Transcriptional mechanism for the paired miR-433 and miR-127 genes by nuclear receptors SHP and ERRgamma.
MicroRNAs (miRNAs, miRs) are genomically encoded small approximately 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 (ERRgamma, 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 ERRgamma. Ectopic expression of ERRgamma induced miR-433 and miR-127 expression, which was repressed by SHP coexpression. In contrast, knockdown ERRgamma decreased miR-433 and miR-127 expression. In addition, the ERRgamma 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 ERRgamma/SHP in a compact space by using overlapping genomic regions.
Song
Guisheng
G
Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
Wang
Li
L
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D014158:Transcription, Genetic
C490916:Esrrg protein, mouse; D035683:MicroRNAs; C533109:Mirn127 microRNA, mouse; C533108:Mirn433 microRNA, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; C099713:nuclear receptor subfamily 0, group B, member 2
Annu Rev Genomics Hum Genet. 2007;8:215-39
17506656
Hepatology. 2008 Jul;48(1):289-98
18537191
Mol Cell Biol. 2007 Jun;27(12):4238-47
17438130
J Med Chem. 2005 May 5;48(9):3107-9
15857113
Hepatology. 2007 Jul;46(1):147-57
17526026
J Biol Chem. 2008 Apr 11;283(15):9674-80
18268015
PLoS One. 2007 Nov 28;2(11):e1265
18043761
Nat Rev Genet. 2008 Feb;9(2):102-14
18197166
Cell Metab. 2005 Oct;2(4):227-38
16213225
Stem Cells. 2008 Jan;26(1):17-29
17916804
Nat Genet. 2005 Jul;37(7):766-70
15965474
Nat Rev Cancer. 2006 Apr;6(4):259-69
16557279
J Biol Chem. 2002 Jan 18;277(3):1739-48
11705994
Science. 2007 Aug 31;317(5842):1220-4
17761882
Gastroenterology. 2008 Mar;134(3):793-802
18325392
Mol Cell Endocrinol. 2007 Jan 29;264(1-2):128-41
17157980
Methods. 2001 Dec;25(4):402-8
11846609
Cancer Cell. 2006 Jun;9(6):435-43
16766263
Nature. 2007 Jun 28;447(7148):1130-4
17554337
Mol Endocrinol. 2007 May;21(5):1132-47
17312270
Trends Endocrinol Metab. 2005 Dec;16(10):478-88
16275121