Spatiotemporal regulation of an Hcn4 enhancer defines a role for Mef2c and HDACs in cardiac electrical patterning.
Spatiotemporal regulation of an Hcn4 enhancer defines a role for Mef2c and HDACs in cardiac electrical patterning.
复制标题
DOI：
10.1016/j.ydbio.2012.10.017
复制
发表时间：
2013-01-01
影响因子：
2.7
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
--
作者：
Vedantham, Vasanth;Evangelista, Melissa;Huang, Yu;Srivastava, Deepak
关键词：
心肌细胞自律性的区域差异允许窦房结（SAN）作为主要心脏起搏点，房室（AV）交界处作为辅助起搏点。控制心脏内自律性分布的调节机制尚不清楚。为了了解心脏自律性的区域变化，我们进行了体内顺式调节元件的分析，控制超极化激活的环核苷酸门控离子通道4（HCN 4）的表达。使用转基因小鼠，我们发现Hcn4在AV传导系统中表达的空间和时间模式需要具有多个保守片段的顺式调节元件。一个高度保守的区域，其中包含一个肌细胞增强因子2C（Mef2C）的结合位点先前在体外描述，诱导报告基因表达，特别是在胚胎非室心肌和出生后的AV束在体内Mef2C依赖的方式。在培养的转基因胚胎中抑制组蛋白去乙酰化酶（HDAC）的活性显示了报告活性向工作心肌的扩展。在成年动物中，由横向主动脉缩窄引起的肥大导致HDAC易位出细胞核，导致工作心肌中Hcn4增强子的异位激活，重演病理性电重构。这些发现揭示了在发育过程中和应对压力时控制心肌细胞自律性分布的机制。
Regional differences in cardiomyocyte automaticity permit the sinoatrial node (SAN) to function as the leading cardiac pacemaker and the atrioventricular (AV) junction as a subsidiary pacemaker. The regulatory mechanisms controlling the distribution of automaticity within the heart are not understood. To understand regional variation in cardiac automaticity, we carried out an in vivo analysis of cis-regulatory elements that control expression of the hyperpolarization-activated cyclic-nucleotide gated ion channel 4 (Hcn4). Using transgenic mice, we found that spatial and temporal patterning of Hcn4 expression in the AV conduction system required cis-regulatory elements with multiple conserved fragments. One highly conserved region, which contained a myocyte enhancer factor 2C (Mef2C) binding site previously described in vitro, induced reporter expression specifically in the embryonic non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo. Inhibition of histone deacetylase (HDAC) activity in cultured transgenic embryos showed expansion of reporter activity to working myocardium. In adult animals, hypertrophy induced by transverse aortic constriction, which causes translocation of HDACs out of the nucleus, resulted in ectopic activation of the Hcn4 enhancer in working myocardium, recapitulating pathological electrical remodeling. These findings reveal mechanisms that control the distribution of automaticity among cardiomyocytes during development and in response to stress.
登录
查看更多内容
影响因子：
10.5
作者：
Hoogaars, Willem M. H.;Engel, Angela;Christoffels, Vincent M.
通讯作者：
Christoffels, Vincent M.
影响因子：
20.1
作者：
Aanhaanen, Wim T. J.;Mommersteeg, Mathilda T. M.;Christoffels, Vincent M.
通讯作者：
Christoffels, Vincent M.
影响因子：
158.5
作者：
Milanesi, R;Baruscotti, M;DiFrancesco, D
通讯作者：
DiFrancesco, D
影响因子：
15.9
作者：
Arnolds, David E.;Liu, Fang;Moskowitz, Ivan P.
通讯作者：
Moskowitz, Ivan P.
影响因子：
11.4
作者：
Herrmann, Stefan;Stieber, Juliane;Ludwig, Andreas
通讯作者：
Ludwig, Andreas