Epigenetics seems to touch nearly all aspects of biology and Penn investigators are rapidly finding how it relates to human health and disease.

Recently, Mitchell Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolismhas been studying the effects of deleting the gene for histone deacetylase 3 (HDAC3) from mice. HDAC3 is an enzyme that removes epigenetic marks from histone proteins and is thus a key regulator of gene expression. In a series of papers, the Lazar team reported that mice that lacked HDAC3 were more susceptible to heart diseasewhen fed a high fat diet, and that they had altered fat storage and blood glucose metabolism.

Meanwhile, Klaus H. Kaestner, PhD, professor of Genetics and member of the Institute of Diabetes, Obesity and Metabolism, found that epigenetic-targeted drugs may be useful in treating diabetes. Both type 1 and type 2 diabetes are characterized by an insufficient number of insulin-producing beta cells in the pancreas. Kaestner's team found that treating another type of pancreas cell, called alpha cells, with a drug that blocks histone methylation, drove the alpha cells into a beta cell-like state, including some insulin production.

In a similar but unrelated project, Ed Morrisey, PhDprofessor of Medicine and Cell and Developmental Biology and the scientific director of the Penn Institute for Regenerative Medicine, found that drugs that alter histone deacetylase activity may improve lung function in patients with chronic obstructive pulmonary disease (COPD). Using genetic and pharmacological approaches, they showed that development of progenitor cells in the lung is specifically regulated by histone deacetylase enzymes. Yet, in patients with COPD, these enzymes are expressed at a much lower than normal level. Restoring drugs that increase histone deacetylase activity may improve not only the symptoms of COPD, but the underlying lung condition as well.

Penn investigators are also finding that epigenetic regulation plays a role in cancer and patients response to chemotherapy. For example, Mariusz A. Wasik, MD, professor of Pathology and Laboratory Medicine, and Qian Zhang, MD, PhD, research assistant professor, and their colleagues, found that a fusion protein that causes a particular type of T cell lymphoma works by epigenetically silencing a tumor suppressor gene, which prohibits cells from becoming malignant. Drugs that reverse those epigenetic changes — some of which are already being used in the clinic — may be a powerful therapy in patients with type of lymphoma.

Conversely, Roger A. Greenberg, MD, PhD, associate investigator, Abramson Family Cancer Research Institute and associate professor of Cancer Biology and colleagues found that another epigenetic modification, histone acetylation, may explain resistance to a promising chemotherapy called PARP inhibition seen in patients. If investigators can find a way to control specific histone acetylation events in the cell with drugs, they might be able to turn resistant tumors into sensitive ones and improve patient responses to therapy.

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