title: Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm.
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.
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Rangarajan D
authors: RD
authors: Nadadur
authors: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Michael T
authors: MT
authors: Broman
authors: 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.
authors: Bastiaan
authors: B
authors: Boukens
authors: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Stefan R
authors: SR
authors: Mazurek
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Xinan
authors: X
authors: Yang
authors: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
authors: Malou
authors: M
authors: van den Boogaard
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Jenna
authors: J
authors: Bekeny
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Margaret
authors: M
authors: Gadek
authors: Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Tarsha
authors: T
authors: Ward
authors: 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.
authors: Min
authors: M
authors: Zhang
authors: Department of Biomedical Engineering, George Washington University, Washington, DC 20052, USA.
authors: Yun
authors: Y
authors: Qiao
authors: 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.
authors: James F
authors: JF
authors: Martin
authors: Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Christine E
authors: CE
authors: Seidman
authors: Department of Genetics, Harvard Medical School, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Jon
authors: J
authors: Seidman
authors: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
authors: Vincent
authors: V
authors: Christoffels
authors: Department of Biomedical Engineering, George Washington University, Washington, DC 20052, USA.
authors: Igor R
authors: IR
authors: Efimov
authors: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Elizabeth M
authors: EM
authors: McNally
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Christopher R
authors: CR
authors: Weber
authors: Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA. imoskowitz@uchicago.edu.
authors: Ivan P
authors: IP
authors: Moskowitz
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000503:physiopathology; D016275:Atrial Function / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057895:Haploinsufficiency; D006339:Heart Rate / Q000235:genetics* / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D057170:Translational Research, Biomedical; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C103172:T-box transcription factor 5