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

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Item Type:Article
Title:Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA
Creators Name:Cui, H. and Schlesinger, J. and Schoenhals, S. and Toenjes, M. and Dunkel, I. and Meierhofer, D. and Cano, E. and Schulz, K. and Berger, M.F. and Haack, T. and Abdelilah-Seyfried, S. and Bulyk, M.L. and Sauer, S. and Sperling, S.R.
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.
Keywords:Atrial Natriuretic Factor, Basic Helix-Loop-Helix Transcription Factors, Cardiac Myocytes, Cardiomegaly, Casein Kinase II, Cell Differentiation, Chromatin, Chromatin Assembly And Disassembly, DNA Helicases, DNA-Binding Proteins, GATA4 Transcription Factor, Gene Expression Regulation, Genetic Transcription, HEK293 Cells, Induced Pluripotent Stem Cells, Myoblasts, Nuclear Proteins, Phosphorylation, Protein Isoforms, Signal Transduction, Small Interfering RNA, Transcription Factors, Animals, Mice, Rats
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press (U.K.)
Volume:44
Number:6
Page Range:2538-2553
Date:7 April 2016
Official Publication:https://doi.org/10.1093/nar/gkv1244
PubMed:View item in PubMed

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