Kashiwagi M, Morgan BA, Georgopoulos KThe chromatin remodeler Mi-2beta is required for establishment of the basal epidermis and normal differentiation of its progeny. Development 134:1571-1582

Harvard University, Cambridge, Massachusetts, United States
Development (Impact Factor: 6.46). 05/2007; 134(8):1571-82. DOI: 10.1242/dev.001750
Source: PubMed


Using conditional gene targeting in mice, we show that the chromatin remodeler Mi-2beta is crucial for different aspects of skin development. Early (E10.5) depletion of Mi-2beta in the developing ventral epidermis results in the delayed reduction of its suprabasal layers in late embryogenesis and to the ultimate depletion of its basal layer. Later (E13.5) loss of Mi-2beta in the dorsal epidermis does not interfere with suprabasal layer differentiation or maintenance of the basal layer, but induction of hair follicles is blocked. After initiation of the follicle, some subsequent morphogenesis of the hair peg may proceed in the absence of Mi-2beta, but production of the progenitors that give rise to the inner layers of the hair follicle and hair shaft is impaired. These results suggest that the extended self-renewal capacity of epidermal precursors arises early during embryogenesis by a process that is critically dependent on Mi-2beta. Once this process is complete, Mi-2beta is apparently dispensable for the maintenance of established repopulating epidermal stem cells and for the differentiation of their progeny into interfollicular epidermis for the remainder of gestation. Mi-2beta is however essential for the reprogramming of basal cells to the follicular and, subsequently, hair matrix fates.

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Available from: Katia Georgopoulos, Sep 29, 2015
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    • "It will be important to investigate if a similar association exists during the specification of other tissue types. In particular, Chd4 has been shown to be required for the maintenance and multilineage differentiation of hematopoietic stem cells as well as for the self-renewal capacity of epidermal precursors (Kashiwagi et al, 2007; Yoshida et al, 2008). Interestingly, several PcG proteins have well-established functions during these processes (van der Lugt et al, 1994; Ohta et al, 2002; Lessard and Sauvageau, 2003; Park et al, 2003; Kamminga et al, 2006; Ezhkova et al, 2009). "
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    ABSTRACT: Polycomb group (PcG) proteins form transcriptional repressor complexes with well-established functions during cell-fate determination. Yet, the mechanisms underlying their regulation remain poorly understood. Here, we extend the role of Polycomb complexes in the temporal control of neural progenitor cell (NPC) commitment by demonstrating that the PcG protein Ezh2 is necessary to prevent the premature onset of gliogenesis. In addition, we identify the chromodomain helicase DNA-binding protein 4 (Chd4) as a critical interaction partner of Ezh2 required specifically for PcG-mediated suppression of the key astrogenic marker gene GFAP. Accordingly, in vivo depletion of Chd4 in the developing neocortex promotes astrogenesis. Collectively, these results demonstrate that PcG proteins operate in a highly dynamic, developmental stage-dependent fashion during neural differentiation and suggest that target gene-specific mechanisms regulate Polycomb function during sequential cell-fate decisions.
    The EMBO Journal 04/2013; 32(11). DOI:10.1038/emboj.2013.93 · 10.43 Impact Factor
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    • "did not cause any significant epidermal defects, but, instead, led to impaired induction and development of the hair follicles (Kashiwagi et al., 2007). The expression of the hair follicle placode markers, including Edar, β-catenin, Lef1, Shh, Patched1 and Bmp2, were also consistently reduced in the Chd4 mutant skin (Kashiwagi et al., 2007). However, the targets of Chd4 and other ATP-dependent chromatin remodellers in keratinocytes remain to be identified. "
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    ABSTRACT: The nucleus is a complex and highly compartmentalized organelle, which undergoes major organization changes during cell differentiation, allowing cells to become specialized and fulfill their functions. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes a programmed transformation from active status, associated with execution of the genetic programs of cornification and epidermal barrier formation, to a fully inactive condition and becomes a part of the keratinized cells of the cornified layer. Tremendous progress achieved within the past two decades in understanding the biology of the nucleus and epigenetic mechanisms controlling gene expression allowed defining several levels in the regulation of cell differentiation-associated gene expression programs, including an accessibility of the gene regulatory regions to DNA-protein interactions, covalent DNA and histone modifications, and ATP-dependent chromatin remodeling, as well as higher-order chromatin remodeling and nuclear compartmentalization of the genes and transcription machinery. Here, we integrate our current knowledge of the mechanisms controlling gene expression during terminal keratinocyte differentiation with distinct levels of chromatin organization and remodeling. We also propose directions to further explore the role of epigenetic mechanisms and their interactions with other regulatory systems in the control of keratinocyte differentiation in normal and diseased skin.
    Journal of Investigative Dermatology 07/2012; 132(11):2505-21. DOI:10.1038/jid.2012.182 · 7.22 Impact Factor
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    • "NuRD components have been reported to interact with Oct4, a protein essential for the maintenance of pluripotency in ES cells (Liang et al, 2008; Pardo et al, 2010; van den Berg et al, 2010), despite the fact that several NuRD components are dispensable for pluripotency (McDonel et al, 2009). NuRD function is also important for homeostasis of both haematopoietic and epithelial stem cells (Williams et al, 2004; Kashiwagi et al, 2007). Aberrant gene expression patterns have been demonstrated in embryonic and somatic cell types in the absence of a functional NuRD complex (Kaji et al, 2006, 2007; Yoshida et al, 2008). "
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    ABSTRACT: Pluripotent cells possess the ability to differentiate into any cell type. Commitment to differentiate into specific lineages requires strict control of gene expression to coordinate the downregulation of lineage inappropriate genes while enabling the expression of lineage-specific genes. The nucleosome remodelling and deacetylation complex (NuRD) is required for lineage commitment of pluripotent cells; however, the mechanism through which it exerts this effect has not been defined. Here, we show that histone deacetylation by NuRD specifies recruitment for Polycomb Repressive Complex 2 (PRC2) in embryonic stem (ES) cells. NuRD-mediated deacetylation of histone H3K27 enables PRC2 recruitment and subsequent H3K27 trimethylation at NuRD target promoters. We propose a gene-specific mechanism for modulating expression of transcriptionally poised genes whereby NuRD controls the balance between acetylation and methylation of histones, thereby precisely directing the expression of genes critical for embryonic development.
    The EMBO Journal 12/2011; 31(3):593-605. DOI:10.1038/emboj.2011.431 · 10.43 Impact Factor
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