Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28847-28858. doi: 10.1073/pnas.2005222117. Epub 2020 Oct 30.
encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein-protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.
编码一个依赖于 ATP 的染色质重塑因子。该基因的突变导致多种发育障碍，包括 CHARGE（眼缺损、心脏缺陷、后鼻孔闭锁、生长/发育迟缓、生殖器官异常和耳部畸形）综合征，其中圆锥干畸形是最常见的心脏缺陷形式。CHD7 如何调节圆锥干发育仍不清楚。在这项研究中，我们确定神经嵴细胞（NCCs）中缺失会导致严重的圆锥干缺陷和围产期致死性，从而提供了小鼠遗传证据，证明 CHD7 细胞自主调节心脏 NCC 发育，从而澄清了文献中的一个长期争议。通过转录组分析，我们表明 CHD7 微调了对心脏 NCC 发育至关重要的基因网络的表达。为了进一步深入了解 CHD7 对基因的调控作用，我们通过将重组 CHD7 孵育在蛋白质阵列上进行了蛋白质-蛋白质相互作用筛选。我们发现 CHD7 与包括 WDR5 在内的几种发育障碍突变蛋白直接相互作用，WDR5 是 H3K4 甲基转移酶复合物的核心组成部分。这种直接相互作用表明，CHD7 可能独立于其重塑功能，招募组蛋白修饰酶到靶位。因此，我们生成了一种携带 ATP 酶缺陷等位基因的小鼠模型，并证明突变 CHD7 保留了募集 H3K4 甲基转移酶活性到其靶位的能力。因此，我们的数据揭示了 CHD7 通过依赖于 ATP 和非依赖于 ATP 的活性来调节心血管发育，为 CHD7 相关先天性疾病的病因提供了线索。重要的是，我们的数据还表明，携带提前终止密码子而非错义突变的患者可能会显示出不同的分子改变；因此，这些患者可能需要个性化的治疗干预。
