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
Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
Department of Cardiovascular Genetics, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Group of Cardiovascular Genetics, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Nucleic Acids Res. 2016 Apr 7;44(6):2538-53. doi: 10.1093/nar/gkv1244. Epub 2015 Nov 17.
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.
DPF3（BAF45c）是BAF染色质重塑复合体的成员。已描述了两种亚型，即DPF3a和DPF3b。后者与组蛋白的乙酰化和甲基化赖氨酸残基结合。在此，我们阐述DPF3a的作用，并描述一种导致病理性心脏肥大的心脏基因转录新途径。在肥大刺激下，酪蛋白激酶2使DPF3a的丝氨酸348磷酸化。这引发了DPF3a与转录抑制因子HEY的相互作用，随后HEY从DNA上释放。此外，BRG1与DPF3a结合，因此在这两种成分相互作用时被招募到HEY基因组靶点。结果，启动了如NPPA和GATA4等下游靶点的转录，病理性心脏肥大得以确立。在人类中，DPF3a在肥厚型心肌病或主动脉瓣狭窄患者的肥厚心脏中显著上调。综上所述，我们表明肥大刺激下DPF3a的激活将心脏胎儿基因表达从被HEY沉默转变为由BRG1激活。因此，我们提出了一种病理性心脏肥大的新途径，抑制该途径是治疗心力衰竭病程的长期治疗目标。
