Abstract
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.
Publication types
-
Research Support, N.I.H., Intramural
MeSH terms
-
3' Untranslated Regions / genetics
-
Animals
-
Cell Differentiation / drug effects
-
Cell Differentiation / physiology
-
Cell Line
-
Embryo, Mammalian / metabolism
-
Embryonic Stem Cells / cytology
-
Embryonic Stem Cells / drug effects
-
Embryonic Stem Cells / metabolism*
-
Enhancer of Zeste Homolog 2 Protein
-
Epigenesis, Genetic / genetics
-
Feedback, Physiological / physiology
-
Gene Expression / genetics
-
Gene Expression Regulation, Developmental / physiology*
-
Histone-Lysine N-Methyltransferase / genetics
-
Histone-Lysine N-Methyltransferase / metabolism*
-
Liver / metabolism
-
Mice
-
Mice, Inbred C57BL
-
MicroRNAs / genetics
-
MicroRNAs / metabolism
-
MicroRNAs / physiology*
-
Models, Biological
-
Muscle Development / physiology
-
Muscle Fibers, Skeletal / cytology
-
Muscle Fibers, Skeletal / metabolism
-
Muscle, Skeletal / cytology
-
Muscle, Skeletal / embryology
-
Muscle, Skeletal / growth & development
-
Muscle, Skeletal / metabolism*
-
MyoD Protein / genetics
-
MyoD Protein / metabolism
-
Myoblasts, Skeletal / cytology
-
Myoblasts, Skeletal / metabolism
-
Myogenin / genetics
-
Myogenin / metabolism
-
Polycomb Repressive Complex 2
-
Transcription Factors / metabolism
-
Tretinoin / pharmacology
Substances
-
3' Untranslated Regions
-
MicroRNAs
-
Mirn199 microRNA, mouse
-
Mirn214 microRNA, mouse
-
MyoD Protein
-
MyoD1 myogenic differentiation protein
-
Myog protein, mouse
-
Myogenin
-
Transcription Factors
-
Tretinoin
-
Enhancer of Zeste Homolog 2 Protein
-
Ezh2 protein, mouse
-
Histone-Lysine N-Methyltransferase
-
Polycomb Repressive Complex 2