Wu Meng, Peng Siwu, Yang Jialiang, Tu Zhidong, Cai Xiaoqiang, Cai Chen-Leng, Wang Zhong, Zhao Yong
1] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Cell Res. 2014 Oct;24(10):1201-13. doi: 10.1038/cr.2014.113. Epub 2014 Aug 22.
The sinoatrial node (SAN) is essential for rhythmic beating of the heart; however, our understanding of what controls proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baf250a, 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, Tbx3 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.
窦房结（SAN）对于心脏的节律性跳动至关重要；然而，我们对控制窦房结正常功能的因素的理解仍很原始。为了探究窦房结功能的分子调控机制，我们在窦房结中特异性删除了Baf250a，它是ATP依赖性染色质重塑复合物SWI/SNF的关键调控成分。窦房结中Baf250a的缺失导致窦性心动过缓。对Baf250a缺失后失调基因的时间序列分析揭示了一个维持起搏细胞身份的转录层级，即Baf250a激活Tbx3的表达，并且Baf250a、Tbx3和组蛋白去乙酰化酶3协同抑制Nkx2.5的表达。这条抑制途径的破坏会开启Nkx2.5的表达，后者刺激Gata4和Tbx5的表达。这三种心脏转录因子进一步开启窦房结中收缩性心肌细胞程序，最终导致病态窦房结综合征（SSD）。我们的研究表明，调节心脏谱系分离的关键遗传途径的破坏可能总体上导致SSD和心律失常。
