It has become clear in recent years that epigenetic modifications are important not only in regulating gene expression within cells; but, also as non-DNA based agents of inheritance that can cause genetically heritable diseases. One important type of epigentic modification that can alter gene expression in human cells is postsynthetic modification of histones proteins. These proteins have an essential role in packaging DNA into chromosomes and they undergo a remarkable variety of post-translational modifications that affect their interaction with DNA and with other proteins involved in regulating gene expression, DNA replication, and folding and packing DNA into higher order structures. We have found that alterations in these modifications underlie a heritable disease.
Friedreich’s ataxia (FRDA) is a crippling degenerative nerve disease that also leads to diabetes and heart disease. Patients typically die in early adulthood from heart failure. We have found that FRDA is caused by a heritable mutation that results in a reduction in histone acetylation, which silences the frataxin gene. We have developed small molecules that inhibit the enzyme histone deacetylase and have been able to show that these molecules increase acetylation of the histones associated with DNA (in the form of chromatin), and that they reactivate frataxin expression in models of FRDA. The results suggest that epigenetic alterations that cause disease can be remediated by appropriately targeting small molecules to enzymes that mediate epigenetic marks.
FRDA is one of a class of diseases referred to as triplet repeat diseases, because they are characterized by an expansion of a simple triplet repeat in particular gene-associated regions of DNA. Huntington’s disease is also a triplet repeat disease and we are developing similar classes of compounds as therapeutics for this disease as well.
This lecture will address epigenetics generally, the role of epigenetic alteration in Friedreich’s ataxia and other epigenetic diseases, the use of epigenetic targets for therapeutic development and our progress in developing promising new molecules for treating these diseases.
Joel M. Gottesfeld is Professor of Molecular Biology at The Scripps Research Institute in La Jolla, California, and he works with Repligen Corporation in developing novel compounds from his laboratory that target epigenetic diseases. Joel earned a B.S. at UC-Berkeley, an M.S. at Oxford University as a Fulbright Fellow, and a Ph.D. at the California Institute of Technology. He did postdoctoral work at the MRC Laboratory of Molecular Biology in Cambridge, England as a Helen Hay Whitney Fellow. Thereafter he joined the faculty at the Scripps Research Institute, where he is a Professor today. Joel also served for two years as Division Head at the Medical Biology Institute in La Jolla. He has published well over 100 research and technical papers. He has been thesis advisor to numerous doctoral students and has hosted more than 25 postdoctoral fellows in his lab. He has been co-chair of Gordon Research Conferences on Gene Regulation and Chromatin Structure, and for many years was a principle organizer of the Asilomar Chromatin Conference. He has served as peer reviewer for many journals, served on numerous NIH peer review panels, and currently is Associate Editor and a member of the Editorial Board of the Journal of Biological Chemistry.
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