Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance.
Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance.
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DOI：
10.1038/ncomms13334
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发表时间：
2016-11-14
影响因子：
16.6
通讯作者：
Earnshaw, William C.
中科院分区：
文献类型：
--
作者：
Molina, Oscar;Vargiu, Giulia;Abad, Maria Alba;Zhiteneva, Alisa;Jeyaprakash, A. Arockia;Masumoto, Hiroshi;Kouprina, Natalay;Larionov, Vladimir;Earnshaw, William C.
着丝粒由含有 CENP-A 核小体的特殊中心染色质组成，与携带转录相关修饰的 H3 核小体混合。我们设计了一种新型合成生物学“原位上位性”分析，其中赖氨酸 4 (H3K4me2) 脱甲基酶 LSD2 上的 H3 二甲基化加上具有竞争活性的合成模块同时靶向合成的 alphoidtetO HAC 着丝粒。这使我们能够将转录与着丝粒处的组蛋白修饰分开。在此，我们报告 H3K4me2 丢失会降低着丝粒转录、CENP-A 组装和稳定性，并导致 H3K9me3 在 HAC 上扩散，最终使着丝粒失活。令人惊讶的是，CENP-28/Eaf6 诱导的与 H4K12 乙酰化相关的 alphoidtetO 阵列转录并不能挽救该表型，而 p65 诱导的与 H3K9 乙酰化相关的转录确实可以挽救。因此，有丝分裂转录加上包括 H3K9ac 在内的组蛋白修饰构成了“表观遗传景观”，允许 CENP-A 组装和中心染色质维持。 H3K4me2 是转录所必需的，H3K9ac 可能形成屏障，防止异染色质扩散和人类着丝粒着丝粒失活。着丝粒是中心染色质结构域，具有携带转录相关修饰的 CENP-A 和 H3 核小体。在这里，作者将合成模块定位到着丝粒，以表明转录和组蛋白修饰是 CENP-A 组装和中心染色质维持所必需的。
Centromeres consist of specialized centrochromatin containing CENP-A nucleosomes intermingled with H3 nucleosomes carrying transcription-associated modifications. We have designed a novel synthetic biology ‘in situ epistasis' analysis in which H3 dimethylated on lysine 4 (H3K4me2) demethylase LSD2 plus synthetic modules with competing activities are simultaneously targeted to a synthetic alphoidtetO HAC centromere. This allows us to uncouple transcription from histone modifications at the centromere. Here, we report that H3K4me2 loss decreases centromeric transcription, CENP-A assembly and stability and causes spreading of H3K9me3 across the HAC, ultimately inactivating the centromere. Surprisingly, CENP-28/Eaf6-induced transcription of the alphoidtetO array associated with H4K12 acetylation does not rescue the phenotype, whereas p65-induced transcription associated with H3K9 acetylation does rescue. Thus mitotic transcription plus histone modifications including H3K9ac constitute the ‘epigenetic landscape' allowing CENP-A assembly and centrochromatin maintenance. H3K4me2 is required for the transcription and H3K9ac may form a barrier to prevent heterochromatin spreading and kinetochore inactivation at human centromeres. Centromeres are centrochromatin domains with CENP-A and H3 nucleosomes carrying transcription-associated modifications. Here the authors target synthetic modules to the centromeres to show that transcription plus histone modifications are required for CENP-A assembly and centrochromatin maintenance.
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影响因子：
4.5
作者：
Chueh, Anderly C.;Northrop, Emma L.;Brettingham-Moore, Kate H.;Choo, K. H. Andy;Wong, Lee H.
通讯作者：
Wong, Lee H.
DOI：
10.1126/science.1259308
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Falk SJ;Guo LY;Sekulic N;Smoak EM;Mani T;Logsdon GA;Gupta K;Jansen LE;Van Duyne GD;Vinogradov SA;Lampson MA;Black BE
通讯作者：
Black BE
影响因子：
4.5
作者：
Du Y;Topp CN;Dawe RK
通讯作者：
Dawe RK
影响因子：
3.5
作者：
Aldrup-Macdonald ME;Sullivan BA
通讯作者：
Sullivan BA
影响因子：
4.5
作者：
Catania S;Pidoux AL;Allshire RC
通讯作者：
Allshire RC