Huanhuan Cui, Jenny Schlesinger, Sophia Schoenhals, Martje Toenjes, Ilona Dunkel, David Meierhofer, Elena Cano, Kerstin Schulz, Michael F. Berger, Timm Haack, Salim Abdelilah-Seyfried, Martha L. Bulyk, Sascha Sauer, Silke R. Sperling
- 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 geneDPF3 (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.…
MetadatenAuthor details: | Huanhuan Cui, Jenny Schlesinger, Sophia Schoenhals, Martje Toenjes, Ilona Dunkel, David Meierhofer, Elena Cano, Kerstin Schulz, Michael F. Berger, Timm Haack, Salim Abdelilah-SeyfriedORCiDGND, Martha L. Bulyk, Sascha Sauer, Silke R. Sperling |
---|
DOI: | https://doi.org/10.1093/nar/gkv1244 |
---|
ISSN: | 0305-1048 |
---|
ISSN: | 1362-4962 |
---|
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/26582913 |
---|
Title of parent work (English): | Nucleic acids research |
---|
Publisher: | Oxford Univ. Press |
---|
Place of publishing: | Oxford |
---|
Publication type: | Article |
---|
Language: | English |
---|
Year of first publication: | 2016 |
---|
Publication year: | 2016 |
---|
Release date: | 2020/03/22 |
---|
Volume: | 44 |
---|
Number of pages: | 16 |
---|
First page: | 2538 |
---|
Last Page: | 2553 |
---|
Funding institution: | Deutsch Forschungsgemeinschaft [DFG 85421021]; European Community [People-2011-ITN-289600]; German Research Foundation [574157]; German Ministry for Research and Education [BMBF] [0315082, 01EA1303]; REBIRTH cluster of excellence; Berlin Institute of Health [BIH-CRG2-ConDi]; China Scholarship Council; European Society of Cardiology |
---|
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
---|
Peer review: | Referiert |
---|