The most common disorder causing sudden cardiac death in young people is the cardiac disease, hypertrophic cardiomyopathy (HCM). Recent studies have suggested that HCM is more common than previously reported and it is now estimated that approximately l in every 500 people in the UK suffer from the disease. HCM is characterised by cardiac hypertrophy, an abnormal thickening of the heart muscle and while most affected individuals show few or no symptoms, others suffer heart failure, arrhythmias, and sudden death. The reason for the emergence of these symptoms in some people, but not others, remains unknown but since the transcriptional levels of a number of genes are indicative of the disease phenotype, the control of transcriptional programs could provide one mechanism to alleviate HCM. The genes encoding the brain and atrial natriuretic peptides (BNP and ANP) are normally highly expressed in the foetal heart with levels reducing during development. High levels of expression of these genes are observed in adult ventricular myocytes in cardiac hypertrophy. One transcription factor that is important in repressing ANP and BNP expression in the normal adult heart is the Repressor Element 1-Silencing Transcription factor (REST). The aim of this study was to investigate the molecular mechanisms of REST-mediated repression and its potential role in hypertrophy. This was achieved by interrogating protein-DNA interactions and chromatin modifications at REST binding sites by chromatin immunoprecipitation and RT-PCR. REST represses its target genes by recruiting two distinct corepressor complexes that include histone deacetylases (HDAC1, HDAC2) and a H3 lysine 4-specific demethylase (LSD1). Inhibition of REST function resulted in an increase in ANP and BNP gene expression that correlated with increases in histone acetylation and dimethylation of H3 lysine 4 at the ANP and BNP promoters. Additionally, increasing REST expression in adult rat cardiomyocytes prevented increases in ANP and BNP expression by the hypertrophic agonist, endothelin-1. This data provides evidence that a therapeutic strategy aimed at augmenting REST and/or the action of its corepressors may be effective in treating cardiac hypertrophy.