MyoR modulates cardiac conduction by repressing Gata4

John P. Harris, Minoti Bhakta, Svetlana Bezprozvannaya, Lin Wang, Christina Lubczyk, Eric N. Olson, Nikhil V. Munshi

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The cardiac conduction system coordinates electrical activation through a series of interconnected structures, including the atrioventricular node (AVN), the central connection point that delays impulse propagation to optimize cardiac performance. Although recent studies have uncovered important molecular details of AVN formation, relatively little is known about the transcriptional mechanisms that regulate AV delay, the primary function of the mature AVN. We identify here MyoR as a novel transcription factor expressed in Cx30.2+ cells of the AVN. We show that MyoR specifically inhibits a Cx30.2 enhancer required for AVN-specific gene expression. Furthermore, we demonstrate that MyoR interacts directly with Gata4 to mediate transcriptional repression. Our studies reveal that MyoR contains two nonequivalent repression domains. While the MyoR C-terminal repression domain inhibits transcription in a context-dependent manner, the N-terminal repression domain can function in a heterologous context to convert the Hand2 activator into a repressor. In addition, we show that genetic deletion of MyoR in mice increases Cx30.2 expression by 50% and prolongs AV delay by 13%. Taken together, we conclude that MyoR modulates a Gata4-dependent regulatory circuit that establishes proper AV delay, and these findings may have wider implications for the variability of cardiac rhythm observed in the general population.

Original languageEnglish (US)
Pages (from-to)649-661
Number of pages13
JournalMolecular and cellular biology
Volume35
Issue number4
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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