小柯机器人

科学家发现打开染色质并激活CpG岛调节基因的新蛋白
2021-07-08 14:54

瑞士巴塞尔大学Dirk Schübeler课题组发现,BANP能够打开染色质并激活CpG岛调控基因。相关论文于2021年7月7日在线发表在《自然》杂志上。

研究人员介绍,哺乳动物基因组中由RNA聚合酶II生成的大多数基因转录本起始于 CpG 岛(CGI)启动子,但人们对其调控的理解仍然有限。这部分是由于人们对转录因子、它们的DNA结合基序以及哪些基因组结合位点在任何给定细胞类型中具有功能的信息不完整。此外,还有一些没有已知结合物的孤儿基序,例如CGCG元件,它与人类组织中的高表达基因相关,并在CGI启动子亚群的转录起始位点附近富集。

通过将单分子足迹与相互作用蛋白质组学结合,研究人员将BTG3相关核蛋白(BANP)鉴定为在小鼠和人类基因组中结合该元件的转录因子。结果表明,BANP是一种强大的CGI激活因子,可控制多能干细胞和终末分化的神经元细胞中的基本代谢基因。BANP结合在体外和体内被其基序的DNA甲基化排斥,这在表观遗传上限制了与CGI的大部分结合,并解释了癌细胞中异常甲基化CGI启动子的差异结合。在与未甲基化的基序结合后,BANP打开了染色质并改变核小体。这些发现将BANP确立为一组必需基因的关键激活因子,并提出了一个模型:CGI启动子的活性依赖于能够打开染色质的甲基化敏感型转录因子。 

附:英文原文

Title: BANP opens chromatin and activates CpG-island-regulated genes

Author: Ralph S. Grand, Lukas Burger, Cathrin Grwe, Alicia K. Michael, Luke Isbel, Daniel Hess, Leslie Hoerner, Vytautas Iesmantavicius, Sevi Durdu, Marco Pregnolato, Arnaud R. Krebs, Sbastien A. Smallwood, Nicolas Thom, Michiel Vermeulen, Dirk Schbeler

Issue&Volume: 2021-07-07

Abstract: The majority of gene transcripts generated by RNA polymerase II in mammalian genomes initiate at CpG island (CGI) promoters1,2, yet our understanding of their regulation remains limited. This is in part due to the incomplete information that we have on transcription factors, their DNA-binding motifs and which genomic binding sites are functional in any given cell type3,4,5. In addition, there are orphan motifs without known binders, such as the CGCG element, which is associated with highly expressed genes across human tissues and enriched near the transcription start site of a subset of CGI promoters6,7,8. Here we combine single-molecule footprinting with interaction proteomics to identify BTG3-associated nuclear protein (BANP) as the transcription factor that binds this element in the mouse and human genome. We show that BANP is a strong CGI activator that controls essential metabolic genes in pluripotent stem and terminally differentiated neuronal cells. BANP binding is repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for differential binding at aberrantly methylated CGI promoters in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. These findings establish BANP as a critical activator of a set of essential genes and suggest a model in which the activity of CGI promoters relies on methylation-sensitive transcription factors that are capable of chromatin opening.

DOI: 10.1038/s41586-021-03689-8

Source: https://www.nature.com/articles/s41586-021-03689-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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