NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function

Abstract

Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuronrestrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and a-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I f and I Ca,T , which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.

Pathophysiological Significance of T-type Ca2+ Channels: Transcriptional Regulation of T-type Ca2+ Channel — Regulation of CACNA1H by Neuron-Restrictive Silencer Factor

“…1A). We confirmed the binding of NRSF to the sequences (10). In addition, when we created transgenic mice carrying cardiac-specific expression of a dominant-negative mutant of NRSF, CACNA1H gene expression was significantly increased in the ventricle of the transgenic mice (DNNRSF Tg).…”

“…The increased expression of NRSF repressor complex may contribute to the repression of T-type Ca 2+ current during the ventricular maturation. Indeed, T-type Ca 2+ current is activated in DNNRSF Tg ventricular myocytes, whereas it is not detectable in adult non-Tg ventricular myocytes (10).…”

REST In Good Times and Bad: Roles In Tumor Suppressor and Oncogenic Activities

“…55 Among nonneuronal tissues, REST was found to be present in normal ventricular myocytes and to repress the expression of multiple fetal cardiac genes. 56 In cardiac dysfunction and arrhythmogenesis, REST expression was inhibited, resulting in the expression of fetal cardiac genes. These results suggest that REST has a role in maintaining normal cardiac structure and function and that its deregulation may cause cardiac dysfunction.…”

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

“…Previous reports have identified some of these target genes and their function in and outside the nervous system. Thus, it is now documented that REST target genes are involved in the reactivation of the fetal cardiac gene programme in hypertrophied and failing hearts [8], and modulate the vascular plasticity/remodelling of human neointimal hyperplasia [9].…”