Histone Deacetylase 7 and Transcriptional Regulatory Networks of the Vascular Endothelium

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Title: Histone Deacetylase 7 and Transcriptional Regulatory Networks of the Vascular Endothelium
Author: Young, Bryan Daniel
Abstract: Cells respond to stimuli in part through the modulation of gene expression . Signal transduction from the environment to the nucleus culminates in the activation of factors that modify chromatin structure to either facilitate or inhibit gene transcription . Histone acetyltransferases (HATs ) and histone deacetylases (HDACs ) are two such classes of enzymes that regulate the epigenetic code . Their opposing actions – to activate transcription by histone acetylation and to inhibit transcription by deacetylation – are tightly regulated to coordinate the vast gene programs required for cellular growth and differentiation . The class II HDACs are restricted in their expression patterns , and each have unique developmental and physiological functions . The studies described here focus on HDAC7 , a class II HDAC that is expressed in vascular endothelial cells and whose function is essential for the maintenance of vascular integrity during embryogenesis . Mice lacking HDAC7 die by e11 .5 with complex cardiovascular malformations including endothelial , vascular smooth muscle , and myocardial defects . By generating HDAC7 conditional knockout mice , it was observed that all of these defects are recapitulated in mice bearing an endothelial -specific deletion of HDAC7 , but no defects are observed upon deletion of HDAC7 in the other cell types that were affected in the HDAC7 nulls . This in vivo evidence demonstrated that HDAC7 acts cell autonomously to maintain normal vascular development , and lead to the identification of the genetic abnormalities and mechanism leading to cardiovascular failure in the HDAC7 knockout . Further , this work begins the investigation of HDAC7 in adult vascular physiology , the findings of which will reveal new mechanisms whereby the vasculature responds to stress signals or disease . To this end , methods have been developed for the deletion of HDAC7 in the adult mouse using an inducible cre recombinase system together with the HDAC7 conditional allele . Additionally , these studies present progress toward the identification of the enhancer elements driving the endothelial -specific expression pattern of HDAC7 . Detailed characterization of this enhancer is likely to implicate new signaling pathways as being involved in the genetic regulation of vascular development and maintenance . Finally , this work investigates the role of microRNAmediated gene silencing in the vascular system by identifying microRNAs involved in MEF2 -dependent signaling in endothelial cells .
URI: http : / /hdl .handle .net /2152 .5 /212
Date: 2010-05-14


Histone Deacetylase 7 and Transcriptional Regulatory Networks of the Vascular Endothelium. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /212 .

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