TY  - JOUR
A1  - Cui, Huanhuan
A1  - Schlesinger, Jenny
A1  - Schoenhals, Sophia
A1  - Toenjes, Martje
A1  - Dunkel, Ilona
A1  - Meierhofer, David
A1  - Cano, Elena
A1  - Schulz, Kerstin
A1  - Berger, Michael F.
A1  - Haack, Timm
A1  - Abdelilah-Seyfried, Salim
A1  - Bulyk, Martha L.
A1  - Sauer, Sascha
A1  - Sperling, Silke R.
T1  - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA
JF  - Nucleic acids research
N2  - 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.
Y1  - 2016
U6  - https://doi.org/10.1093/nar/gkv1244
SN  - 0305-1048
SN  - 1362-4962
VL  - 44
SP  - 2538
EP  - 2553
PB  - Oxford Univ. Press
CY  - Oxford
ER  -