Transcriptional mechanism for the paired miR-433 and miR-127 genes by nuclear receptors SHP and ERRγ

MicroRNAs (miRNAs, miRs) are genomically encoded small ∼22 nt RNA molecules that have been shown to mediate translational repression of target mRNAs involved in cellular proliferation, differentiation and death. Despite intensive studies on their physiological and pathological functions, the molecular mechanism of how miRNA gene transcription is regulated remains largely unknown. Microarray profiling revealed 21 miRNAs clustered on chromosome 12, including miR-433 and miR-127, that were co-upregulated in small heterodimer partner (SHP, NR0B2) SHP knockouts (SHP^-/-) liver. Gene cloning revealed that the 3′-coding region of pri-miR-433 served as the promoter region of pri-miR-127. Estrogen related receptor (ERRγ, NR3B3) robustly activated miR-433 and miR-127 promoter reporters through ERRE, which was transrepressed by SHP. The strong elevation of miR-433 and miR-127 in Hepa-1 cells correlated with the down-regulation of SHP and up-regulation of ERRγ. Ectopic expression of ERRγ induced miR-433 and miR-127 expression, which was repressed by SHP coexpression. In contrast, knockdown ERRγ decreased miR-433 and miR-127 expression. In addition, the ERRγ agonist GSK4716 induced miR-433 and miR-127 expression both in vitro and in vivo, respectively. In summary, the coupled miR-433 and miR-127 genes were transcribed from independent promoters regulated by nuclear receptors ERRγ/SHP in a compact space by using overlapping genomic regions.