U1 snRNP regulates chromatin retention of noncoding RNAs

Abstract

Thousands of noncoding transcripts exist in mammalian genomes, and they preferentially localize to chromatin. Here, to identify cis-regulatory elements that control RNA-chromatin association, we developed a high-throughput method named RNA element for subcellular localization by sequencing (REL-seq). Coupling REL-seq with random mutagenesis (mutREL-seq), we discovered a key 7-nt U1 recognition motif in chromatin-enriched RNA elements. Reporter assays indicated a direct role for U1 snRNP recognition in regulating RNA-chromatin localization. Globally, U1 motifs and U1 binding are strongly enriched in long noncoding RNA (lncRNA) transcripts. Inhibition of U1 snRNA, and of U2 to a lesser degree, led to global reduction in chromatin association of hundreds of lncRNAs. For promoter- and enhancer-associated noncoding RNAs, U1 binds to their genomic neighborhoods, and their chromatin association depends on both U1 and U2 snRNAs. These findings reveal that U1 snRNP, perhaps together with the splicing machinery, acts widely to promote the chromatin association of noncoding transcripts.