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

• Published in: Nucleic acids research Vol. 44; no. 6; pp. 2538 - 2553
• Main Authors: Cui, Huanhuan, Schlesinger, Jenny, Schoenhals, Sophia, Tönjes, Martje, Dunkel, Ilona, Meierhofer, David, Cano, Elena, Schulz, Kerstin, Berger, Michael F, Haack, Timm, Abdelilah-Seyfried, Salim, Bulyk, Martha L, Sauer, Sascha, Sperling, Silke R
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 07-04-2016
• Subjects: 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; Gene regulation, Chromatin and Epigenetics; 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; Rats; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkv1244

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.