HOPX governs a molecular and physiological switch between cardiomyocyte progenitor and maturation gene programs
HOPX governs a molecular and physiological switch between cardiomyocyte progenitor and maturation gene programs
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DOI：
10.1101/2022.04.17.488603
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发表时间：
2022-04
期刊：
影响因子：
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通讯作者：
Clayton E. Friedman;S. W. Cheetham;R. Mills;M. Ogawa;Meredith A. Redd;H. Chiu;Sophie Shen;Yuliangzi Sun;Dalia Mizikovsky;R. Bouveret;Xiaoli Chen;H. Voges;Scott Paterson;J. D. De Angelis;Stacey B. Andersen;Sohye Yoon;G. Faulkner;Kelly A. Smith;R. Harvey;Benjamin M. Hogan;Q. Nguyen;Kazu Kikuchi;James E. Hudson;N. Palpant
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文献类型：
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作者：
Clayton E. Friedman;S. W. Cheetham;R. Mills;M. Ogawa;Meredith A. Redd;H. Chiu;Sophie Shen;Yuliangzi Sun;Dalia Mizikovsky;R. Bouveret;Xiaoli Chen;H. Voges;Scott Paterson;J. D. De Angelis;Stacey B. Andersen;Sohye Yoon;G. Faulkner;Kelly A. Smith;R. Harvey;Benjamin M. Hogan;Q. Nguyen;Kazu Kikuchi;James E. Hudson;N. Palpant
这项研究建立了仅有同源结构域的蛋白HOPX，作为控制心肌祖细胞和成熟基因程序之间的分子开关的决定因素。全基因组足迹的时间进程单细胞基因表达显示，HOPX通过调节相互排斥的发育基因程序的活性而与核心心脏网络相互作用并控制。上游肥大和增殖途径竞争调节HOPX转录。有丝分裂信号优先于肥大生长信号以抑制HOPX并维持心肌祖细胞基因程序。生理学研究表明，HOPX直接控制心肌细胞应激反应、机电耦合、增殖和收缩的遗传控制。我们使用人类全基因组关联研究(Gwas)来表明，HOPX-Regulome中的遗传变异与影响心脏结构和功能的复杂特征显著相关。总而言之，这项研究为HOPX在相互竞争的上游途径之间提供了一种机械联系，在这些途径中，HOPX充当分子开关，控制支撑心肌细胞代谢、信号和功能成熟的基因调控程序。
This study establishes the homeodomain only protein, HOPX, as a determinant controlling the molecular switch between cardiomyocyte progenitor and maturation gene programs. Time-course single-cell gene expression with genome-wide footprinting reveal that HOPX interacts with and controls core cardiac networks by regulating the activity of mutually exclusive developmental gene programs. Upstream hypertrophy and proliferation pathways compete to regulate HOPX transcription. Mitogenic signals override hypertrophic growth signals to suppress HOPX and maintain cardiomyocyte progenitor gene programs. Physiological studies show HOPX directly governs genetic control of cardiomyocyte cell stress responses, electro-mechanical coupling, proliferation, and contractility. We use human genome-wide association studies (GWAS) to show that genetic variation in the HOPX-regulome is significantly associated with complex traits affecting cardiac structure and function. Collectively, this study provides a mechanistic link situating HOPX between competing upstream pathways where HOPX acts as a molecular switch controlling gene regulatory programs underpinning metabolic, signaling, and functional maturation of cardiomyocytes.