Researchers to focus on abnormal fetal growth and chronic kidney disease

The National Institutes of Health (NIH) has awarded Albert Einstein College of Medicine of Yeshiva University two grants totaling $3.5 million to study epigenetic changes - chemical modifications of genes caused by stress, diet or other environmental influences - and how they contribute to human diseases and biological processes.

The NIH will award approximately $62 million to medical institutions over the next five years to study the impact of epigenetic changes on a number of diseases and conditions, including tumor development, hardening of the arteries, autism, glaucoma, asthma, aging, and abnormal growth and development. The grants will build on the work of the NIH Roadmap for Medical Research's Epigenomics Program.

Einstein's grants will focus on epigenetic modifications related to abnormal fetal growth and to chronic kidney disease, led, respectively, by Francine H. Einstein, M.D., assistant professor of obstetrics & gynecology and women's health and Katalin Susztak M.D., Ph.D., associate professor of medicine. Their research will illuminate the total repertoire of epigenetic influences - referred to as the "epigenome"- that characterize each of these conditions.

"The goal of epigenomics research is in part to understand how human diseases are caused and how environmental factors affect them," says John M. Greally, M.B., B.Ch., Ph.D., associate professor of genetics and of medicine at Einstein, who directs Einstein's Center for Epigenomics. "This research is also driven by the fact that epigenetic processes are inherently reversible and could therefore respond to therapies that reverse long-term damage to the cells. These pioneering studies by Drs. Einstein and Susztak are the first steps towards this ultimate goal."

"Epigenomics represents the next phase in our understanding of genetic regulation of health and disease," says NIH Director Francis Collins, M.D., Ph.D. "These awards will address the extent to which diet and environmental exposures produce long-lasting effects through changes in DNA regulation." Dr. Collins notes that the initiative "is expected to profoundly alter the way we understand, diagnose and treat disease."

The main epigenetic modification being studied in these projects is DNA methylation, the addition of methyl groups to the cytosine bases of DNA, often associated with silencing of nearby genes. DNA methylation is one of a number of epigenetic regulatory mechanisms that control gene expression in normal cells but can become altered in disease. For example, epigenetic changes have been found in every type of cancer that researchers have studied.

The larger of the two grants awarded to Einstein, for $2.03 million over five years, will address the epigenetic changes that influence abnormal fetal growth.

"We know that very small and very large newborns have a higher chance of developing problems like diabetes or cardiovascular disease later in life," says Dr. Einstein. "So, we are trying to determine the epigenetic changes in these babies that make them more susceptible to chronic disease and premature death."

The researchers hypothesize that conditions during fetal development alter epigenetic patterns of DNA methylation in stem cells. These changes may be a marker for, or contribute to, susceptibility to type 2 diabetes and other age-related diseases. Dr. Greally and Cristina Montagna, Ph.D., assistant professor of genetics and of pathology at Einstein, are co-principal investigators on this study.

The second grant, for $1.49 million over four years, will address the epigenetic landscape of chronic kidney disease, which affects some 20 million people in the U.S. and is associated with a three-to-five-fold increase in mortality. The researchers suspect that unfavorable environmental conditions, such as poor nutrition during pregnancy, can imprint abnormal DNA methylation patterns on the fetal kidney.

Epigenetic changes may also explain why diabetes is the leading cause of renal (kidney) failure. "People with diabetes who control blood glucose levels develop fewer complications," says Dr. Susztak. "But they still face a greater risk for kidney failure and other complications - probably because their bodies remember periods from long ago when their glucose was not well controlled. We want to learn whether this so-called hyperglycemic memory is coded in DNA methylation patterns."

A total of 22 epigenomics grants were awarded by the NIH in this round of funding. Einstein was one of only two institutions to receive two or more grants.