Research ArticleCARDIAC ARRHYTHMIA

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

Science Translational Medicine  31 Aug 2016:
Vol. 8, Issue 354, pp. 354ra115
DOI: 10.1126/scitranslmed.aaf4891

You are currently viewing the abstract.

View Full Text

Via your Institution

Log in through your institution

Log in through your institution


The genetic underpinnings of atrial fibrillation

The irregular heartbeat of atrial fibrillation puts people in danger of stroke and heart disease; genomic studies have identified gene variants that increase the risk for this abnormality. Nadadur et al. now reveal how these genes influence the beat of the heart’s atrium. In a mouse model of atrial fibrillation, which lacks one of these genes, Tbx5, the authors describe a multitiered transcriptional network that links seven of these atrial fibrillation risk loci. Organized as an incoherent feed-forward loop, this network tightly controls expression of atrial rhythm genes, and its perturbation by the risk loci causes susceptibility to atrial fibrillation.

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.

View Full Text

Related Content