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GATA4突变的疾病模型揭示了人类心脏生成中的转录因子合作性

Yen-Sin Ang¹, Renee N Rivas¹, Alexandre J S Ribeiro²

¹Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.

|December 17, 2016

概括

一个GATA4基因突变会损害心脏细胞功能,并破坏基因调节,导致心脏缺陷. 这项研究揭示了转录因子的突变如何通过影响蛋白质相互作用和DNA结合引起疾病.

科学领域:

分子生物学
遗传学
心脏病学

背景情况:

高度保存的转录因子中的突变会破坏基因网络,导致人类的疾病.
一个关键的心脏转录因子GATA4,在突变时与心脏隔膜缺陷和心肌病有关.
了解GATA4突变的分子机制对于诊断和治疗先天性心脏病至关重要.

研究的目的:

研究人类心肌细胞中异构GATA4-G296S错误突变的功能后果.
阐明GATA4- G296S突变对TBX5的相互作用及其在心脏基因调节中的作用.
探索这种突变如何影响色素状态和细胞功能障碍,导致心脏形态遗传缺陷.

主要方法:

使用来自GATA4- G296S突变患者的诱导多能干细胞 (iPS) 的心肌细胞.
分析心肌细胞收缩性,处理和代谢活动.
在心脏增强剂中进行了GATA4和TBX5的同时占用性研究,并评估了基因表达和染色质可访问性.

主要成果:

GATA4- G296S突变影响了心肌细胞收缩能力,处理能力和代谢功能.
这种突变破坏了TBX5对心脏超级增强剂的招募,导致参与心脏隔离的基因失调.
这种突变还导致非心脏基因的GATA4/TBX5中介抑制失效,并改变了内皮促进体的染色质状态.

结论:

在GATA4中引起疾病的误解突变可以破坏与TBX5的转录合作性.
异常的染色质状态和细胞功能障碍,包括形态遗传缺陷,是转录网络中断的结果.
这项研究提供了GATA4相关心脏病的分子基础.

关键词:

其他国家一个TBX5 出生缺陷心肌疾病遗传性心脏缺陷疾病建模表观遗传学基因调节心脏的发育系统生物学

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