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

Cui, H., Schlesinger, J., Schoenhals, S., Tönjes, M., Dunkel, I., Meierhofer, D., et al. (2016). Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA. Nucleic Acids Research (London), 46(6), 2538-2553. doi:10.1093/nar/gkv1244.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-BE44-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-1304-F
Genre: Journal Article

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 Creators:
Cui, Huanhuan , Author
Schlesinger, Jenny1, Author              
Schoenhals, Sophia, Author
Tönjes, Martje1, Author              
Dunkel, Ilona1, Author
Meierhofer, David2, Author              
Cano, Elena, Author
Schulz, Kerstin, Author
Berger, Michael F., Author
Haack, Timm, Author
Abdelilah-Seyfried, Salim , Author
Bulyk, Martha L. , Author
Sauer, Sascha3, 4, Author              
Sperling, Silke R.1, Author
Affiliations:
1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              
3Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479662              
4CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2015-11-012015-11-172016-04-07
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: CoNE: 1093/nar/gkv1244
DOI: 10.1093/nar/gkv1244
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Title: Nucleic Acids Research (London)
  Other : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 46 (6) Sequence Number: - Start / End Page: 2538 - 2553 Identifier: ISSN: 0305-1048
CoNE: /journals/resource/110992357379342