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The Role of T-box 20 in Midgestation Cardiomyocytes


T-box transcription factor 20 (TBX20) is a transcription factor belonging to the highly conserved T-box family. During cardiogenesis, Tbx20 is expressed in multiple cell lineages critical for heart formation, including cardiac progenitors, endoderm, cardiomyocytes, endocardial cells and endothelial cells. Mutations in TBX20 are associated with congenital heart disease (CHD) including atrial septal defects (ASDs), ventricular septal defects (VSDs) and mitral stenosis (MS). Global or endocardial ablation of Tbx20 results in cardiac malformations and embryonic lethality. The potential function of Tbx20 in midgestation cardiomyocytes has yet to be explored. To address this question,cardiomyocyte-specific inducible Tnnt2-rtTA; TetO-Cre was used to ablate Tbx20 by inductions at E8.5, resulting in mutants termed Tbx20 cKO. Tbx20 cKOs exhibited embryonic lethality at E14.5, with mutant hearts displaying ASDs, VSDs, and hypoplasia of ventricles and left atria. Proliferation was significantly reduced in lineage-traced cardiomyocytes of Tbx20 cKOs. An intersection of RNA-seq analyses of purified cardiomyocytes with TBX20-GFP ChIP-seq of embryonic hearts, in conjunction with RNA in situ analyses, revealed that TBX20 in cardiomyocytes directly regulated genes required for myocyte proliferation, and multiple aspects of cardiomyocyte identity and patterning. Of note, TBX20 was discovered to directly regulate COUP-TFII, a key regulator of atrial identity. Tbx20 cKO atria exhibited decreased expression of COUP-TFII and other atrial markers, as well as overexpression of ventricular-specific gene. Our work sheds light on mechanisms by which mutations in TBX20 cause congenital heart disease and highlight a pivotal cell autonomous role for TBX20 in atrial myocyte development.

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