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

There is evidence for a shared genetic basis of atrial septal defects (ASDs) and atrial fibrillation (AF), but it remains unclear how genetic susceptibility leads to these distinct human atrial diseases. Here, we used directed differentiation of human induced pluripotent stem cell to ventricular or atrial cardiomyocytes (CMs) to define gene regulatory networks (GRNs) of human ventricular or atrial CM identity. In ventricular, atrial, or both types of CMs, we uncovered accessible chromatin regions, transcription factor motifs and key regulatory nodes, including the transcription factor TBX5, which is linked to ASDs and AF in humans. Complete TBX5 loss resulted in a near absence of atrial CMs with a concomitant increase in abundance of other cell types. Reduced dosage of TBX5 in human atrial CMs caused cellular, electrophysiologic and molecular phenotypes consistent with features of atrial CM dysfunction. This included dose-dependent aberrant accessibility of many chromatin regions leading to perturbed TBX5-sensitive gene regulatory networks of atrial CM identity. These results suggest that genetic susceptibility to some human atrial diseases may impair developmental gene regulation for proper atrial CM identity.