title: Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA.
abstract: DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Schlesinger
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Schoenhals
authors.affiliation: Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Martje
authors.initials: M
authors.lastname: Tönjes
authors.affiliation: Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Dunkel
authors.affiliation: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Cano
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schulz
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Hannover Medical School, Institute of Molecular Biology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Haack
authors.affiliation: Hannover Medical School, Institute of Molecular Biology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany Potsdam University, Institute of Biochemistry and Biology, Department of Animal Physiology, Karl-Liebknecht Str. 24-25, 14476 Potsdam-Golm, Germany.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdelilah-Seyfried
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Bulyk
authors.affiliation: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany silke.sperling@charite.de.
authors.forename: Silke R
authors.initials: SR
authors.lastname: Sperling
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D047390:Casein Kinase II; D002843:Chromatin; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D009687:Nuclear Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D014157:Transcription Factors; C452161:DPF3 protein, human; C484170:GATA4 protein, human; C498179:HELT protein, human; C472955:NPPA protein, human; C084108:SMARCA4 protein, human