Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.
Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.
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DOI：
10.1161/circresaha.122.322223
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发表时间：
2023-06-23
影响因子：
20.1
通讯作者：
Conlon, Frank L.
中科院分区：
文献类型：
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作者：
Shi, Wei;Scialdone, Angel P.;Emerson, James I.;Mei, Liu;Wasson, Lauren K.;Davies, Haley A.;Seidman, Christine E.;Seidman, Jonathan G.;Cook, Jeanette G.;Conlon, Frank L.
左心室致密化不全(LVNC)是一种常见的心肌病，与过度的小梁形成和心肌变薄有关。LVNC患者容易发生心功能不全，猝死的风险很高。虽然心脏基因的零星和遗传突变与LVNC有关，但对人类LVNC的机制了解有限。我们筛选了儿科心脏基因组联合会的完整外显子组序列数据库，并鉴定了一个具有从头CHD4(染色域解旋酶DNA结合蛋白4)先证者的队列，CHD4M202I，患有先天性心脏缺陷。我们设计了CHD4M202I的人源化小鼠模型(小鼠CHD4M195I)。采用组织学分析、免疫组织化学、流式细胞术、透射电子显微镜和超声心动图分析心脏解剖和功能。通过体外培养、免疫纯化结合质谱、转录图谱和染色质免疫共沉淀等方法研究CHD4M195I介导的室壁缺陷的发生机制。CHD4M195I/M195I小鼠出现双室过度小梁和致密化不全，出生时死亡。CHD4M195I组心肌细胞增殖显著增加，过度小梁形成与ECM蛋白积聚和ECM蛋白水解酶ADAMTS1(Adam Metallopeptidase with血栓反应蛋白I型基序1)减少有关。我们用ADAMTS1挽救了CHD4M195I心脏过度增殖和过度小梁形成的缺陷。从机制上讲，CHD4M195I蛋白显示出与心内膜BRG1(SWI/SNF相关、基质相关、肌动蛋白依赖的染色质调节因子，A亚家族，成员4)的亲和力增强。这种增强的亲和力导致ADAMTS1转录的去抑制失败，从而损害了ADAMTS1介导的小梁终止。我们的研究揭示了染色质重构体CHD4在小鼠或人类中如何调节室腔成熟，以及与错义突变CHD4M195I相关的心脏缺陷可以通过使用ADAMTS1来减少。
Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I, with congenital heart defects. We engineered a humanized mouse model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. CHD4M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.
影响因子：
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作者：
Ham SA;Yoo T;Lee WJ;Hwang JS;Hur J;Paek KS;Lim DS;Han SG;Lee CH;Seo HG
通讯作者：
Seo HG