We organized the first International Symposium on Skin Epigenetics at the Centre for Skin Sciences at the University of Bradford (West Yorkshire, UK) on 2nd and 3rd April 2012.* The goal of the Symposium was to bring together two research communities—skin and chromatin biologists—and discuss the most important aspects of epigenetic regulatory mechanisms that control skin development and regeneration. The symposium was attended by more than 80 participants from countries across Europe, Australia, Japan, Singapore, and USA, and representing academic institutions and industry.
Epigenetic regulation of gene expression programs in the skin is a novel trend in research in cutaneous biology, and several landmark papers arising in the field were published recently (reviewed in
Botchkarev et al., 2012
; Botchkareva, 2012
; Frye and Benitah, 2012
; Yi and Fuchs, 2012
; Zhang et al., 2012
). The Symposium program included six Keynote lectures, the inaugural John M. Wood Memorial Lecture, and six sessions that covered major levels of epigenetic regulation.DNA modifications and control of gene expression
Prof. Wolf Reik (Babraham Institute, Cambridge, UK) presented his work on the DNA methylation and hydroxymethylation that occurs during mammalian development. The recently discovered oxidation of 5-methylcytosyne into 5-hydroxymethylcytosine by the Ten–Eleven Translocation family of hydroxylases has important roles in the dynamic reprogramming of the methylation patterns in the zygote and in ES cells, respectively. These new DNA modifications might prevent replication-mediated methylation of newly synthesized DNA, lead to removal of the modified cytosine by nucleotide excision repair machinery, or work through other yet unknown mechanisms. It has been suggested that 5-hydroxymethylcytosine represents a new epigenetic mark involved in the control of gene transcription, whereas Ten–Eleven Translocation proteins have important roles in regulating the pluripotency of embryonic stem cells and induced pluripotent stem cells (reviewed in
Branco et al., 2012
).Professor Cheng-Ming Chuong (University of Southern California, Los Angeles, CA) described the role of DNA methyltransferase 1 in mouse skin development and homeostasis. His group found that DNA methyltransferase 1 ablation in the murine skin epithelia leads to alterations in the epidermal thickness and progressive reduction in hair follicle size, number, and cycling activity, suggesting that DNA methylation is important for the control of stem cell homeostasis during the development and maintenance of ectodermal organs (
Li et al., 2012
).Histone modifications, skin development, and homeostasis
Professor Sarah Millar (University of Pennsylvania, Philadelphia, USA) spoke about the essential role of histone deacetylases (HDACs) in ectodermal development and homeostasis: Hdac1 and 2 are redundant during embryonic skin morphogenesis, and depletion of both genes leads to a marked failure of epidermal proliferation, stratification, and hair follicle development; by contrast, Hdac1 and 2 have nonredundant roles in postnatal skin. Deletion of Hdac1 leads to the upregulation of p16/INK4a in rapidly proliferating hair matrix keratinocytes, causing abnormalities in hair growth. Thus, rapidly proliferating epithelial cells are particularly sensitive to the loss of HDAC1/2, suggesting that specific inhibitors of these enzymes might serve as potential candidates to treat epidermal malignancies (
LeBoeuf et al., 2010
).Dr Shawn Coley (University of Leicester, UK) presented his studies demonstrating that a compound (Hdac1−/-; Hdac2+/-) and double knockout of Hdac1/2 mice exhibit a significant block in T-cell development and accumulation of immature CD4low/CD8high cells, independently of T-cell receptor signaling, leading to the development of lethal T-cell malignancies. This suggests that HDAC1/2 have an essential role in T-cell development and control of genomic stability (
Dovey et al., 2010
).Dr Andrey Panteleyev (University of Dundee, UK; now in National Research Center Kurchatov Institute, Moscow, Russia) discussed the interplay between hypoxia-inducible factor/aryl hydrocarbon receptor nuclear translocator containing transcription factors and HDACs. His group demonstrated that hypoxia-inducible factor/aryl hydrocarbon receptor nuclear translocator machinery inhibits the expression of several genes in the epidermis, including fillagrin, keratin 10, and loricrin, in a HDAC-dependent manner. They also revealed a novel mechanism of post-translational regulation of HDAC1, 2, and 3 by hypoxia-inducible factor/aryl hydrocarbon receptor nuclear translocator through proteasomal degradation in keratinocytes (
Robertson et al., 2012
).Dr Klaas Mulder from Professor Fiona Watt’s Lab (Wellcome Trust Centre for Stem Cell Research, Cambridge, CA) reported that an small interfering RNA–mediated genetic screen for epigenetic regulators in epidermal stem cells reveals new factors involved in the control of stem cell maintenance and differentiation. This indicates that gene expression programs controlling epidermal stem cell maintenance are regulated through the interplay between diverse epigenetic strategies (
Mulder et al., 2012
).Inaugural John M. Wood memorial lecture
