Hu, K. M. | Search bioRxiv

bioRxiv2025

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 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, electrophysiologic 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.

developmental biology↗

bioRxiv2024

A TBX5-dependent compartment boundary patterns the cardiac interventricular septum

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. Here, we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors cause IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.

developmental biology↗