The TBX20-TLE Interaction is Essential for the Second Heart Field

Edwards, W.; Bussey, O.; Conlon, F.

doi:10.1101/2022.09.27.509637

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bioRxiv · 10.1101/2022.09.27.509637

The TBX20-TLE Interaction is Essential for the Second Heart Field

Edwards, W.·Bussey, O.·Conlon, F.

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Abstract

Tbx20 plays a multifaceted role in cardiac morphogenesis and controls a broad gene regulatory network. However, the mechanism by which Tbx20 activates and represses target genes in a tissue-specific and temporal manner remains unclear. Studies show that Tbx20 directly interacts with the Transducin-like Enhancer of Split (TLE) family of proteins to mediate transcriptional repression of downstream target genes. However, a functional role for the Tbx20-TLE transcriptional repression complex during heart development is not established. To this end, we generated a mouse model with a two-amino acid substitution in the Tbx20 EH1 domain, thereby disrupting the Tbx20-TLE interaction (Tbx20EH1mut). We demonstrate that disruption of this interaction impairs critical morphogenic events, including cardiac looping and chamber formation, and ultimately leads to embryonic lethality. Transcriptional profiling of Tbx20EH1mut hearts and analysis of putative Tbx20 direct targets reveals misexpression of the retinoic acid pathway and cardiac progenitor genes, demonstrating that the Tbx20-TLE interaction serves to inhibit cardiac progenitor programs in the developing heart. We find that loss of this interaction also results in perturbations of the second heart field progenitor population, implying that altered cardiac progenitor function may underly the observed cardiac defects in our model. Our studies indicate that TLE-mediated repression is a primary mechanism by which Tbx20 systematically controls gene expression.

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Edwards, W., Bussey, O., Conlon, F.. 2022-09-28. The TBX20-TLE Interaction is Essential for the Second Heart Field. https://doi.org/10.1101/2022.09.27.509637

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