Impaired CHD6 function links misregulation of autophagy and DNA damage response to premature ageing [RNA-Seq]

Members of the Chromodomain-Helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies. CHD6 is the least studied member of this family, and we were motivated to dissect its in-cell roles by discovering a mutated CHD6 allele in a patient suffering from the rare Hallermann-Streiff premature aging syndrome (HSS). We generated isogenic iPSC lines carrying (or not) this single point mutation in the CHD6 SANT/SLIDE domain, which allow studying HSS-relevant cell identities. Using these lines, we show for the first time that CHD6 binds the promoters of a cohort of autophagy and stress response genes across cell types. This CHD6 mutation impairs its ability to recruit co-factors and regulate genes in response to DNA damage and autophagy stimulation, thus leading to accumulation of unresolved DNA damage burden. By combining genomics and functional assays, we describe a molecular mechanism underlying chromatin control of autophagic flux and genotoxic stress surveillance that is broadly applicable to human cell types and can explain HSS establishment.

染色质解旋酶DNA结合（Chromodomain-Helicase-DNA binding, CHD）蛋白家族的成员均为染色质重塑因子，在人类疾病发生发展中扮演关键角色。CHD6是该家族中研究程度最低的成员，我们在一名罹患罕见霍尔曼-斯特里夫早衰综合征（Hallermann-Streiff premature aging syndrome, HSS）的患者体内发现了突变的CHD6等位基因，由此着手解析其在细胞内的功能角色。我们构建了携带（或不携带）CHD6 SANT/SLIDE结构域单点突变的同基因诱导多能干细胞（induced pluripotent stem cell, iPSC）系，该细胞模型可用于研究与HSS相关的细胞身份特征。利用这些细胞系，我们首次证实CHD6可在多种细胞类型中结合一批自噬相关基因与应激反应基因的启动子区域。该CHD6突变会削弱其招募辅因子以及响应DNA损伤与自噬刺激以调控基因表达的能力，进而导致未修复的DNA损伤负荷积累。通过整合基因组学与功能实验手段，我们阐明了染色质调控自噬流与遗传毒性应激监测的分子机制，该机制可广泛适用于人类各类细胞研究，并可解释HSS的发病机制。