The Histone Acetyltransferase Mst2 Protects Active Chromatin from Epigenetic Silencing by Acetylating the Ubiquitin Ligase Brl1.
The Histone Acetyltransferase Mst2 Protects Active Chromatin from Epigenetic Silencing by Acetylating the Ubiquitin Ligase Brl1.
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DOI：
10.1016/j.molcel.2017.05.026
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发表时间：
2017-07-20
期刊：
影响因子：
16
通讯作者：
Bühler M
中科院分区：
文献类型：
--
作者：
Flury V;Georgescu PR;Iesmantavicius V;Shimada Y;Kuzdere T;Braun S;Bühler M
功能不同的染色质状态的忠实传播对于维持细胞身份至关重要，它的破坏可能导致癌症等疾病。尽管维持压抑状态的机制已经被深入研究，但保护活性染色质免受失活信号影响的调节回路还没有得到很好的理解。在这里，我们报告了一个正反馈循环，可以保留RNA聚合酶II转录基因的转录能力状态。我们发现Pdp3将组蛋白乙酰转移酶Mst 2募集到H3K36me3标记的染色质。因此，Mst 2结合到全基因组的所有转录活性区域。除了乙酰化组蛋白H3K14之外，Mst 2还乙酰化组蛋白H2B泛素连接酶复合物的组分Brl1。Brl1乙酰化增加组蛋白H2B泛素化，其正反馈于转录并防止异位异染色质组装。我们的工作揭示了一个分子途径，确保表观基因组的完整性，并强调了对染色质的转录活性和非活性状态的分区的重要性，反对反馈回路。组蛋白乙酰转移酶Mst 2乙酰化泛素连接酶Brl1 Brl1乙酰化抑制RNAi引导的异染色质形成的起始H3K36me3隔离Mst 2以防止异染色质的非法激活不同染色质状态的划分对于维持细胞身份是至关重要的。Flury等人证明了将乙酰转移酶复合物锚定到活跃转录的基因上可以保护常染色质免于转化为异染色质。该机制通过涉及非组蛋白靶标的乙酰化的正反馈回路起作用，乙酰化反过来介导组蛋白泛素化。
Faithful propagation of functionally distinct chromatin states is crucial for maintaining cellular identity, and its breakdown can lead to diseases such as cancer. Whereas mechanisms that sustain repressed states have been intensely studied, regulatory circuits that protect active chromatin from inactivating signals are not well understood. Here we report a positive feedback loop that preserves the transcription-competent state of RNA polymerase II-transcribed genes. We found that Pdp3 recruits the histone acetyltransferase Mst2 to H3K36me3-marked chromatin. Thereby, Mst2 binds to all transcriptionally active regions genome-wide. Besides acetylating histone H3K14, Mst2 also acetylates Brl1, a component of the histone H2B ubiquitin ligase complex. Brl1 acetylation increases histone H2B ubiquitination, which positively feeds back on transcription and prevents ectopic heterochromatin assembly. Our work uncovers a molecular pathway that secures epigenome integrity and highlights the importance of opposing feedback loops for the partitioning of chromatin into transcriptionally active and inactive states. A positive feedback loop maintains euchromatic genes in an active state The histone acetyltransferase Mst2 acetylates the ubiquitin ligase Brl1 Brl1 acetylation inhibits initiation of RNAi-directed heterochromatin formation H3K36me3 sequesters Mst2 to prevent illegitimate activation of heterochromatin The partitioning of distinct chromatin states is crucial for maintaining cellular identity. Flury et al. demonstrate that anchoring an acetyltransferase complex to actively transcribed genes protects euchromatin from transformation into heterochromatin. This mechanism acts through a positive feedback loop that involves acetylation of a non-histone target, which in turn mediates histone ubiquitylation.
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