Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function
Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function
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DOI：
10.1172/jci59472
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发表时间：
2011-12-01
影响因子：
15.9
通讯作者：
Evans, Sylvia M.
中科院分区：
文献类型：
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作者：
Shen, Tao;Aneas, Ivy;Evans, Sylvia M.
TBX 20的人类突变或变体与先天性心脏病、心肌病和心律失常有关。为了研究这些疾病患者的心脏疾病是否是由于胚胎或心肌中Tbx 20的持续需求，我们特异性消融了小鼠成年心肌细胞中的Tbx 20。该消融导致严重心肌病伴心律失常发作，在Tbx 20消融后1 - 2周内死亡。考虑到这种戏剧性的表型，我们确定了分子特征，将Tbx 20作为维持成人心脏心肌细胞功能的遗传程序的中心整合者。Tbx 20的缺失导致编码关键转录因子、离子通道和细胞骨架/肌原纤维蛋白的许多基因的表达下调。对成年心脏中Tbx 20结合区域的全基因组ChIP分析显示，这些基因中的许多是Tbx 20的直接下游靶点，并发现了以前未描述的Tbx 20 DNA结合位点。生物信息学和体内功能分析揭示了一组转录因子，与Tbx 20一起工作，整合多种环境信号以维持成年心脏中的离子通道基因表达。我们的数据提供了对TBX 20突变导致人类成人心脏病的机制的深入了解。
Human mutations in or variants of TBX20 are associated with congenital heart disease, cardiomyopathy, and arrhythmias. To investigate whether cardiac disease in patients with these conditions results from an embryonic or ongoing requirement for Tbx20 in myocardium, we ablated Tbx20 specifically in adult cardiomyocytes in mice. This ablation resulted in the onset of severe cardiomyopathy accompanied by arrhythmias, with death ensuing within 1 to 2 weeks of Tbx20 ablation. Accounting for this dramatic phenotype, we identified molecular signatures that posit Tbx20 as a central integrator of a genetic program that maintains cardiomyocyte function in the adult heart. Expression of a number of genes encoding critical transcription factors, ion channels, and cytoskeletal/myofibrillar proteins was downregulated consequent to loss of Tbx20. Genome-wide ChIP analysis of Tbx20-binding regions in the adult heart revealed that many of these genes were direct downstream targets of Tbx20 and uncovered a previously undescribed DNA-binding site for Tbx20. Bioinformatics and in vivo functional analyses revealed a cohort of transcription factors that, working with Tbx20, integrated multiple environmental signals to maintain ion channel gene expression in the adult heart. Our data provide insight into the mechanisms by which mutations in TBX20 cause adult heart disease in humans.