TY - JOUR
T1 - Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm
AU - Nadadur, Rangarajan D.
AU - Broman, Michael T.
AU - Boukens, Bastiaan
AU - Mazurek, Stefan R.
AU - Yang, Xinan
AU - van den Boogaard, Malou
AU - Bekeny, Jenna
AU - Gadek, Margaret
AU - Ward, Tarsha
AU - Zhang, Min
AU - Qiao, Yun
AU - Martin, James F.
AU - Seidman, Christine E.
AU - Seidman, Jon
AU - Christoffels, Vincent
AU - Efimov, Igor R.
AU - McNally, Elizabeth M.
AU - Weber, Christopher R.
AU - Moskowitz, Ivan P.
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.1126/scitranslmed.aaf4891
DO - https://doi.org/10.1126/scitranslmed.aaf4891
M3 - Article
C2 - 27582060
SN - 1946-6242
VL - 8
SP - 354ra115
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 354
ER -