ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4

Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Cell stem cell (Impact Factor: 22.27). 02/2013; 12(2):193-203. DOI: 10.1016/j.stem.2012.12.014
Source: PubMed


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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    • "This subunit is an essential regulator of adult stem cell function [25], [28]. BAF53 is involved in self renewal of progenitor and stem cells, like long-term HSC (hematopoietic stem cells), myeloid progenitor cell [29], neural stem and progenitor cells [10] and epidermal progenitor cells [30]. "
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    ABSTRACT: Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes.
    PLoS ONE 10/2014; 9(10):e108858. DOI:10.1371/journal.pone.0108858 · 3.23 Impact Factor
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    • "This is because of differential expression of the SWI/SNF subunit actin-like 6a (ACTL6a/BAF53a) that binds the SWI/SNF complex and prevents it from binding to its target genes (Bao et al. 2013). Loss of ACTL6a results in loss of stem cell proliferation and exit from the cell cycle as well as premature differentiation of the epidermis, in part owing to activation of KLF4 expression (Table 1) (Bao et al. 2013), a critical regulator of epidermal differentiation (Segre et al. 1999). Studies in other systems have shown that ACTL6a is also required in neuronal stem cells and hematopoietic stem cells to maintain stem cell proliferation (Lessard et al. 2007; Krasteva et al. 2012), suggesting that ACTL6a might be a general regulator of stem cell proliferation and commitment (Perdigoto et al. 2013). "
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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 · 9.47 Impact Factor
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    ABSTRACT: Chromatin regulators have recently emerged as key players in the control of tissue development and tumorigenesis. One specific chromatin regulator, the Polycomb complex, has been shown to regulate the identity of embryonic stem cells, but its role in controlling fates of multipotent progenitors in developing tissues is still largely unknown. Recent findings have revealed that this complex plays a critical role in control of skin stem cell renewal and differentiation. Moreover, the expression of Polycomb complex components is often aberrant in skin diseases, including skin cancers. This review will detail recent findings on Polycomb control of skin and highlight critical unknown questions.
    Cellular and Molecular Life Sciences CMLS 02/2012; 69(13):2161-72. DOI:10.1007/s00018-012-0920-x · 5.81 Impact Factor
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