Balas Maggie M, Hartwick Erik W, Barrington Chloe, Roberts Justin T, Wu Stephen K, Bettcher Ryan, Griffin April M, Kieft Jeffrey S, Johnson Aaron M
Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Sci Adv. 2021 Apr 14;7(16). doi: 10.1126/sciadv.abc9191. Print 2021 Apr.
Human Polycomb Repressive Complex 2 (PRC2) catalysis of histone H3 lysine 27 methylation at certain loci depends on long noncoding RNAs (lncRNAs). Yet, in apparent contradiction, RNA is a potent catalytic inhibitor of PRC2. Here, we show that intermolecular RNA-RNA interactions between the lncRNA HOTAIR and its targets can relieve RNA inhibition of PRC2. RNA bridging is promoted by heterogeneous nuclear ribonucleoprotein B1, which uses multiple protein domains to bind HOTAIR regions via multivalent protein-RNA interactions. Chemical probing demonstrates that establishing RNA-RNA interactions changes HOTAIR structure. Genome-wide HOTAIR/PRC2 activity occurs at genes whose transcripts can make favorable RNA-RNA interactions with HOTAIR. We demonstrate that RNA-RNA matches of HOTAIR with target gene RNAs can relieve the inhibitory effect of a single lncRNA for PRC2 activity after B1 dissociation. Our work highlights an intrinsic switch that allows PRC2 activity in specific RNA contexts, which could explain how many lncRNAs work with PRC2.
人类多梳抑制复合物2（PRC2）在某些位点对组蛋白H3赖氨酸27的甲基化催化作用依赖于长链非编码RNA（lncRNA）。然而，明显矛盾的是，RNA是PRC2的一种强效催化抑制剂。在此，我们表明lncRNA HOTAIR与其靶标之间的分子间RNA-RNA相互作用能够解除RNA对PRC2的抑制作用。异质性核核糖核蛋白B1促进RNA桥接，该蛋白通过多价蛋白质-RNA相互作用利用多个蛋白质结构域结合HOTAIR区域。化学探针实验表明，建立RNA-RNA相互作用会改变HOTAIR的结构。全基因组范围内，HOTAIR/PRC2活性出现在其转录本能够与HOTAIR形成有利RNA-RNA相互作用的基因上。我们证明，HOTAIR与靶基因RNA的RNA匹配能够在B1解离后解除单个lncRNA对PRC2活性的抑制作用。我们的研究突出了一种内在开关，该开关在特定RNA环境中允许PRC2发挥活性，这可以解释众多lncRNA如何与PRC2协同发挥作用。
