CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.
CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.
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CHD7 通过 ATP 依赖性和非依赖性活动调节心血管发育。
DOI：
10.1073/pnas.2005222117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Jiao,Kai
中科院分区：
文献类型：
--
作者：
Yan,Shun;Thienthanasit,Rassarin;Chen,Dongquan;Engelen,Erik;Brühl,Joanna;Crossman,DavidK;Kesterson,Robert;Wang,Qin;Bouazoune,Karim;Jiao,Kai
CHD7 编码 ATP 依赖性染色质重塑因子。该基因的突变会导致多种发育障碍，包括 CHARGE（眼睛缺损、心脏缺陷、后鼻孔闭锁、生长/发育迟缓、生殖器异常和耳朵异常）综合征，其中圆锥干异常是最常见的心脏缺陷形式。 CHD7 如何调节圆锥干发育尚不清楚。在这项研究中，我们确定神经嵴细胞（NCC）中Chd7的缺失会导致严重的圆锥干缺陷和围产期死亡，从而提供小鼠遗传证据证明CHD7细胞自主调节心脏NCC的发展，从而澄清文献中长期存在的争议。通过转录组分析，我们发现 CHD7 微调对心脏 NCC 发展至关重要的基因网络的表达。为了进一步了解 CHD7 的基因调控，我们通过在蛋白质阵列上孵育重组 CHD7 来进行蛋白质-蛋白质相互作用筛选。我们发现 CHD7 直接与几种发育障碍突变蛋白相互作用，包括 H3K4 甲基转移酶复合物的核心成分 WDR5。这种直接相互作用表明，CHD7 可能会独立于其重塑功能而招募组蛋白修饰酶来靶向位点。因此，我们生成了一个含有 ATP 酶缺陷等位基因的小鼠模型，并证明突变体 CHD7 保留了将 H3K4 甲基转移酶活性招募到其靶标的能力。因此，我们的数据揭示了 CHD7 通过 ATP 依赖性和非依赖性活动调节心血管发育，揭示了 CHD7 相关先天性疾病的病因学。重要的是，我们的数据还表明，携带过早终止密码子与错义突变的患者可能会表现出不同的分子改变；因此，这些患者可能需要个性化的治疗干预。
CHD7encodes 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 ofChd7in 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.