Table 1.
Summary of the effects of removal of the different epigenetic regulators from the epidermis
| Protein | Function | Mutant/type of inactivation | Phenotype | References |
|---|---|---|---|---|
| DNA methylation | ||||
| DNA methyltransferases (DNMTs) | DNA methylation | DNMT1 cKO in mouse epidermis | Loss of the methylation-dependent repression of epidermal differentiation genes leads to differentiation of basal cells, uneven thickened epidermis and sebaceous gland hyperplasia. Up-regulation of cell-cycle inhibitor p16INK4A results in loss of proliferation, progressive aging, and increased apoptosis in the hair follicle stem cells that leads to progressive alopecia. | Li et al. 2012 |
| KD of DNMT1 in human keratinocytes xeonografted in immune-deficient mice | Premature differentiation and epidermal hypoplasia. Decreased proliferation potential and cell-cycle arrest because of up-regulation of the Ink4a/Arf/Ink4b locus and abnormal expression of differentiation genes leads to tissue loss. | Sen et al. 2010 | ||
| Chemical inhibition of DNMTs with 5-azacytidine in human keratinocytes | Differentiation and inhibition of growth, in part by affecting expression of genes of the epidermal differentiation complex (EDC). | Okada et al. 1984; Rosl et al. 1988; Elder and Zhao 2002 | ||
| UHRF1 | DNMT1 targeting by binding to hemimethylated DNA | In vitro KD of UHRF1 in human keratinocytes | UHRF1 depletion results in derepression of differentiation genes and reduced proliferation. | Sen et al. 2010; Mulder et al. 2012 |
| Gadd45A/B | DNA demethylation by interaction with DNA excision repair complexes | In vitro KD or overexpression of Gadd45A/B in human keratinocytes | Lack of Gadd45A or B impairs epidermal differentiation while their forced expression induces premature differentiation. | Sen et al. 2010 |
| Posttranslational histone modification | ||||
| Polycomb repressive complex2 (PRC2) | Trimethylation of lysine 27 on histone H3 (H3K27me3) | Ezh2 cKO in mouse embryonic epidermis | Loss of H3K27me3 results in up-regulation of epidermal differentiation genes (including many of genes of the EDC cluster) and precocious epidermal development. | Ezhkova et al. 2009 |
| Ezh1/2 2KO in mouse embryonic epidermis | Loss of Ezh1/2 from epidermal progenitors results in an increase in the number of differentiated Merkel cells, as a result of loss H3K27me3 repression of Sox2, a master regulator of Merkel cell differentiation. Loss of Ezh1/2 also results in decreased proliferation and subsequent degeneration of the hair follicles caused by activation of the Ink4a/Arf/Ink4b locus. | Ezhkova et al. 2011; Bardot et al. 2013; Lesko et al. 2013 | ||
| JMJD3 | Lysine-specific demethylase | In vitro KD and o/e of JMJD3 in human keratinocytes | Loss of JMJD3 demethylation activity arrests differentiation of human epidermal keratinocytes while expression of an active JMJD3 results in premature differentiation. | Sen et al. 2008 |
| Setd8 | Monomethylation of lysine 20 on histone H4 (H4K20mel) | Setd8 cKO in mouse embryonic and adult epidermis | Loss of Setd8-dependent histone methylation resulted in loss of proliferation and impaired differentiation, followed by loss of the interfollicular epidermis and sebaceous glands. | Driskell et al. 2012 |
| Histone deacetylases (HDACs) | Histone deacetylation | HDAC1/2 cKO in mouse embryonic epidermis | Removal of HDAC1/2 from the embryonic epidermis results in loss of stem cell proliferation, loss of stratification of the epidermis, lack of hair follicles, and eventual apoptosis in the basal layer because of increased expression of the p63-repressed genes p16INK4a, p21, and p53. | LeBoeuf et al. 2010 |
| Treatment of adult mouse skin with HDAC inhibitor trichostatin A | HDAC inhibition in the adult skin induces the hair follicle stem cells to proliferate and exit the stem cell compartment. | Frye et al. 2007 | ||
| In vitro treatment of human keratinocytes or epidermal explants with HDAC inhibitors | HDAC inhibition in human keratinocytes results in arrest of proliferation and premature expression of differentiation markers. | Saunders et al. 1999; Elder and Zhao 2002; Frye et al. 2007; Markova et al. 2007 | ||
| Chromatin remodeling | ||||
| SWI/SNF | Chromatin remodeling | Brg1 and Brm 2KO in mouse embryonic epidermis | Loss of Brg1 and Brm in the developing epidermis leads to aberrant expression of differentiation genes and results in defective formation of the skin barrier. | Indra et al. 2005 |
| ACTL6a cKO in mouse adult epidermis and KD in human keratinocytes | 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 caused by activation of KLF4 expression. | Bao et al. 2013 | ||
| Brg1 cKO in hair follicle stem cells | Loss of Brg1 in the bulge results in loss of the hair follicle stem cells over time, partly because of ectopic expression of the cell-cycle inhibitor p27. | Xiong et al. 2013 | ||
| Nuclear architecture remodeling | ||||
| Satb1 | Large-scale chromatin remodeler | Satb1 KO in mouse embryonic and postnatal epidermis | Removal of Satb1 from epidermis increases the volume and spacing of the EDC locus within the nucleus, accompanied by down-regulation of the EDC and thinner epidermis. | Fessing et al. 2011 |