Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription.
Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription.
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组蛋白H3K9me状态在RNAi和可遗传的转录沉默中的独特作用
DOI：
10.1038/nature23267
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发表时间：
2017-07-27
期刊：
影响因子：
64.8
通讯作者：
Moazed D
中科院分区：
文献类型：
--
作者：
Jih G;Iglesias N;Currie MA;Bhanu NV;Paulo JA;Gygi SP;Garcia BA;Moazed D
异色DNA结构域通过沉默重复的DNA元件和转座子，在调节基因表达和维持基因组稳定性方面发挥着重要作用。从裂解酵母到哺乳动物，DNA重复序列上的异染色质组装涉及与RNA干扰(RNAi)途径相关的小非编码RNAs(SRNAs)的活动。通常，来自长的非编码RNA的sRNA引导含有Argavite的效应器复合体与互补的新生RNA结合，启动组蛋白H3赖氨酸9的二甲基化和三甲基化(分别为H3K9me2和H3K9me3)和异染色质的形成。H3K9me反过来又需要将RNAi招募到染色质中，以促进SRNA扩增。然而，抑制转录的异染色质的形成如何通过一种促进sRNA生成的共转录机制进行仍然是矛盾的。在这里，使用哺乳动物SUV39H H3K9甲基转移酶的裂解酵母S.pombe同源物CLR4，我们设计了阻止H3K9me3但允许H3K9me2催化的活性部位突变。我们发现H3K9me2定义了一种功能上不同的异染色质状态，足以在着丝粒周围DNA重复处发生RNAi依赖的共转录基因沉默(CTGs)。与转录沉默的H3K9me3结构域不同，H3K9me2结构域在转录上是活跃的，包含与常染色质转录相关的修饰，并将RNAi介导的转录降解与H3K9me结构域的建立结合起来。这两种H3K9me状态以不同的效率招募阅读器蛋白，解释了它们不同的下游沉默功能。此外，H3K9me结构域的RNAi非依赖表观遗传需要从H3K9me2到H3K9me3的转换。我们的发现表明，H3K9me2和H3K9me3在功能上定义了不同的染色质状态，并揭示了一种形成转录允许的异染色质的机制，该机制与其在sRNA介导的基因组防御中广泛保守的作用相一致。
Heterochromatic DNA domains play important roles in regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. From fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway. Typically, sRNAs, originating from long noncoding RNAs, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and tri-methylation (H3K9me2 and H3K9me3, respectively) and heterochromatin formation. H3K9me is in turn required for recruitment of RNAi to chromatin to promote sRNA amplification. Yet, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast S. pombe homolog of mammalian SUV39H H3K9 methyltransferases, we designed active site mutations that block H3K9me3, but allow H3K9me2 catalysis. We show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing (CTGS) at pericentromeric DNA repeats. Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Our findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct chromatin states and uncover a mechanism for formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in sRNA-mediated genome defense.
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影响因子：
16
作者：
Motamedi, Mohammad R.;Hong, Eun-Jin Erica;Li, Xue;Gerber, Scott;Denison, Carilee;Gygi, Steven;Moazed, Danesh
通讯作者：
Moazed, Danesh
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
DOI：
10.1038/nrg3355
发表时间：
2013-02
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0601676103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Recht, J;Tsubota, T;Allis, CD
通讯作者：
Allis, CD
DOI：
10.1007/s13361-016-1434-9
发表时间：
2016-10
影响因子：
3.2
作者：
Paulo, Joao A.;O'Connell, Jeremy D.;Gygi, Steven P.
通讯作者：
Gygi, Steven P.