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Nucleic Acids Research Advance Access published online on September 6, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn567
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene regulation, Chromatin and Epigenetics

Transcriptional mechanism for the paired miR-433 and miR-127 genes by nuclear receptors SHP and ERR{gamma}

Guisheng Song1,2 and Li Wang1,2,*

1Department of Medicine and 2Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA

*To whom correspondence should be addressed. Tel: +1 801 58 74 61 6; Fax: +1 801 58 79 41 5; Email: l.wang{at}hsc.utah.edu

Received June 13, 2008. Revised August 15, 2008. Accepted August 21, 2008.

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 (ERR{gamma}, 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 ERR{gamma}. Ectopic expression of ERR{gamma} induced miR-433 and miR-127 expression, which was repressed by SHP coexpression. In contrast, knockdown ERR{gamma} decreased miR-433 and miR-127 expression. In addition, the ERR{gamma} 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 ERR{gamma}/SHP in a compact space by using overlapping genomic regions.


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