title: MyoR modulates cardiac conduction by repressing Gata4.
abstract: The cardiac conduction system coordinates electrical activation through a series of interconnected structures, including the atrioventricular node (AVN), the central connection point that delays impulse propagation to optimize cardiac performance. Although recent studies have uncovered important molecular details of AVN formation, relatively little is known about the transcriptional mechanisms that regulate AV delay, the primary function of the mature AVN. We identify here MyoR as a novel transcription factor expressed in Cx30.2(+) cells of the AVN. We show that MyoR specifically inhibits a Cx30.2 enhancer required for AVN-specific gene expression. Furthermore, we demonstrate that MyoR interacts directly with Gata4 to mediate transcriptional repression. Our studies reveal that MyoR contains two nonequivalent repression domains. While the MyoR C-terminal repression domain inhibits transcription in a context-dependent manner, the N-terminal repression domain can function in a heterologous context to convert the Hand2 activator into a repressor. In addition, we show that genetic deletion of MyoR in mice increases Cx30.2 expression by 50% and prolongs AV delay by 13%. Taken together, we conclude that MyoR modulates a Gata4-dependent regulatory circuit that establishes proper AV delay, and these findings may have wider implications for the variability of cardiac rhythm observed in the general population.
authors.affiliation: Department of Internal Medicine (Cardiology Division), UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine (Cardiology Division), UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Minoti
authors.initials: M
authors.lastname: Bhakta
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bezprozvannaya
authors.affiliation: Department of Internal Medicine (Cardiology Division), UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine (Cardiology Division), UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lubczyk
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, USA Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Internal Medicine (Cardiology Division), UT Southwestern Medical Center, Dallas, Texas, USA Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, USA Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas, USA McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USA Nikhil.Munshi@UTSouthwestern.edu.
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Munshi
mesh_terms: D000818:Animals; D001283:Atrioventricular Node / Q000166:cytology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006339:Heart Rate / Q000502:physiology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017630:Connexins; D050991:GATA4 Transcription Factor; D008156:Luciferases; D014157:Transcription Factors; D001616:beta-Galactosidase; C484171:Gata4 protein, mouse; C498766:Hand2 protein, mouse; C117673:Msc protein, mouse; C510757:connexin 30.2, mouse