Interplay between the Chd4/NuRD Complex and the Transcription Factor Znf219 Controls Cardiac Cell Identity

Abstract

The sarcomere regulates striated muscle contraction. This structure is composed of several myofibril proteins, isoforms of which are encoded by genes specific to either the heart or skeletal muscle. The chromatin remodeler complex Chd4/NuRD regulates the transcriptional expression of these specific sarcomeric programs by repressing genes of the skeletal muscle sarcomere in the heart. Aberrant expression of skeletal muscle genes induced by the loss of Chd4 in the heart leads to sudden death due to defects in cardiomyocyte contraction that progress to arrhythmia and fibrosis. Identifying the transcription factors (TFs) that recruit Chd4/NuRD to repress skeletal muscle genes in the myocardium will provide important information for understanding numerous cardiac pathologies and, ultimately, pinpointing new therapeutic targets for arrhythmias and cardiomyopathies. Here, we sought to find Chd4 interactors and their function in cardiac homeostasis. We therefore describe a physical interaction between Chd4 and the TF Znf219 in cardiac tissue. Znf219 represses the skeletal-muscle sarcomeric program in cardiomyocytes in vitro and in vivo, similarly to Chd4. Aberrant expression of skeletal-muscle sarcomere proteins in mouse hearts with knocked down Znf219 translates into arrhythmias, accompanied by an increase in PR interval. These data strongly suggest that the physical and genetic interaction of Znf219 and Chd4 in the mammalian heart regulates cardiomyocyte identity and myocardial contraction.

ZNF219, a novel transcriptional repressor, inhibits transcription of the prototype foamy virus by interacting with the viral LTR promoter

“…In mammals, the NuRD complex is approximately 1 MDa and comprises at least six to seven proteins, which generally exist as two or more paralogs: CHD4 (and its paralogues CHD3 and CHD5), MTA1 (plus MTA2 and MTA3), HDAC1 (and HDAC2), GATAD2A (and GATAD2B), MBD3 (and MBD2), RBBP4 (and RBBP7), and CDK2AP1 ( Low et al., 2016 ). Physical interaction between CHD4 and ZNF219 has been reported in cardiac tissues ( El Abdellaoui-Soussi et al., 2022 ). Recently, we found that the host protein TRIM28 is enriched in the PFV 5’LTR promoter region and positively regulates H3K9me3 marks ( Yuan et al., 2021 ).…”

Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies

“…Anti-Mi2 autoantibodies recognise chromodomain helicase DNA-binding (CHD) proteins, a family of ATP-dependent chromatin remodelers that are functionally critical subunits of the nucleosome remodelling and deacetylase (CHD4/NuRD) complex, a well-described transcriptional repressor 9 10. Although CHD3 and CHD4 are the most common target antigens tested in anti-Mi2 serological assays, CHD3 , CHD4 and CHD5 share significant sequence homology and are likely recognised by autoantibodies in anti-Mi2-positive DM patients.…”