Role of the Nucleosome Remodeling and Deacetylase Complex in Heart Failure

The nucleosome remodeling and deacetylase (NuRD) complex, built around the ATP-dependent chromatin remodeler CHD4 and the histone deacetylases HDAC1/2, has been implicated in cardiac gene regulation during development, but its role in the transcriptional and chromatin changes that accompany pathological cardiac hypertrophy and progression to heart failure in the adult heart has not been directly tested. We generated tamoxifen-inducible, cardiomyocyte-specific Chd4 knockout mice and subjected adult knockout and littermate control animals to transverse aortic constriction (TAC) to induce pressure-overload hypertrophy, assessing cardiac function by echocardiography and chromatin and transcriptional state by ATAC-seq, CHD4 and H3K27ac ChIP-seq, and RNA-sequencing over an eight-week time course. Cardiomyocyte-specific CHD4 loss did not affect baseline cardiac structure or function but significantly worsened pressure-overload-induced hypertrophy, with knockout hearts showing 34% greater left ventricular mass increase and a significantly faster decline in fractional shortening than controls by six weeks post-TAC. ATAC-seq identified 2,146 genomic regions that gained accessibility specifically in knockout hearts following TAC, strongly enriched near genes of the fetal cardiac gene program (Nppa, Nppb, Myh7, Acta1), which were derepressed to a significantly greater extent in knockout hearts. CHD4 ChIP-seq in control hearts showed direct CHD4 occupancy at the promoters and enhancers of these fetal genes, lost in knockout hearts alongside a corresponding gain of H3K27ac, consistent with a repressive function normally maintained by NuRD-mediated deacetylation and unmasked during pathological stress in its absence. Pharmacological CHD4 ATPase inhibition administered only after TAC surgery phenocopied the genetic knockout, indicating that this protective activity acts during the stress response itself rather than only during prior development. These results identify cardiomyocyte CHD4 as a direct repressor of the pathological fetal gene program that restrains, without eliminating, maladaptive hypertrophic remodeling under pressure overload.