.html
The completed human genome sequence has been metaphorically described as “the book of life.” Expanding upon this metaphor, the map of the epigenetic DNA methylation modifications that adorn the human genome in one cell may be regarded as a single volume in the vast encyclopedia of epigenomes that may be found within the human body. The volume cover depicts a mosaic of an anatomical drawing of a human torso taken from the book “De humani corporis fabrica” (On the Structure of the Human Body) by Andreas Vesalius (1514–1564), who is often regarded as the founder of modern human anatomy. The mosaic is composed of the letter C, which represents the methylcytosine bases identified through shotgun sequencing of bisulfite-converted human genomic DNA, in which only methylated cytosines were not converted to uracil. Together this forms a graphic portrayal of the first comprehensive DNA methylomes of humans, constituting the first two volumes of the potentially vast “Encyclopedia Epigenetica”. Cover image by Ryan Lister. Letter C images: Leo Reynolds, chrisinplymouth, Karyn Christner, Eva Ekeblad (www.flickr.com). Karyotype image: NHGRI Talking Glossary of Genetics.