Presenter: Anna Jacobsen
Authors: Anna Jacobsen, Kathryn Davis, James Fulcher, Aman Makaju, Sarah Franklin
Faculty Advisor: Sarah Franklin
Institution: University of Utah
Epigenetics is the process of influencing gene expression without altering DNA sequence and includes the post-translational modification of histones. In response to histone modifications, chromatintransforms between condensed, transcriptionally suppressed heterochromatin and loose, transcriptionally active euchromatin. The mechanisms and implications of this phenomenon in heart disease are the subject of extensive research. The development of heart disease is associated with specific changes in gene expression. However, we are only beginning to understand the epigenetic processes that regulate these changes. One type of posttranslational modification involves the addition and removal of methyl groups on histone lysine residues, carried out by methyltransferases. SET7/9, a methyltransferase, is one such enzyme which has been shown to trimethylate histone 3 lysine 4 (H3K4me3). We recently coupled an in vitromethyltransferase assay with mass spectrometry to unbiasedly identify additional lysine residues methylated by specific methyltransferases. Our results identified a new lysine residue modified by SET7/9: monomethylation at histone 3 lysine 122 (H3K122me). This methylated residue has been detected in breast cancer cells and kidney cells, but the presence of H3K122me in other tissues has not been examined. The functional significance of monomethylation on H3K122 is also currently unknown. Therefore, we quantified H3K122me abundance in a variety of healthy mouse tissues using immunoblotting. In addition, to understand the role of this modification in heart disease, we quantified levels of H3K122me in heart tissue from mice subjected to three models of cardiac stress: 1) pressure-overload via transverse aortic constriction, 2) ischemic injury via permanent occlusion of the LAD, and 3) isoproterenol infusion. Information from these experiments has allowed us to identify a novel lysine residue methylated by SET7/9 and to determine its prevalence in vivo. Through this work we are beginning to elucidate the functional significance of this modification and its role in the pathophysiology of heart disease.