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Mol. Cell. Biol. doi:10.1128/MCB.00269-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The repressor element 1-silencing transcription factor regulates cardiac specific gene expression using multiple chromatin modifying complexes

Institute of Membrane & Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK

^* To whom correspondence should be addressed. Email: i.c.wood{at}leeds.ac.uk.

	Abstract

Cardiac hypertrophy is associated with a dramatic change in the gene expression profile of cardiac myocytes. Many genes important during development of the foetal heart but repressed in the adult tissue are re-expressed resulting in gross physiological changes that lead to arrhythmias, cardiac failure and sudden death. One transcription factor thought to be important in repressing expression of foetal genes in the adult heart is the transcriptional repressor, repressor element 1-silencing transcription factor (REST). Although REST has been shown to repress several foetal cardiac genes and inhibition of REST function is sufficient to induce cardiac hypertrophy, the molecular mechanisms employed in this repression are not known. Here we show that continued REST expression prevents the increase in the genes encoding brain and atrial natriuretic peptides, BNP (Nppb) and ANP (Nppa), in adult rat ventricular myocytes in response to endothelin-1 and inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter proximal regions of these genes. Furthermore using deletions of individual REST repression domains, we show that the combined activity of two domains of REST are required to efficiently repress transcription of the Nppb gene however a single repression domain is sufficient to repress the Nppa gene. These data provide some of the first insights into the molecular mechanism that may be important for the changes in gene expression profile seen in cardiac hypertrophy.