Silencing the genome with linker histones
Silencing the genome with linker histones
复制标题
用连接组蛋白沉默基因组
DOI：
10.1073/pnas.2009513117
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hansen, Jeffrey C.
中科院分区：
文献类型：
--
作者：
Hansen, Jeffrey C.
真核生物基因组的核心是一种核蛋白复合体，称为染色质。染色质的亚基是核小体，它是由146个碱基的DNA包裹在核心组蛋白(H_2A、H_2B、H_3和H_4)的八聚体周围形成的。由中间连接的DNA片段连接的核小体阵列以其最简单的形式表示染色质纤维。实际上，包含基因组某一特定区域的染色质纤维与一组独特的蛋白质相关联，这些蛋白质规定了该染色质区域的功能。例如，活性基因的常染色质将与转录因子、染色质重构体和染色质修饰酶结合。另一方面，被构成异染色质转录沉默的基因将与组蛋白H3赖氨酸9三甲基化(H3K9me3)标记的核小体组装在一起，并与HP1和其他蛋白质结合。虽然结构性异染色质和转录沉默之间的联系已经确定，但沉默是如何实现的还不是很清楚。在PNAS中，Healton等人(1)表明连接物组蛋白H1富含在构成异染色质中，该构成异染色质可以沉默小鼠胚胎干细胞(MESCs)中的重复元件，并且H1的急性缺失导致重复元件基因表达的大幅下调。令人惊讶的是，H1通过两种根本不同的机制发挥作用，一种涉及H1-蛋白质相互作用，另一种涉及调控异染色质结构域的高阶结构(图1)。这些结果对连接子组蛋白在染色质中的作用提出了新的问题。连接子组蛋白是大多数真核基因组中最丰富的染色质相关蛋白，每个核小体平均有0.5到1.3个H1，取决于细胞类型[2]。在体细胞中存在7种H1序列变体。所有变体都具有相同的一般结构，如图1所示。中心∼80残基折叠成球状的有翼螺旋基序，而∼35-残基的N-末端结构域和长∼100-残基的C-末端结构域无序。H1通过其有翼的螺旋结构域与核小体结合。斯库尔奇实验室以前的研究表明，小鼠的正常发育需要连接器组蛋白(3)。如果一个或两个变种的基因被敲除，由于其余变种的表达增加，正常的核H1水平保持不变。然而，当三个变异基因(H1c/d/e)被敲除时，小鼠表现出胚胎致死性(3)。虽然普遍存在，但接头组蛋白在整个基因组中的分布并不均匀。例如，在包含转录活性基因启动子(5，6)的染色质中，连接物组蛋白水平降低。相反，Healton等人(1)感兴趣的是识别基因组中富含连接子组蛋白的那些区域。他们使用ISOR算法分析了H1d变体的现有染色质免疫沉淀序列数据，发现它显著富含带有H3K9me3修饰的染色质，这是结构性异染色质的标志。同样，浓缩铀
Eukaryotic genomes at their core consist of a nucleoprotein complex termed chromatin. The subunit of chromatin is the nucleosome, which is formed from 146 bp of DNA wrapped around an octamer of core histone proteins (H2A, H2B, H3, and H4). An array of nucleosomes connected by intervening linker DNA segments represents the chromatin fiber in its simplest form. In reality, the chromatin fiber that encompasses a given region of the genome is associated with a distinctive set of proteins that specify the functionality of that chromatin region. For example, the euchromatin of an active gene will be bound to transcription factors, chromatin remodelers, and chromatinmodifying enzymes. On the other hand, a gene that is transcriptionally silenced by constitutive heterochromatin will be assembled with nucleosomes marked by histone H3 lysine 9 trimethylation (H3K9me3) and bound to HP1 and other proteins. While the connection between constitutive heterochromatin and transcriptional silencing is well established, how silencing is achieved is not well understood. In PNAS, Healton et al.(1) show that linker histone H1 is enriched in the constitutive heterochromatin that silences repetitive elements in mouse embryonic stem cells (mESCs), and that acute depletion of H1 leads to substantial derepression of repetitive element gene expression. Surprisingly, H1 exerts its effects through two fundamentally different mechanisms, one involving H1–protein interactions and the other involving modulation of the higher-order structure of heterochromatin domains (Fig. 1). These results raise new questions regarding how linker histones function in chromatin.Linker histones are the most abundant chromatinassociated proteins in most eukaryotic genomes, with an average of 0.5 to 1.3 H1 per nucleosome depending on cell type (2). There are seven H1 sequence variants in somatic cells. All variants share the same general structure shown in Fig. 1. The central∼ 80 residues fold into a globular winged helix motif while the∼ 35-residue N-terminal domain and the long∼ 100-residue C-terminal domain (CTD) are disordered. H1 binds to the nucleosome via its winged helix domain. Previous studies from the Skoultchi laboratory have shown that linker histones are required for proper development in mice (3). If the genes for one or two variants are knocked out, normal nuclear H1 levels are maintained due to increased expression of the remaining variants (4). However, when three variant genes (H1c/d/e) are knocked out, mice display embryonic lethality (3). Although ubiquitous, the distribution of linker histones throughout the genome is not uniform. For instance, linker histone levels are reduced in the chromatin that encompasses transcriptionally active gene promoters (5, 6). In contrast, Healton et al.(1) were interested in identifying those regions of the genome that were enriched in linker histones. They used the ISOR algorithm to analyze available chromatin immunoprecipitation-sequence data for the H1d variant and found that it was significantly enriched in chromatin bearing the H3K9me3 modification, a hallmark of constitutive heterochromatin. Similarly, enrichment of
影响因子：
8.8
作者：
Izzo, Annalisa;Kamieniarz-Gdula, Kinga;Schneider, Robert
通讯作者：
Schneider, Robert