CRAMP1 drives linker histone expression to enable Polycomb repression

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rachael E. Matthews, Joshua Miguel C. Danac, Emily L. Naden, Laura E. Farleigh Smith, Sri Lestari, Akhila Gungi, Alex Appert, Toby Buttress, Ankit Verma, Oliver Sinclair, Faye Chong, John Suberu, Robin Antrobus, Boyan Bonev, Mark A. Dawson, Adam J. Reid, Richard T. Timms, Julie Ahringer, Iva A. Tchasovnikarova
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引用次数: 0

Abstract

In contrast to the well-understood role of core histones in DNA packaging, the function of the linker histone (H1) remains enigmatic. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for H1 in Polycomb repressive complex 2 (PRC2) function. A CRISPR-Cas9 genetic screen using a fluorescent PRC2 reporter identified an essential role for the poorly characterized gene CRAMP1 in PRC2-mediated repression. CRAMP1 localizes to the promoters of expressed H1 genes and positively regulates their transcription. CRAMP1 ablation simultaneously depletes all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, we find that linker histones preferentially localize to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, these data demonstrate a prominent role for linker histones in epigenetic repression by PRC2.

Abstract Image

CRAMP1驱动连接体组蛋白表达,从而抑制Polycomb
与核心组蛋白在DNA包装中的作用相比,连接组蛋白(H1)的功能仍然是谜。挑战连接组蛋白是异染色质的普遍特征的流行观点,这里我们显示了Polycomb抑制复合体2 (PRC2)功能中H1的关键要求。使用荧光PRC2报告基因的CRISPR-Cas9基因筛选发现,在PRC2介导的抑制中,特征不明显的基因CRAMP1发挥了重要作用。CRAMP1定位于表达H1基因的启动子,并积极调节其转录。CRAMP1消融同时消耗所有连接蛋白,导致h3k27me3标记位点的选择性分解和PRC2靶基因的抑制,而不伴随PRC2占用或酶活性的丧失。引人注目的是,我们发现在不同的细胞类型和生物体中,连接蛋白优先定位于H3K27me3标记的基因组位点。总之,这些数据表明连接蛋白在PRC2的表观遗传抑制中起着重要作用。
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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
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