This Award was introduced to acknowledge the contribution of Professor John M. Wood, a pioneering biochemist and triple invitation-only Nobel prize nominee (chemistry), to the development of cutaueous research (together with his wife Professor K. Schallreuter) at the University of Bradford (
Schallreuter et al., 1994
; Schallreuter et al., 2001
; Wood and Schallreuter, 2008
; Tobin et al., 2008
)The Award recipient Prof. Greg Barsh (HudsonAlpha Institute for Biotechnology, Huntsville, AL and Stanford University, CA) described his studies on the genomics of color patterning in cats, dogs, and zebras (
Barsh, 2007
; Candille et al., 2007
). His combination of comprehensive genomic approaches revealed a number of genes that are involved in establishing and maintaining some, but not all, pigmentation patterns in these animals, suggesting that undiscovered epigenetic mechanisms also have a role in the molecular control of skin pigmentation patterns.Polycomb genes and stem cell activity
Polycomb proteins are important epigenetic regulators, and Dr Elena Ezhkova (Mount Sinai School of Medicine, New York, NY) discussed the role of key Polycomb repressive complex 2 components Ezh1 and Ezh2 in the control of maintenance and differentiation of epithelial stem cells in the skin. By using epidermis-specific depletion of Ezh1 and Ezh2 genes, the crucial role of the Polycomb repressive complex 2 complexes in controlling gene expression programs that protect epithelial stem cells from premature differentiation was demonstrated. Simultaneous depletion of Ezh1 and Ezh2 in the skin epithelium led to the inhibition of hair follicle stem cell proliferation and to defects in their differentiation in vivo and in vitro, resulting in hair follicle abnormalities and eventual hair follicle loss (
Ezhkova et al., 2009
; Ezhkova et al., 2011
). Thus, Polycomb repressive complex 2 complexes control gene expression programs important to ensure the skin epithelial stem cell differentiation in a timely manner.Dr Salvador Aznar-Benitah (Center for Genomic Regulation, Barcelona, Spain) provided functional analysis of several epigenetic regulators, including Jarid2 and Cbx4 detected by a genetic screen, in the control of epidermal progenitor cell differentiation both in vitro and in vivo (
Luis et al., 2011
; Mejetta et al., 2011
). Surprisingly, his studies demonstrated that subunits of the same Polycomb complexes exert specific and even opposite functions with respect to the control of stem cell functions important to the regulation of epidermal morphogenesis and homeostasis.Dr Michaela Frye (Wellcome Trust Centre for Stem Cell Research, Cambridge, UK) described the roles of Setd8 histone methylase and HDAC-containing Sin3A co-repressor complex in epidermal stem cell biology. Setb8 is required for the survival and differentiation of the epithelial stem cell, whereas depletion of Sin3A activities leads to defects in the epidermal progenitor cell proliferation and differentiation (
Nascimento et al., 2011
; Driskell et al., 2012
). These findings indicate that specific histone modification activities are important in establishing regulatory networks controlling stem cell maintenance in the skin epithelium.Dr Egor Prokhortchouk (Centre ‘Bioengeneering’, Russian Academy of Sciences, Moscow, Russia) spoke about the role of the methyl DNA–binding protein Kaiso in the control of skin development and hair growth (
Prokhortchouk et al., 2001
), including changes in hair follicle cycling in Kaiso-deficient mice. Interestingly, several genes associated with epithelial stem cell differentiation operate as direct targets of Kaiso-mediated gene repression, suggesting that Kaiso might be involved in the control of epidermal stem cell differentiation dynamics.MicroRNAs in skin development and regeneration
Dr Thomas Andl (Vanderbilt University, Nashville, TN) discussed the importance of microRNAs (miRNAs) in the fine-tuning, buffering, and ‘noise reduction’ of gene expression developed during evolution (
Ning and Andl, 2012
). Vertebrates, including mammals, have expanded their miRNA repertoire substantially. He observed that miR-31 is highly expressed in ‘activated’ skin conditions (such as wound healing, carcinogenesis, and psoriasis), and that elevated miR-31 levels in a transgenic mouse model results in aberrant wound healing and hair loss.Dr Rui Yi (University of Colorado, Boulder, USA) spoke about the essential roles of miRNAs in governing a self-renewal and migration of mouse skin stem cells, including new data on the role of Argonaute proteins as essential components of the miRNA-induced silencing complex that have important roles in both miRNA biogenesis and function. Interestingly, when both Ago1 and Ago2 are ablated in the skin, the global expression of miRNAs is significantly compromised and causes severe defects in skin morphogenesis (
Wang et al., 2012
).Dr Natalia Botchkareva (University of Bradford, UK) provided an overview on how miRNA/messenger RNA regulatory networks are involved in the control of skin development, epidermal homeostasis, hair cycle–associated tissue remodeling, and pigmentation. She talked about miR-31, which is abundantly present in anagen hair follicles and exerts inhibitory effects on hair follicle growth by targeting multiple genes (
Mardaryev et al., 2010
