title: Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c.
abstract: The myogenic regulatory factor MyoD has been implicated as a key regulator of myogenesis, and yet there is little information regarding its upstream regulators. We found that Deltex2 inhibits myogenic differentiation in vitro, and that skeletal muscle stem cells from Deltex2 knockout mice exhibit precocious myogenic differentiation and accelerated regeneration in response to injury. Intriguingly, Deltex2 inhibits myogenesis by suppressingMyoDtranscription, and the Deltex2 knockout phenotype can be rescued by a loss-of-function allele forMyoDIn addition, we obtained evidence that Deltex2 regulates MyoD expression by promoting the enrichment of histone 3 modified by dimethylation at lysine 9 at a key regulatory region of theMyoDlocus. The enrichment is attributed to a Deltex2 interacting protein, Jmjd1c, whose activity is directly inhibited by Deltex2 and whose expression is required for MyoD expression in vivo and in vitro. Finally, we find that Deltex2 causes Jmjd1c monoubiquitination and inhibits its demethylase activity. Mutation of the monoubiquitination site in Jmjd1c abolishes the inhibitory effect of Deltex2 on Jmjd1c demethylase activity. These results reveal a mechanism by which a member of the Deltex family of proteins can inhibit cellular differentiation, and demonstrate a role of Deltex in the epigenetic regulation of myogenesis.
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Dan
authors.identifier: 0000-0001-8134-4312
authors.initials: D
authors.lastname: Luo
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Antoine
authors.identifier: 0000-0002-8316-4531
authors.initials: A
authors.lastname: de Morree
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Stephane
authors.initials: S
authors.lastname: Boutet
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Navaline
authors.initials: N
authors.lastname: Quach
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Vanita
authors.initials: V
authors.lastname: Natu
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Arjun
authors.initials: A
authors.lastname: Rustagi
authors.affiliation: The Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305; rando@stanford.edu.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.|Neurology Service, VA Palo Alto Health Care System, Palo Alto, CA 94304.|Research Enhancement Award Program (REAP), Rehabilitation Research & Development Service, VA Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D017385:Sequence Homology; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C554520:JMJD1c protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C514629:Dtx2 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Deltex2; Jmjd1c; MyoD; differentiation; myoblast