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Sci Transl Med. 2016 Aug 31;8(354):354ra115. doi: 10.1126/scitranslmed.aaf4891.

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

Author information

1
Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
2
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
3
Department of Biomedical Engineering, George Washington University, Washington, DC 20052, USA. Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
4
Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
5
Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA. Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX 77030, USA. Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Biomedical Engineering, George Washington University, Washington, DC 20052, USA.
8
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
9
Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA. imoskowitz@uchicago.edu.

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.

PMID:
27582060
PMCID:
PMC5266594
DOI:
10.1126/scitranslmed.aaf4891
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no competing interests.

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