Flury Valentin, Georgescu Paula Raluca, Iesmantavicius Vytautas, Shimada Yukiko, Kuzdere Tahsin, Braun Sigurd, Bühler Marc
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Biomedical Center Munich, Physiological Chemistry, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152 Planegg-Martinsried, Germany.
Mol Cell. 2017 Jul 20;67(2):294-307.e9. doi: 10.1016/j.molcel.2017.05.026. Epub 2017 Jun 22.
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.
功能不同的染色质状态的忠实传播对于维持细胞特性至关重要，其破坏会导致诸如癌症等疾病。尽管维持抑制状态的机制已得到深入研究，但保护活性染色质免受失活信号影响的调控回路仍未被充分理解。在此，我们报告了一个正反馈回路，该回路维持RNA聚合酶II转录基因的转录活性状态。我们发现Pdp3将组蛋白乙酰转移酶Mst2招募至H3K36me3标记的染色质上。由此，Mst2在全基因组范围内与所有转录活性区域结合。除了乙酰化组蛋白H3K14外，Mst2还乙酰化Brl1，后者是组蛋白H2B泛素连接酶复合物的一个组分。Brl1的乙酰化增加了组蛋白H2B的泛素化，这对转录产生正反馈并防止异位异染色质组装。我们的工作揭示了一条确保表观基因组完整性的分子途径，并突出了相反反馈回路对于将染色质划分为转录活性和非活性状态的重要性。
