Non-coding RNA LEVER sequestration of PRC2 can mediate long range gene regulation

Identification of a long non-coding RNA LEVER, that inhibits the Polycomb Repressive Complex 2 (PRC2) and controls nearby embryonic form of beta-globin gene, provides additional evidence for PRC2-RNA functional interaction. 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 beta-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 epsilon-globin locus and beta-globin locus control region (LCR), resulting in a repressive effect on epsilon-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.

Automated summary

This study identified a long non-coding RNA (LEVER) that inhibits the Polycomb Repressive Complex 2 (PRC2) and controls nearby embryonic form of beta-globin gene. The findings provide additional evidence for the functional interaction between PRC2 and RNA. The study reveals the gene-regulatory role of PRC2-RNA interactions and demonstrates the ability of a local process to regulate the expression of neighboring genes.