title: Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents.
abstract: BACKGROUND
  Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an induced Purkinje-like state characterized by prolonged action potential duration and expression of Purkinje-enriched genes.
  
  
  OBJECTIVE
  To understand the mechanism by which canonical Notch signaling causes action potential prolongation.
  
  
  RESULTS
  We find that endogenous Purkinje cells have reduced peak K+current, Ito, and IK,slowwhen compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K+current density, as well as the outward K+current components Ito,fand IK,slow. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a and downregulation of K+channel subunit genes that contribute to Ito,fand IK,slow. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K+current amplitudes and mimics physiological hypertrophy. Notch-induced changes in K+current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J (recombination signal binding protein for immunoglobulin kappa J region) binding and loss of active histone marks on K+channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes.
  
  
  CONCLUSIONS
  In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology and may provide a novel target for arrhythmia drug design.
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Khandekar
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Springer
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hicks
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Weinheimer
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Trelles
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
authors.affiliation: Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Rentschler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*
chemical_list: D024642:Potassium Channels, Voltage-Gated; D051880:Receptors, Notch
keywords: Brugada syndrome; Notch receptors Purkinje cells; action potential; cardiomyopathies; cellular reprogramming; electrophysiology