Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease.

While atrial septal defects (ASDs) and atrial fibrillation (AF) present differently, there is evidence that they share some genetic basis. Here, we have used directed differentiation of human induced pluripotent stem cells into atrial or ventricular cardiomyocytes (CMs) to delineate gene regulatory networks (GRNs) that define each identity. We uncovered accessible chromatin regions, transcription factor motifs and key regulatory nodes specific to, or shared by, both CM types, including the transcription factor TBX5, which is linked to genetic susceptibility of ASDs and AF in humans. Complete TBX5 loss resulted in a near absence of atrial CMs, with a concomitant increase in the abundance of other cell types. Reduced dosage of TBX5 in human atrial CMs caused cellular, electrophysiological and molecular phenotypes consistent with features of atrial CM dysfunction. This included dose-dependent aberrant accessibility of many chromatin regions and perturbation of gene regulatory networks of atrial CM identity. These results suggest that, in addition to stemming from ion channel or extracellular matrix dysfunction, atrial diseases such as ASDs or AF may result from disruptions of atrial CM identity.