RNA MEDIATES LONG-RANGE REGULATION OF β-GLOBIN CLUSTER BY INHIBITING EZH2

Abstract

Polycomb Repressive Complex 2 (PRC2) is an epigenetic gene repressor that plays important role in regulating cell differentiation and developmental processes. Previous studies have reported that PRC2 interacts with RNA, but the properties and biological functions of such interaction are still elusive. In this study, we evidenced previous viewpoints that PRC2 interacts with nascent RNAs in a ‘promiscuous’ manner, and this interaction inhibits PRC2 function on global scales. More importantly, we identified a novel nuclear long non-coding RNA, LEVER, which mapped upstream of the globin locus, as confirmed by Nanopore sequencing. As a PRC2-interacting nascent RNA, LEVER prevents the accumulation of the H3K27 repressive histone marks on the local chromatin, suppresses chromatin interactions between the ε-globin locus, and β-globin locus control region (LCR), thereby negatively regulating ε-globin expression. Our findings elucidate a novel pathway for globin regulation with potential implications for the treatment of β-hemoglobin disorders.