Lineage-specific transcriptional regulation of DICER by MITF in melanocytes.
DICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression--an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17 approximately 92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.
Levy
Carmit
C
Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, MA 02115, USA.
Khaled
Mehdi
M
Robinson
Kathleen C
KC
Veguilla
Rosa A
RA
Chen
Po-Hao
PH
Yokoyama
Satoru
S
Makino
Eiichi
E
Lu
Jun
J
Larue
Lionel
L
Beermann
Friedrich
F
Chin
Lynda
L
Bosenberg
Marcus
M
Song
Jun S
JS
Fisher
David E
DE
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D000078404:Epidermal Cells; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C497234:MITF protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D011518:Proto-Oncogene Proteins; D043244:Ribonuclease III