Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis

Abstract

Summary Super-enhancers are an emerging sub-class of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and a unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.

Coactivator condensation at super-enhancers links phase separation and gene control

“…Super-enhancers (SEs) regulate genes with prominent roles in healthy and diseased cellular states (14, 15, 19–25, 49, 50). SEs and their components have been proposed to form phase-separated condensates (30), but with no direct evidence.…”

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

“…Several related possibilities exist. (a) Mutations in miR biogenesis, processing, and regulation (e.g., DROSHA, DICER, superenhancers) may cause global deregulation in miR levels (20,63), preferentially effecting miR-145 in the cell-of-origin of pten-deficient tumors. (b) Genetic and epigenetic alterations at the miR-143/145 locus may change its expression.…”

Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP

“…For metaplots around TSS, UCSC canonical genes were filtered to remove any genes that overlapped within 5 kb of the TSS. For metaplots at enhancers, we aligned against centers of all Oct4/Sox2/Nanog defined enhancer peaks (typical enhancers and super-enhancers) according to a previous report (Suzuki et al, 2017; Whyte et al, 2013). Subsequently, we filtered out any overlapping enhancers peaks within a 3 kb window and also any that overlapped a UCSC canonical gene.…”

“…Reads were aligned to the mouse genome build mm9 or human genome build hg19 using bowtie as described previously (Suzuki et al, 2017). Pausing indices were calculated as shown in Figure 6C.…”