Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Commun Biol. 2022 Apr 11;5(1):343. doi: 10.1038/s42003-022-03250-x.
Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator required for gene silencing during development. Although PRC2 is a well-established RNA-binding complex, the biological function of PRC2-RNA interaction has been controversial. Here, we study the gene-regulatory role of the inhibitory PRC2-RNA interactions. We report a nuclear long non-coding RNA, LEVER, which mapped 236 kb upstream of the β-globin cluster as confirmed by Nanopore sequencing. LEVER RNA interacts with PRC2 in its nascent form, and this prevents the accumulation of the H3K27 repressive histone marks within LEVER locus. Interestingly, the accessible LEVER chromatin, in turn, suppresses the chromatin interactions between the ε-globin locus and β-globin locus control region (LCR), resulting in a repressive effect on ε-globin gene expression. Our findings validate that the nascent RNA-PRC2 interaction inhibits local PRC2 function in situ. More importantly, we demonstrate that such a local process can in turn regulate the expression of neighboring genes.
多梳抑制复合物 2（PRC2）是一种表观遗传调节剂，在发育过程中用于基因沉默。尽管 PRC2 是一个成熟的 RNA 结合复合物，但 PRC2-RNA 相互作用的生物学功能一直存在争议。在这里，我们研究了抑制性 PRC2-RNA 相互作用的基因调控作用。我们报告了一种核长非编码 RNA，LEVER，其通过纳米孔测序确认为β-珠蛋白基因簇上游 236kb 处。LEVER RNA 与 PRC2 以其新生形式相互作用，这阻止了 H3K27 抑制性组蛋白标记在 LEVER 基因座内的积累。有趣的是，可及的 LEVER 染色质反过来抑制了 ε-珠蛋白基因座和 β-珠蛋白基因座控制区（LCR）之间的染色质相互作用，从而对 ε-珠蛋白基因表达产生抑制作用。我们的研究结果证实了新生 RNA-PRC2 相互作用抑制了局部 PRC2 功能。更重要的是，我们证明了这样一个局部过程可以反过来调节相邻基因的表达。
