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Environmental Factor, October 2012

Epigenetic studies can shed light on causes underlying complex disease

By Ashley Godfrey

Robert Wright, M.D.

After his seminar, Wright gave a separate talk to NIEHS fellows and other trainees from around the area. Wright shared his experience of many years of writing and receiving grants, and offered his advice to the young scientists about how to both be successful and deal with rejection. (Photo courtesy of Steve McCaw)

Todd Jusko, Ph.D.

“Dr. Wright’s visit to NIEHS was a tremendous opportunity for trainees in the Epidemiology Branch to learn about the grant writing process from a senior extramural investigator within our discipline,” stated Jusko. “We also opened up the grant writing seminar to trainees in epidemiology at local universities and received a great turnout.” (Photo courtesy of Steve McCaw)

In a seminar Sept. 10 at NIEHS, grantee Robert Wright, M.D., explained the importance of epigenetics in reproductive health research. Wright, who is director of the division of environmental health at Mount Sinai School of Medicine, spoke to a capacity audience gathered to hear his presentation, “Environmental Epigenetics and Reproductive Health.”

As Wright explained, epigenetic changes, often called marks, regulate gene expression without changing DNA sequence. Epigenetics is a separate cell code allowing cells containing the identical DNA sequence to differentiate into distinct cell types, such as neurons or epithelial cells.

These marks regulate if and when specific genes are expressed, and drive many of the interactions between genes and environment. Epigenetic marks are modifiable and can be important mediators for the effects of environmental exposures, such as toxic chemicals. Environmental modification of epigenetic marks in specific tissues may be the mechanism behind complex diseases, such as fetal growth restriction.

Understanding the importance of DNA methylation

"Epigenetic studies, like those underway by Dr. Wright and his colleagues, will help us understand the mechanisms underlying exposure-disease associations," stated Todd Jusko, Ph.D., a fellow in the NIEHS Biomarker-based Epidemiology Group and host for Wright’s visit.

DNA methylation is the most studied epigenetic mark. Wright is interested in studying methylation patterns in DNA taken from target tissues critical to fetal growth, such as umbilical cord blood vessels and placenta. A toxic chemical that reduces growth would likely alter methylation in one or all of these tissues. Wright and his colleagues believe this approach will shed light on some of the factors that influence fetal growth restriction.

Why is reproductive health so well suited to epigenetic research?

Epigenetics differs from genetics in that the cell type that is being studied is a critical component of the research, whereas DNA sequence is the same in all cells. Genomic DNA methylation patterns vary by cell type. For this reason, studying methylation from DNA collected from white blood cells may not be relevant to neurodevelopmental health. Brain tissue is needed for such a study, which has obvious drawbacks.

In contrast, the tissues important for studying fetal growth are easy to access noninvasively and typically are discarded after delivery. In this research, Wright has partnered with Andrea Baccarelli, M.D., Ph.D., (http://www.hsph.harvard.edu/faculty/andrea-baccarelli/)  of the Harvard School of Public Health, to scan the methylome of multiple target tissues relevant to fetal growth — placenta, umbilical artery, umbilical vein, and cord blood. Using a comprehensive analysis of DNA methylation throughout the genome, they will extend this pilot study to a larger set of children.

Wright hopes the results will help answer the question of whether methylation patterns mediate common environmental risk factors for fetal growth restriction, and ultimately point to potential therapeutic and preventive strategies. “The promise of epigenetics is [that] the marks are modifiable, unlike DNA sequence,” he said.

Looking for function in a desert of non-function

One of the questions Wright wants to study is whether methylation of noncoding DNA is important to health. Wright is interested in studying DNA methylation in genomic areas traditionally believed to be non-functional, so-called repetitive elements. Once called junk DNA, these areas account for more than 50 percent of the total DNA sequence.

Repetitive elements are large pieces of ancient DNA sequence that originated from viruses and contain the same sequence repeated throughout the genome. According to Wright, one third of the total DNA methylation occurs within these elements.

According to new research published by the Encyclopedia of DNA Elements (ENCODE) consortium, (http://genome.ucsc.edu/ENCODE/)  there is evidence that repetitive elements may have evolutionary function. It is known that repetitive elements can move and reinsert in new places in the genome. At the individual level, this transposition might lead to overt disease, such as cancer, or cause subtle effects on gene expression. 

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Wright is interested in finding out whether repetitive element transposition can be affected by environmental or other factors in chronic disease development. “We [as researchers] have consistently underestimated the importance of these elements,” he concluded.

Citation: Wright RO, Schwartz J, Wright RJ, Bollati V, Tarantini L, Park SK, Hu H, Sparrow D, Vokonas P, Baccarelli A. (http://www.ncbi.nlm.nih.gov/pubmed/20064768)  2010. Biomarkers of lead exposure and DNA methylation within retrotransposons. Environ Health Perspect 118(6):790-795.

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




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