title: Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis.
abstract: Although the two catalytic subunits of the SWI/SNF chromatin-remodeling complex--Brahma (Brm) and Brg1--are almost invariably co-expressed, their mutually exclusive incorporation into distinct SWI/SNF complexes predicts that Brg1- and Brm-based SWI/SNF complexes execute specific functions. Here, we show that Brg1 and Brm have distinct functions at discrete stages of muscle differentiation. While Brg1 is required for the activation of muscle gene transcription at early stages of differentiation, Brm is required for Ccnd1 repression and cell cycle arrest prior to the activation of muscle genes. Ccnd1 knockdown rescues the ability to exit the cell cycle in Brm-deficient myoblasts, but does not recover terminal differentiation, revealing a previously unrecognized role of Brm in the activation of late muscle gene expression independent from the control of cell cycle. Consistently, Brm null mice displayed impaired muscle regeneration after injury, with aberrant proliferation of satellite cells and delayed formation of new myofibers. These data reveal stage-specific roles of Brm during skeletal myogenesis, via formation of repressive and activatory SWI/SNF complexes.
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Albini
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho Toto
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dall'Agnese
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
authors.forename: Barbora
authors.initials: B
authors.lastname: Malecova
authors.affiliation: CNR-Istituto di Farmacologia Traslazionale, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cenciarelli
authors.affiliation: CNR-Istituto di Biologia Cellulare e Neurobiologia Fondazione Santa Lucia, Rome, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Felsani
authors.affiliation: CNR-Istituto di Biologia Cellulare e Neurobiologia Fondazione Santa Lucia, Rome, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Caruso
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
authors.affiliation: Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA IRCCS Fondazione Santa Lucia, Rome, Italy lpuri@sanfordburnham.org.
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D051379:Mice; D032342:Muscle Cells; D024510:Muscle Development / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C530105:Ccnd1 protein, mouse; D009687:Nuclear Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Brahma; SNF/SWI; cyclin D1; skeletal myogenesis; transcription