Zouaz Amel, Auradkar Ankush, Delfini Marie Claire, Macchi Meiggie, Barthez Marine, Ela Akoa Serge, Bastianelli Leila, Xie Gengqiang, Deng Wu-Min, Levine Stuart S, Graba Yacine, Saurin Andrew J
Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille, France.
MGX-Montpellier GenomiX c/o Institut de Génomique Fonctionnelle, Montpellier, France.
EMBO J. 2017 Oct 2;36(19):2887-2906. doi: 10.15252/embj.201695751. Epub 2017 Sep 4.
In metazoans, the pausing of RNA polymerase II at the promoter (paused Pol II) has emerged as a widespread and conserved mechanism in the regulation of gene transcription. While critical in recruiting Pol II to the promoter, the role transcription factors play in transitioning paused Pol II into productive Pol II is, however, little known. By studying how Hox transcription factors control transcription, we uncovered a molecular mechanism that increases productive transcription. We found that the Hox proteins AbdA and Ubx target gene promoters previously bound by the transcription pausing factor M1BP, containing paused Pol II and enriched with promoter-proximal Polycomb Group (PcG) proteins, yet lacking the classical H3K27me3 PcG signature. We found that AbdA binding to M1BP-regulated genes results in reduction in PcG binding, the release of paused Pol II, increases in promoter H3K4me3 histone marks and increased gene transcription. Linking transcription factors, PcG proteins and paused Pol II states, these data identify a two-step mechanism of Hox-driven transcription, with M1BP binding leading to Pol II recruitment followed by AbdA targeting, which results in a change in the chromatin landscape and enhanced transcription.
在多细胞动物中，RNA聚合酶II在启动子处的暂停（暂停的Pol II）已成为基因转录调控中一种广泛且保守的机制。虽然转录因子在将Pol II招募到启动子方面至关重要，但它们在将暂停的Pol II转变为有活性的Pol II过程中所起的作用却鲜为人知。通过研究Hox转录因子如何控制转录，我们发现了一种增加有活性转录的分子机制。我们发现Hox蛋白AbdA和Ubx靶向先前被转录暂停因子M1BP结合的基因启动子，这些启动子含有暂停的Pol II并富含启动子近端的多梳蛋白家族（PcG）蛋白，但缺乏经典的H3K27me3 PcG标记。我们发现AbdA与M1BP调控基因的结合导致PcG结合减少、暂停的Pol II释放、启动子H3K4me3组蛋白标记增加以及基因转录增加。这些数据将转录因子、PcG蛋白和暂停的Pol II状态联系起来，确定了Hox驱动转录的两步机制，即M1BP结合导致Pol II招募，随后是AbdA靶向，这导致染色质景观的改变和转录增强。
