Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm

Rangarajan D. Nadadur, Michael T. Broman, Bastiaan Boukens, Stefan R. Mazurek, Xinan Yang, Malou Van Den Boogaard, Jenna Bekeny, Margaret Gadek, Tarsha Ward, Min Zhang, Yun Qiao, James F. Martin, Christine E. Seidman, Jon Seidman, Vincent Christoffels, Igor R. Efimov, Elizabeth M. McNally, Christopher R. Weber, Ivan P. Moskowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2. In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice. These results defined a transcriptional architecture for atrial rhythm control organized as an incoherent feed-forward loop, driven by TBX5 and modulated by PITX2. TBX5/PITX2 interplay provides tight control of atrial rhythm effector gene expression, and perturbation of the co-regulated network caused AF susceptibility. This work provides a model for the molecular mechanisms underpinning the genetic implication of multiple AF genome-wide association studies loci and will contribute to future efforts to stratify patients for AF risk by genotype.

Original languageEnglish (US)
Article number354ra115
JournalScience translational medicine
Volume8
Issue number354
DOIs
StatePublished - Aug 31 2016

ASJC Scopus subject areas

  • Medicine(all)

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