). She emphasized the existence of a cross talk between miRNAs and other epigenetic regulators, such as chromatin remodelers, which is important for skin homeostasis (Botchkareva, 2012
).Higher-order chromatin remodeling and three-dimensional genome organization
Professor Wendy Bickmore (MRC Human Genetics Unit, Edinburgh, UK) discussed how chromatin compaction regulates gene expression in mammalian cells, including how the Polycomb complex–mediated gene compaction acts to regulate the spatial and temporal activation of genes during stem cell differentiation and mouse development. She compared two major technologies used to study higher-order chromatin folding—fluorescent in-situ hybridization versus chromosomal conformation capture technique—and emphasized an importance of the combination of both approaches in analyses of three-dimensional genome organization (
Dostie and Bickmore, 2012
).Professor Terumi Kohwi-Shigematsu (Lawrence Berkeley National Laboratory, Berkley, CA) spoke about the dynamic and specific interactions of gene loci in mammalian nuclei mediated by the genome-organizing protein SATB1 (
Kohwi-Shigematsu et al., 2012
), emphasizing their importance in the control of tissue-specific gene expression programs.Dr Michael Fessing (University of Bradford, UK) reported that higher-order chromatin remodeling in the epidermis is significantly impaired in p63-deficient skin epithelia, and that p63 directly regulates several chromatin modifiers, including Satb1 and Brg1. Satb1 deficiency leads to the alteration in higher-order chromatin folding and gene expression within the epidermal differentiation complex locus (
Fessing et al., 2011
). Thus, p63 controls gene expression programs in epidermal progenitor cells during skin morphogenesis partly by regulating higher-order chromatin remodelers.Dr Andrey Sharov (Boston University, MA) described the distinct nuclear architecture and higher-order chromatin organization of lineage-specific genes in human melanocytes and keratinocytes. Several melanocyte-specific gene loci are localized much more in the interior three-dimensional nuclear space in human primary melanocytes in comparison with keratinocytes, demonstrating that specialized skin cell lineages establish different nuclear architecture and higher-order genome organization to control cell type–specific programs of gene expression.
Nuclear architecture, cytoskeleton, and their alterations during development and aging
Professor Chris Hutchinson (University of Durham, UK) reported that anchoring of the nuclear membrane protein emerin to the inner nuclear membrane by A-type lamins is important in the regulation of beta-catenin-mediated Wnt signaling in the dermal fibroblasts. Emerin–lamin complexes control beta-catenin nuclear export and its cytoplasmic degradation. Moreover, emerin is required also for dermal fibroblast differentiation into adipocytes. These findings support an essential role of nuclear membrane components in cellular signaling through the regulation of shuffling of signaling-activated transcription modulators between the nucleus and cytoplasm, as well as in cytoplasmic degradation of such modulators (
Hutchison, 2012
).Dr Iakowos Karakesisoglou (University of Durham, UK) reported that nesprin interchain associations control nuclear shape, three-dimensional genome organization, and gene expression. Nesprins-1/-2/-3/-4 are nuclear envelope proteins that connect nuclei to the cytoskeleton. These nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size, and also has a role in the control of skin repair after wounding (
Lu et al., 2012
).Dr Andrei Mardaryev (University of Bradford, UK) described the role of p63 in the control of nuclear architecture. The transcription profiling of p63-null skin epithelium revealed the downregulation of selected genes encoding the components of nuclear envelope, including lamin B1, plectin, Sun-1, and nesprin-2/3, suggesting that p63 controls cell type–specific gene expression during epidermal morphogenesis partly by regulating nuclear membrane assembly and functions.
Conclusions and future plans
The symposium served as an important step in the integration of research in chromatin and skin biology, and provided a valuable platform for further development of skin epigenetics. The generated background information will be important for further analyses of the epigenetic mechanisms that control reorganization of gene expression programs in different skin cell lineages during differentiation, as well in many pathological conditions including neoplastic skin disorders. A large number of epigenetic drugs are currently tested to manage distinct types of malignancies and other disorders outside of the skin (reviewed in
Heightman, 2011
). We must bridge the gap between our current knowledge of basic epigenetic mechanisms and those that control skin development and regeneration in order to develop a new generation of drugs for the treatment of skin disorders. Hopefully, this symposium will help establish skin epigenetics as a novel area of basic and applied cutaneous research.ACKNOWLEDGMENTS
The symposium organizers appreciate support of the sponsors (Aderans Research, BASF, Alliance-Boots, L’Oreal, The Company of Biologists, and Unilever).
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