小柯机器人

美国威尔康奈尔医学院Ari M. Melnick研究团队的研究发现组蛋白H1缺失通过破坏三维（3D）染色质结构诱导淋巴瘤发生。该项研究成果在线发表在2020年12月9日出版的《自然》上。

在本研究中，研究人员发现淋巴瘤相关H1等位基因是淋巴瘤中遗传诱导的基因突变。破坏H1的功能导致基因组产生结构重塑，其特征是大量染色质从紧实到松弛状态的改变。这种松弛作用造成表观遗传发生明显变化，这主要是由于组蛋白36位赖氨酸（H3K36me2）二甲基化增加和/或抑制性组蛋白27位赖氨酸（H3K27me3）三甲基化缺失造成的。这些变化导致通常在早期发育过程中沉默的干细胞基因表达。在小鼠中，H1c和H1e（分别也称为H1f2和H1f4）的缺失导致生发中心B细胞的适应性增强和自我更新，最终造成侵袭性淋巴瘤繁殖潜力的增加。

总体而言，该研究数据表明，通常需要组蛋白H1才能将早期发育的基因隔离到在结构上难以接近的基因组区室中。该研究还证明H1是真正的肿瘤抑制因子，并证明H1的突变主要通过三维基因组重构来促进恶性转化，从而导致表观遗传重编程和抑制发育沉默基因。

研究人员表示，接头组蛋白H1与核小体结合并促进染色质收缩，然而对其生物学功能了解甚少。编码H1亚型B–E基因中的突变（H1B、H1C、H1D和H1E；分别称为H1-5、H1-2、H1-3和H1-4）在B细胞淋巴瘤中高度发生。尚不清楚这些突变与癌症发生的相关性及其涉及的机制。

附：英文原文

Title: Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Author: Nevin Yusufova, Andreas Kloetgen, Matt Teater, Adewola Osunsade, Jeannie M. Camarillo, Christopher R. Chin, Ashley S. Doane, Bryan J. Venters, Stephanie Portillo-Ledesma, Joseph Conway, Jude M. Phillip, Olivier Elemento, David W. Scott, Wendy Bguelin, Jonathan D. Licht, Neil L. Kelleher, Louis M. Staudt, Arthur I. Skoultchi, Michael-Christopher Keogh, Effie Apostolou, Christopher E. Mason, Marcin Imielinski, Tamar Schlick, Yael David, Aristotelis Tsirigos, C. David Allis, Alexey A. Soshnev, Ethel Cesarman, Ari M. Melnick

Issue&Volume: 2020-12-09

Abstract: Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B–E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms that are involved are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in a profound architectural remodelling of the genome, which is characterized by large-scale yet focal shifts of chromatin from a compacted to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily owing to a gain of histone H3 dimethylation at lysine 36 (H3K36me2) and/or loss of repressive H3 trimethylation at lysine 27 (H3K27me3). These changes unlock the expression of stem cell genes that are normally silenced during early development. In mice, loss of H1c and H1e (also known as H1f2 and H1f4, respectively) conferred germinal centre B cells with enhanced fitness and self-renewal properties, ultimately leading to aggressive lymphomas with an increased repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We also establish H1 as a bona fide tumour suppressor and show that mutations in H1 drive malignant transformation primarily through three-dimensional genome reorganization, which leads to epigenetic reprogramming and derepression of developmentally silenced genes.

DOI: 10.1038/s41586-020-3017-y

Source: https://www.nature.com/articles/s41586-020-3017-y

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