Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells.
Polycomb group (PcG) proteins exert essential functions in the most disparate biological processes. The contribution of PcG proteins to cell commitment and differentiation relates to their ability to repress transcription of developmental regulators in embryonic stem (ES) cells and in committed cell lineages, including skeletal muscle cells (SMC). PcG proteins are preferentially removed from transcribed regions, but the underlying mechanisms remain unclear. Here, PcG proteins are found to occupy and repress transcription from an intronic region containing the microRNA miR-214 in undifferentiated SMC. Differentiation coincides with PcG disengagement, recruitment of the developmental regulators MyoD and myogenin, and activation of miR-214 transcription. Once transcribed, miR-214 negatively feeds back on PcG by targeting the Ezh2 3'UTR, the catalytic subunit of the PRC2 complex. miR-214-mediated Ezh2 protein reduction accelerates SMC differentiation and promotes unscheduled transcription of developmental regulators in ES cells. Thus, miR-214 and Ezh2 establish a regulatory loop controlling PcG-dependent gene expression during differentiation.
Juan
Aster H
AH
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kumar
Roshan M
RM
Marx
Joseph G
JG
Young
Richard A
RA
Sartorelli
Vittorio
V
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004622:Embryo, Mammalian / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology; D015870:Gene Expression / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D024510:Muscle Development / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D020413:3' Untranslated Regions; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; C534781:Mirn214 microRNA, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D018008:Myogenin; D014157:Transcription Factors; D014212:Tretinoin; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2