C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts

Abstract

MicroRNAs are tiny RNA molecules that play important regulatory roles in a broad range of developmental, physiological or pathological processes. Despite recent progress in our understanding of miRNA processing and biological functions, little is known about the regulatory mechanisms that control their expression at the transcriptional level. C19MC is the largest human microRNA gene cluster discovered to date. This 100-kb long cluster consists of 46 tandemly repeated, primate-specific pre-miRNA genes that are flanked by Alu elements (Alus) and embedded within a ∼400- to 700-nt long repeated unit. It has been proposed that C19MC miRNA genes are transcribed by RNA polymerase III (Pol-III) initiating from A and B boxes embedded in upstream Alu repeats. Here, we show that C19MC miRNAs are intron-encoded and processed by the DGCR8-Drosha (Microprocessor) complex from a previously unidentified, non-protein-coding Pol-II (and not Pol-III) transcript which is mainly, if not exclusively, expressed in the placenta.

MicroRNAs, immune cells and pregnancy

“…As a result, although many of the miRNAs found to be differentially expressed in the placenta have different targets, they may be controlled by the same promoters and work in a synergistic manner. 10,108 Three miRNA clusters have recently been assessed as potential biomarkers of placenta-related pregnancy disorders such as pre-term labor, and pre-eclampsia. These clusters include C19MC, miR-371-3 (both located on chromosome 19) and C14 (located on chromosome 14).…”

“…These clusters include C19MC, miR-371-3 (both located on chromosome 19) and C14 (located on chromosome 14). 10,108 The C19MC miRNA cluster (the most extensively researched of the three) is expressed in trophoblast and placenta-derived stromal cells. 109 Previously, three miRNAs from the C19MC family, miR517a-3P, miR519a-3P and miR-520c-3P, were found in the choriocarcinoma trophoblast cell lines JEG-3 and BeWo.…”

MicroRNA or Not MicroRNA?

“…The resulting pre-microRNA hairpin uses the exportin-5 pathway to reach the cytoplasm, where it is cleaved to generate the mature miRNA. Early reports [17] of pre-microRNAs originating from pol-III transcription have recently been refuted [18]. A survey of human pol-III transcription [19], furthermore, recovered no annotated microRNA except two mis-annotations: a vault RNA (hsa-mir-886) and the Y5 RNA (hsa-mir-1975).…”

Genome-wide impact of a recently expanded microRNA cluster in mouse

“…The Sfmbt2 cluster expansion in mouse may additionally provide a useful model for other species-and lineage-specific miRNA expansions. For instance, in humans, an analogous primate-specific miRNA expansion is present on Chromosome 19 (C19MC), with a total of 46 miRNAs within a 100-kb interval being processed from the highly repetitive intron of a maternally imprinted placental noncoding RNA (45,46). In addition to a number of novel, primate-specific seeds, this cluster includes miRNAs with the seed "AAGUGC," found in miR-371-373 (the human counterpart of the miR-290-295 cluster) (47).…”