Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.

IF 9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cell Systems Pub Date : 2022-11-16 Epub Date: 2022-09-26 DOI:10.1016/j.cels.2022.09.001
Yuejun Jessie Wang, Xicheng Zhang, Chi Keung Lam, Hongchao Guo, Cheng Wang, Sai Zhang, Joseph C Wu, Michael Snyder, Jingjing Li
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引用次数: 0

Abstract

Despite a strong genetic component, only a few genes have been identified in congenital heart diseases (CHDs). We introduced systems analyses to uncover the hidden organization on biological networks of mutations in CHDs and leveraged network analysis to integrate the protein interactome, patient exomes, and single-cell transcriptomes of the developing heart. We identified a CHD network regulating heart development and observed that a sub-network also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHDs and neurodevelopmental conditions. At a small scale, we experimentally verified uncharacterized cardiac functions of several proteins. At a global scale, our study revealed developmental dynamics of the network and observed its association with the hypoplastic left heart syndrome (HLHS), which was further supported by the dysregulation of the network in HLHS endothelial cells. Overall, our work identified previously uncharacterized CHD factors and provided a generalizable framework applicable to studying many other complex diseases. A record of this paper's Transparent Peer Review process is included in the supplemental information.

先天性心脏病新生突变的系统分析确定了左心发育不全综合征的蛋白质网络。
尽管有很强的遗传成分,但只有少数基因在先天性心脏病(CHDs)中被鉴定出来。我们引入了系统分析来揭示冠心病突变生物网络中的隐藏组织,并利用网络分析来整合发育中的心脏的蛋白质相互作用组、患者外显子组和单细胞转录组。我们确定了一个调节心脏发育的冠心病网络,并观察到一个子网络也调节胎儿大脑发育,从而为冠心病和神经发育疾病之间的临床合并症提供了机制见解。在小范围内,我们通过实验验证了几种蛋白质的未表征的心脏功能。在全球范围内,我们的研究揭示了该网络的发育动态,并观察到其与左心发育不全综合征(HLHS)的关联,这进一步得到了HLHS内皮细胞中该网络失调的支持。总的来说,我们的工作确定了以前未表征的冠心病因素,并提供了适用于研究许多其他复杂疾病的可推广框架。本文的透明同行评议过程记录包含在补充信息中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Systems
Cell Systems Medicine-Pathology and Forensic Medicine
CiteScore
16.50
自引率
1.10%
发文量
84
审稿时长
42 days
期刊介绍: In 2015, Cell Systems was founded as a platform within Cell Press to showcase innovative research in systems biology. Our primary goal is to investigate complex biological phenomena that cannot be simply explained by basic mathematical principles. While the physical sciences have long successfully tackled such challenges, we have discovered that our most impactful publications often employ quantitative, inference-based methodologies borrowed from the fields of physics, engineering, mathematics, and computer science. We are committed to providing a home for elegant research that addresses fundamental questions in systems biology.
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