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ZNF410通过控制CHD4来抑制胎儿珠蛋白
作者:小柯机器人 发布时间:2021/4/18 19:08:58

美国哈佛医学院Daniel E. Bauer团队发现,ZNF410通过控制CHD4来抑制胎儿珠蛋白。相关论文于2021年4月15日在线发表于国际学术期刊《自然—遗传学》。

通过转录因子(TF)CRISPR筛选,研究人员发现,锌指蛋白(ZNF)410是胎儿血红蛋白(HbF)的抑制因子。ZNF410并不直接与编码γ-珠蛋白的基因结合,而是其染色质富集仅集中在CHD4处,后者编码NuRD核小体重塑因子,这本身是HbF抑制所必需的。CHD4具有两个ZNF410结合的调控元件,以及27个ZNF410结合基序,这构成了独特的基因组簇。这些元件完全说明了ZNF410对胎儿珠蛋白阻抑的作用。敲除ZNF410或其小鼠同源物Zfp410可将CHD4水平降低60%,这足以在抑制细胞或机体毒性的同时充分抑制HbF。

这些研究提示了一个治疗β-血红蛋白疾病的潜在靶点。更广泛地说,ZNF410代表一类特殊的基因调节因子,能够专一地调节一种染色质亚复合物。

据介绍,已知的HbF沉默子具有潜在得β-血红蛋白病治疗性抑制靶向作用。

附:英文原文

Title: ZNF410 represses fetal globin by singular control of CHD4

Author: Divya S. Vinjamur, Qiuming Yao, Mitchel A. Cole, Connor McGuckin, Chunyan Ren, Jing Zeng, Mir Hossain, Kevin Luk, Scot A. Wolfe, Luca Pinello, Daniel E. Bauer

Issue&Volume: 2021-04-15

Abstract: Known fetal hemoglobin (HbF) silencers have potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here, through transcription factor (TF) CRISPR screening, we identify zinc-finger protein (ZNF) 410 as an HbF repressor. ZNF410 does not bind directly to the genes encoding γ-globins, but rather its chromatin occupancy is concentrated solely at CHD4, encoding the NuRD nucleosome remodeler, which is itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for the effects of ZNF410 on fetal globin repression. Knockout of ZNF410 or its mouse homolog Zfp410 reduces CHD4 levels by 60%, enough to substantially de-repress HbF while eluding cellular or organismal toxicity. These studies suggest a potential target for HbF induction for β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved TF with singular devotion to regulation of a chromatin subcomplex.

DOI: 10.1038/s41588-021-00843-w

Source: https://www.nature.com/articles/s41588-021-00843-w

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex