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The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes
Nature Genetics ( IF 30.8 ) Pub Date : 2021-06-21 , DOI: 10.1038/s41588-021-00887-y
Brian M Ortmann 1 , Natalie Burrows 2 , Ian T Lobb 2 , Esther Arnaiz 1 , Niek Wit 1 , Peter S J Bailey 1 , Louise H Jordon 1 , Olivia Lombardi 3 , Ana Peñalver 2 , James McCaffrey 2, 4 , Rachel Seear 1 , David R Mole 3 , Peter J Ratcliffe 5, 6 , Patrick H Maxwell 2 , James A Nathan 1
Affiliation  

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.



中文翻译:

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

缺氧诱导转录因子 (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。在这里,我们使用全基因组诱变来识别参与 HIF 转录活性的基因,并定义对组蛋白 H3 赖氨酸 4 (H3K4) 甲基转移酶 SET1B 的要求。SET1B 缺失导致 HIF 靶基因转录激活的选择性减少,导致 SET1B 缺陷异种移植物中的细胞生长、血管生成和肿瘤建立受损。从机制上讲,我们表明 SET1B 在缺氧条件下在染色质上积累,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,与降低的启动子乙酰化和基因表达相关。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 靶基因如何受到差异调节的深入了解。

更新日期:2021-06-21
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