Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity.
Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity.
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DOI：
10.1371/journal.pgen.1002175
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
West AG
中科院分区：
文献类型：
--
作者：
Ma MK;Heath C;Hair A;West AG
染色质修饰的基因组图谱为将基因组划分为不同染色质状态的域提供了证据，这有助于协调基因调控。染色质结构域完整性的维持可能需要边界的设置。HS4绝缘子元件标记了位于鸡β-珠蛋白基因簇上游的异染色质区域的3 ′边界。在这里，我们表明，HS4招募E3连接酶RNF20/BRE1A介导H2B单泛素化（H2Bub1）在这个绝缘子。敲除实验表明RNF20是H2Bub1和进行性H3K4甲基化所必需的。RNF20的消耗导致HS4染色质边界处的活性组蛋白修饰特征的崩溃，其中H2Bub1、H3K4甲基化以及H3、H4和H2A.Z的超乙酰化迅速丢失。在FOLR1基因的HSA/HSB调控元件上发生了一组非常相似的事件，它们标志着同一异染色质区域的5 ′边界。我们发现，持久的H2Bub1在HSA/HSB和HS4元素是必需的染色质边界的完整性。边界功能的丧失导致H3K9me2、H3K9me3和H4K20me3在整个50 kb F0LR1和β-珠蛋白区域上的顺序扩散以及F0LR1表达的沉默。这些发现表明，HSA/HSB和HS4边界元件指导了一系列活性组蛋白修饰，这些修饰保护了FOLR1和β-珠蛋白基因座免受相邻异染色质结构域的普遍侵蚀。我们建议，许多基因位点采用H2Bub1依赖的边界，以防止异染色质扩散。真核生物中基因的转录发生在染色质的背景下，染色质是DNA、组蛋白和调节因子的复合物。染色质蛋白和组蛋白的全基因组分析表明，基因组被组织成不同染色质状态的结构域，协调基因调控。染色质结构域的完整性可能需要设置它们的边界。被称为染色质绝缘子或边界元件的DNA序列可以在转录允许和抑制染色质结构域之间建立边界。我们已经研究了两个染色质边界元件，侧面分别位于鸡FOLR1和β-珠蛋白基因之间的浓缩染色质区域。这些元件募集介导组蛋白H2B泛素化的酶。组蛋白H2B泛素化指导了一系列所谓的"主动"组蛋白修饰事件，这些事件有利于染色质的可及性。我们观察到一个显着的崩溃的活性组蛋白修饰签名在两个染色质边界后，泛素化的H2B的耗尽。这种边界功能的丧失导致抑制性染色质在整个FOLR 1和β-球蛋白基因区域上全面扩散，从而导致基因沉默。我们提出，在许多基因位点的染色质边界采用H2B泛素化，以限制抑制性染色质的侵入。
Genomic maps of chromatin modifications have provided evidence for the partitioning of genomes into domains of distinct chromatin states, which assist coordinated gene regulation. The maintenance of chromatin domain integrity can require the setting of boundaries. The HS4 insulator element marks the 3′ boundary of a heterochromatin region located upstream of the chicken β-globin gene cluster. Here we show that HS4 recruits the E3 ligase RNF20/BRE1A to mediate H2B mono-ubiquitination (H2Bub1) at this insulator. Knockdown experiments show that RNF20 is required for H2Bub1 and processive H3K4 methylation. Depletion of RNF20 results in a collapse of the active histone modification signature at the HS4 chromatin boundary, where H2Bub1, H3K4 methylation, and hyperacetylation of H3, H4, and H2A.Z are rapidly lost. A remarkably similar set of events occurs at the HSA/HSB regulatory elements of the FOLR1 gene, which mark the 5′ boundary of the same heterochromatin region. We find that persistent H2Bub1 at the HSA/HSB and HS4 elements is required for chromatin boundary integrity. The loss of boundary function leads to the sequential spreading of H3K9me2, H3K9me3, and H4K20me3 over the entire 50 kb FOLR1 and β-globin region and silencing of FOLR1 expression. These findings show that the HSA/HSB and HS4 boundary elements direct a cascade of active histone modifications that defend the FOLR1 and β-globin gene loci from the pervasive encroachment of an adjacent heterochromatin domain. We propose that many gene loci employ H2Bub1-dependent boundaries to prevent heterochromatin spreading. The transcription of genes in eukaryotes occurs within the context of chromatin, a complex of DNA, histone proteins, and regulatory factors. Whole-genome profiling of chromatin proteins and histones that are post-translationally modified has revealed that genomes are organized into domains of distinct chromatin states that coordinate gene regulation. The integrity of chromatin domains can require the setting of their boundaries. DNA sequences known as chromatin insulator or boundary elements can establish boundaries between transcriptionally permissive and repressive chromatin domains. We have studied two chromatin boundary elements that flank a condensed chromatin region located between the chicken FOLR1 and β-globin genes, respectively. These elements recruit enzymes that mediate the ubiquitination of histone H2B. Histone H2B ubiquitination directs a cascade of so-called “active” histone modification events that favor chromatin accessibility. We observe a striking collapse of the active histone modification signature at both chromatin boundaries following the depletion of ubiquitinated H2B. This loss of boundary function leads to the comprehensive spreading of repressive chromatin over the entire FOLR1 and β-globin gene region, resulting in gene silencing. We propose that chromatin boundaries at many gene loci employ H2B ubiquitination to restrict the encroachment of repressive chromatin.
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DOI：
10.1073/pnas.94.2.575
发表时间：
1997-01-21
影响因子：
11.1
作者：
Chung, JH;Bell, AC;Felsenfeld, G
通讯作者：
Felsenfeld, G
过乙酰化形式的替换组蛋白H2A.Z是鸡肉中活性基因的特征。
影响因子：
14.9
作者：
Bruce K;Myers FA;Mantouvalou E;Lefevre P;Greaves I;Bonifer C;Tremethick DJ;Thorne AW;Crane-Robinson C
通讯作者：
Crane-Robinson C
影响因子：
5.3
作者：
Chandrasekharan, Mahesh B.;Huang, Fu;Sun, Zu-Wen
通讯作者：
Sun, Zu-Wen
影响因子：
21.3
作者：
Giles, Keith E.;Ghirlando, Rodolfo;Felsenfeld, Gary
通讯作者：
Felsenfeld, Gary
影响因子：
64.5
作者：
CHUNG, JH;WHITELEY, M;FELSENFELD, G
通讯作者：
FELSENFELD, G