ACTL6a Enforces the Epidermal Progenitor State by Suppressing SWI/SNF-Dependent Induction of KLF4
ABSTRACT Somatic progenitors suppress differentiation to maintain tissue self-renewal. The mammalian SWI/SNF chromatin-remodeling complex regulates nucleosome packaging to control differentiation in embryonic and adult stem cells. Catalytic Brg1 and Brm subunits are required for these processes; however, the roles of SWI/SNF regulatory subunits are not fully understood. Here, we show that ACTL6a/BAF53A modulates the SWI/SNF complex to suppress differentiation in epidermis. Conditional loss of ACTL6a resulted in terminal differentiation, cell-cycle exit, and hypoplasia, whereas ectopic expression of ACTL6a promoted the progenitor state. A significant portion of genes regulated by ACTL6a were found to also be targets of KLF4, a known activator of epidermal differentiation. Mechanistically, we show that ACTL6a prevents SWI/SNF complex binding to promoters of KLF4 and other differentiation genes and that SWI/SNF catalytic subunits are required for full induction of KLF4 targets. Thus, ACTL6a controls the epidermal progenitor state by sequestering SWI/SNF to prevent activation of differentiation programs.
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ABSTRACT: In a cell, the chromatin state is controlled by the highly regulated interplay of epigenetic mechanisms ranging from DNA methylation and incorporation of different histone variants to posttranslational modification of histones and ATP-dependent chromatin remodeling. These changes alter the structure of the chromatin to either facilitate or restrict the access of transcription machinery to DNA. These epigenetic modifications function to exquisitely orchestrate the expression of different genes, and together constitute the epigenome of a cell. In the skin, different epigenetic regulators form a regulatory network that operates to guarantee skin stem cell maintenance while controlling differentiation to multiple skin structures. In this review, we will discuss recent findings on epigenetic mechanisms of skin control and their relationship to skin pathologies.Cold Spring Harbor Perspectives in Medicine 02/2014; 4(2). DOI:10.1101/cshperspect.a015263 · 7.56 Impact Factor
Article: SWItching On Epidermal Cell Fate[Show abstract] [Hide abstract]
ABSTRACT: Chromatin regulatory complexes are well known regulators of stem cell fate; however, the mechanisms regulating their activity are not well understood. In this issue of Cell Stem Cell, Bao et al. (2013) show that ACTL6a inhibits targeting of the SWI/SNF complex to differentiation genes, thereby preserving the epidermal progenitor state.Cell stem cell 02/2013; 12(2):141-2. DOI:10.1016/j.stem.2013.01.011 · 22.15 Impact Factor
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ABSTRACT: Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and young adults, is characterized by a partially differentiated myogenic phenotype. We have previously shown that the blocking of tumor growth and resumption of differentiation can be achieved by re-expression of miR-206, a muscle-enriched microRNA missing in RMS. In this work, we focused on BAF53a, one of the genes downregulated in miR-206-expressing RMS cells, which codes for a subunit of the SWI/SNF chromatin remodeling complex. Here we show that the BAF53a transcript is significantly higher in primary RMS tumors than in normal muscle, and is a direct target of miR-206. Sustained expression of BAF53a interferes with differentiation in myogenic cells, whereas its silencing in RMS cells increases expression of myogenic markers and inhibits proliferation and anchorage-independent growth. Accordingly, BAF53a silencing also impairs embryonal RMS and alveolar RMS tumor growth, inducing their morphological and biochemical differentiation. These results indicate that failure to downregulate the BAF53a subunit may contribute to the pathogenesis of RMS, and suggest that BAF53a may represent a novel therapeutic target for this tumor.Oncogene advance online publication, 3 June 2013; doi:10.1038/onc.2013.188.Oncogene 06/2013; DOI:10.1038/onc.2013.188 · 8.56 Impact Factor