英国剑桥大学James A. Nathan研究组取得最新进展。他们发现缺氧诱导转录因子 (HIF)复合物募集组蛋白甲基转移酶 SET1B以激活特定的缺氧诱导基因。这一研究成果于2021年6月21日发表在国际顶尖学术期刊《自然—遗传学》上。

他们使用全基因组诱变来识别参与 HIF 转录活动的基因，并定义对组蛋白 H3 赖氨酸 4 (H3K4) 甲基转移酶 SET1B 的需求。SET1B 缺失导致 HIF 靶基因转录激活的选择性减少，从而导致 SET1B 缺陷异种移植物中细胞生长、血管生成和肿瘤建立受损。

从机制上讲，他们表明 SET1B缺氧时在染色质上积累，并被 HIF 复合物募集到 HIF 靶基因。HIF 靶位点 H3K4 三甲基化的选择性诱导是 HIF 和 SET1B 依赖性的，当受损时，与启动子乙酰化和基因表达降低相关。总之，这些发现表明 SET1B 是位点特异性组蛋白甲基化的决定因素，并提供了对 HIF 靶基因如何差异调控的见解。

据悉，HIF是细胞适应低氧水平的基础，但尚不清楚它们如何与染色质相互作用并激活其靶基因。

附：英文原文

Title: The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes

Author: Brian M. Ortmann, Natalie Burrows, Ian T. Lobb, Esther Arnaiz, Niek Wit, Peter S. J. Bailey, Louise H. Jordon, Olivia Lombardi, Ana Pealver, James McCaffrey, Rachel Seear, David R. Mole, Peter J. Ratcliffe, Patrick H. Maxwell, James A. Nathan

Issue&Volume: 2021-06-21

Abstract: Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated. The histone H3K4 methyltransferase SET1B is recruited to a subset of hypoxia-inducible genes by the HIF complex. Loss of SET1B reduces HIF transcriptional activity in hypoxia and impairs tumor formation in xenograft models.

DOI: 10.1038/s41588-021-00887-y

Source: https://www.nature.com/articles/s41588-021-00887-y