Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node

• Published in: Cell research Vol. 24; no. 10; pp. 1201 - 1213
• Main Authors: Wu, Meng, Peng, Siwu, Yang, Jialiang, Tu, Zhidong, Cai, Xiaoqiang, Cai, Chen-Leng, Wang, Zhong, Zhao, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2014; Nature Publishing Group
• Subjects: 631/208/176; 631/337; 692/699/75/29; Animals; Antineoplastic Agents, Hormonal - pharmacology; ATP; Biomedical and Life Sciences; Cell Biology; Chromatin Immunoprecipitation; Cluster Analysis; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenesis, Genetic; GATA4 Transcription Factor - metabolism; HEK293 Cells; Histone Deacetylases - metabolism; Homeobox Protein Nkx-2.5; Homeodomain Proteins - metabolism; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; original-article; Sinoatrial Node - metabolism; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Tamoxifen - pharmacology; Time series; Transcription Factors - metabolism; 心肌; 心脏起搏器; 收缩; 程序; 窦房结; 编排; 表观遗传; 镇压; transcription; chromatin; epigenetics
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2014.113

The sinoatrial node （SAN） is essential for rhythmic beating of the heart; however, our understanding of what con- trols proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baj250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Thx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease （SSD）. Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general.