CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network [multiome]

Atrial fibrillation (AF), the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity, and causes spontaneous AF. Here we investigated mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase canonically associated with the NuRD repressor complex, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). Combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. CHD4-repressed genes included sarcomeric proteins from non-CM cell lineages. CHD4-activated genes were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.