Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA

Huanhuan Cui; Jenny Schlesinger; Sophia Schoenhals; Martje Tönjes; Ilona Dunkel; David Meierhofer; Elena Cano; Kerstin Schulz; Michael F Berger; Timm Haack; Salim Abdelilah-Seyfried; Martha L Bulyk; Sascha Sauer; Silke R Sperling

doi:10.1093/nar/gkv1244

Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA

Nucleic Acids Res. 2016 Apr 7;44(6):2538-53. doi: 10.1093/nar/gkv1244. Epub 2015 Nov 17.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
⁵ Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
⁶ Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
⁷ 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.
⁸ Hannover Medical School, Institute of Molecular Biology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.
⁹ 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.
¹⁰ 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.
¹¹ Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany.
¹² 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atrial Natriuretic Factor / genetics
Atrial Natriuretic Factor / metabolism
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cardiomegaly / genetics*
Cardiomegaly / metabolism
Cardiomegaly / pathology
Casein Kinase II / genetics
Casein Kinase II / metabolism
Cell Differentiation
Chromatin / chemistry*
Chromatin / metabolism
Chromatin Assembly and Disassembly*
DNA Helicases / genetics*
DNA Helicases / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
GATA4 Transcription Factor / genetics
GATA4 Transcription Factor / metabolism
Gene Expression Regulation
HEK293 Cells
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Mice
Myoblasts / cytology
Myoblasts / metabolism
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Phosphorylation
Protein Isoforms / genetics
Protein Isoforms / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Rats
Signal Transduction
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic

Substances

Basic Helix-Loop-Helix Transcription Factors
Chromatin
DNA-Binding Proteins
DPF3 protein, human
GATA4 Transcription Factor
GATA4 protein, human
HELT protein, human
NPPA protein, human
Nuclear Proteins
Protein Isoforms
RNA, Small Interfering
Transcription Factors
Atrial Natriuretic Factor
Casein Kinase II
SMARCA4 protein, human
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding