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Second International Symposium—Epigenetic Regulation of Skin Regeneration and Aging: From Chromatin Biology towards the Understanding of Epigenetic Basis of Skin Diseases

2017; Elsevier BV; Volume: 137; Issue: 8 Linguagem: Inglês

10.1016/j.jid.2017.01.037

1523-1747

Vladimir A. Botchkarev,

Immune Cell Function and Interaction

After the First International Symposium on Skin Epigenetics at the University of Bradford (UK) in 2012 (Botchkarev et al., 2013Botchkarev V.A. Fessing M.Y. Botchkareva N.V. Westgate G. Tobin D.J. First International Symposium “Epigenetic Control of Skin Development and Regeneration”: how chromatin regulators orchestrate skin functions.J Invest Dermatol. 2013; 133: 1918-1921Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar), the research in this area has progressed substantially toward understanding how epigenetic regulatory machinery operates in concert with signaling pathways and transcription factors to control gene expression in normal skin and how epigenetic mechanisms are dysregulated in many pathological conditions including inflammatory skin disorders and cancer. To summarize recent achievements in skin epigenetics and to provide an opportunity for investigators to meet again and discuss the most important aspects of this rapidly expanding area, International Symposium “Epigenetic Regulation of Skin Regeneration and Aging” was held on March 17–19, 2016, in the Centre for Skin Sciences at the University of Bradford, UK. The Symposium was attended by over 110 participants from Europe, China, Japan, Singapore, and the United States, representing academic institutions as well as pharmaceutical and personal care industries. The Symposium program included eight Keynote lectures, the John M. Wood Memorial Lecture, and 27 talks organized into six sessions. In the Opening lectures, Prof. Cheng-Ming Chuong (University of Southern California, Los Angeles) and Prof. Fiona Watt (King’s College London, UK) introduced skin as an excellent model for epigenetic research, and Prof. Terumi Kohwi-Shigematsu (University of California, San Francisco) presented data on how epigenetic machinery contributes to neoplastic cell transformation. Following up the previous research on the role of DNA methyltransferase 1 in the control of hair follicle development and aging of mice (Li et al., 2012Li J. Jiang T.X. Hughes M.W. Wu P. Yu J. Widelitz R.B. et al.Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1.J Invest Dermatol. 2012; 132: 2681-2690Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), Chuong described about how keratin genes are organized in the chicken genome. Similar to mammals, chicken keratin genes are clustered into distinct loci on chromosomes 25 and 27; whereas β-keratin genes on chromosome 25 show more inter-appendage differences in their expression, those on chromosome 27 show more intra-appendage differences, thus providing specific molecular targets for the study of epigenetic regulation (Wu et al., 2015Wu P. Ng C.S. Yan J. Lai Y.C. Chen C.K. Lai Y.T. et al.Topographical mapping of alpha- and beta-keratins on developing chicken skin integuments: functional interaction and evolutionary perspectives.Proc Natl Acad Sci USA. 2015; 112: E6770-E6779Crossref PubMed Scopus (58) Google Scholar). Watt described interplay between signaling and epigenetic mechanisms in the context of a recently discovered network of interactions involving different epigenetic regulators that affects two functionally related gene sets involved in the anchorage of epidermal stem cells to their niches (Mulder et al., 2012Mulder K.W. Wang X. Escriu C. Ito Y. Schwarz R.F. Gillis J. et al.Diverse epigenetic strategies interact to control epidermal differentiation.Nat Cell Biol. 2012; 14: 753-763Crossref PubMed Scopus (115) Google Scholar). Kohwi-Shigematsu discussed how the chromatin architectural protein and genome organizer SATB1 enables cells to change their phenotypes by regulating genes through higher-order chromatin reorganization and epigenetic modification in cancers of distinct cell types to regulate epigenetic modification, transcription, and drive metastasis (Kohwi-Shigematsu et al., 2012Kohwi-Shigematsu T. Kohwi Y. Takahashi K. Richards H.W. Ayers S.D. Han H.J. et al.SATB1-mediated functional packaging of chromatin into loops.Methods. 2012; 58: 243-254Crossref PubMed Scopus (29) Google Scholar, Kohwi-Shigematsu et al., 2013Kohwi-Shigematsu T. Poterlowicz K. Ordinario E. Han H.J. Botchkarev V.A. Kohwi Y. Genome organizing function of SATB1 in tumor progression.Semin Cancer Biol. 2013; 23: 72-79Crossref PubMed Scopus (94) Google Scholar). DNA methylation/hydroxymethylation and different chemical modifications of the histone proteins play pivotal roles in the control of gene activation/silencing and promoter/enhancer interactions in epithelial stem cells and their progenies (Avgustinova and Benitah, 2016Avgustinova A. Benitah S.A. Epigenetic control of adult stem cell function.Nat Rev Mol Cell Biol. 2016; 17: 643-658Crossref PubMed Scopus (144) Google Scholar). Prof. Wolf Reik (Babraham Institute, Cambridge, UK) presented his work on mechanisms that regulate epigenetic reprogramming, which appears to be conserved in mammals and is essential for imprinting, transition to pluripotency, and the generation of induced pluripotent stem cells. His laboratory has identified signaling events that regulate DNA methylation dynamics during early development and that connect reprogramming firmly with naïve pluripotency; ongoing work is focused on the roles of these pathways in natural and experimental reprogramming (von Meyenn et al., 2016von Meyenn F. Iurlaro M. Habibi E. Habibi E. Liu N.Q. Salehzadeh-Yazdi A. et al.Impairment of DNA methylation maintenance is the main cause of global demethylation in naive embryonic stem cells.Mol Cell. 2016; 62: 848-861Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Prof. Salvador Benitah’s laboratory (Institute for Research in Biomedicine, Barcelona, Spain) reported that de novo DNA methylation catalyzed by Dnmt3a and Dnmt3b occurs in human epidermal stem cells and their differentiated counterparts at the most active subset of enhancers in a histone H3K36me3-dependent manner. Both Dnmt3a and Dnmt3b bind to superenhancers associated with genes that either define the ectodermal lineage or establish the stem cell and differentiated states: Dnmt3a is required to maintain high levels of DNA hydroxymethylation at the center of the enhancers, and Dnmt3b is necessary to maintain high levels of DNA methylation along the enhancer (Rinaldi et al., 2016Rinaldi L. Datta D. Serrat J. Morey L. Solanas G. Avgustinova A. et al.Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis.Cell Stem Cell. 2016; 19: 1-11Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Prof. Sarah Millar (University of Pennsylvania, Philadelphia) discussed the roles for histone deacetylases (HDACs) and their interaction with transcription factors leading to chromatin compaction and transcriptional repression. Following up previous work showing the roles for HDAC1 and HDAC2 in the control of embryonic epidermal development (LeBoeuf et al., 2010LeBoeuf M. Terrell A. Trivedi S. Sinha S. Epstein J.A. Olson E.N. et al.Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.Dev Cell. 2010; 19: 807-818Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar), she reported that, in contrast to ubiquitous expression of HDAC1/2 in skin epithelia, genetic deletion of Hdac3 in embryonic mouse epidermis disrupts stepwise differentiation of the epidermis. These data show that HDAC3 coordinates expression of differentiation proteins and lipids to establish a functional barrier via distinct molecular mechanisms. Dr. Yuri Schwartz (University of Umea, Sweden) and Dr. Elena Ezhkova (Mount Sinai School of Medicine, New York, NY) presented the data on how Polycomb Group proteins operate as epigenetic repressors essential for control of development and cell differentiation (Schwartz and Pirrotta, 2014Schwartz Y.B. Pirrotta V. Ruled by ubiquitylation: a new order for polycomb recruitment.Cell Rep. 2014; 8: 321-325Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Dr. Schwartz discussed similarities and differences between Polycomb mechanisms in different species and linked them to recently discovered pervasive nontargeted survey of the genome by Polycomb Group proteins (Lee et al., 2015Lee H.G. Kahn T.G. Simcox A. Schwartz Y.B. Pirrotta V. Genome-wide activities of polycomb complexes control pervasive transcription.Genome Res. 2015; 25: 1170-1181Crossref PubMed Scopus (92) Google Scholar). Dr. Ezhkova reported that the loss of function of core components of the different Polycomb complexes (PRC1 vs. PRC2) can result in different or even opposing biological outcomes, despite their shared genomic targets (Dauber et al., 2016Dauber K.L. Perdigoto C.N. Valdes V.J. Santoriello F.J. Cohen I. Ezhkova E. Dissecting the roles of polycomb repressive complex 2 subunits in the control of skin development.J Invest Dermatol. 2016; 136: 1647-1655Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, Perdigoto et al., 2016Perdigoto C.N. Dauber K.L. Bar C. Tsai P.C. Valdes V.J. Cohen I. et al.Polycomb-mediated repression and sonic hedgehog signaling interact to regulate Merkel cell specification during skin development.PLoS Genet. 2016; 12: e1006151Crossref PubMed Scopus (42) Google Scholar). Prof. Jonathan Higgins (Newcastle University, UK) discussed how histone H3T3 phosphorylation regulates protein association and dissociation from chromosomes during mitosis and can recruit “reader” proteins or displace them from chromatin. Future research will aim to generate the first genome-wide maps of mitotic histone phosphorylation and to uncover roles of histone phosphorylation in the decisions to retain bookmarks or release proteins from chromatin. This will help uncover mechanisms for memorizing and reprogramming gene expression during cell division (Wang and Higgins, 2013Wang F. Higgins J.M. Histone modifications and mitosis: countermarks, landmarks, and bookmarks.Trends Cell Biol. 2013; 23: 175-184Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Prof. Bogi Andersen (University of California, Irvine) reported on the role of the transcription factor GRHL3 and epigenetic factors in the control of human epidermal keratinocyte differentiation and migration: during differentiation, GRHL3 primarily binds to superenhancers and activates transcription of epidermal differentiation genes, and during migration, GRHL3 binds to promoter regions and represses the expression of inhibitors of migration (Hopkin et al., 2012Hopkin A.S. Gordon W. Klein R.H. Espitia F. Daily K. Zeller M. et al.GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program.PLoS Genet. 2012; 8: e1002829Crossref PubMed Scopus (60) Google Scholar, Peyrard-Janvid et al., 2014Peyrard-Janvid M. Leslie E.J. Kousa Y.A. Smith T.L. Dunnwald M. Magnusson M. et al.Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development.Am J Hum Genet. 2014; 94: 23-32Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). These data suggest that alterations in the enhancer structure and spatial rearrangement in chromatin binding of key transcription factors are responsible for the different functional states of keratinocytes. The 2016 John M. Wood Memorial Lecturer Prof. Elaine Fuchs (Rockefeller University, New York, NY) described her most recent work on the epigenetics and transcriptional regulation of stem cells during tissue regeneration, wound repair, and malignant progression. Her team has unravelled interactions between stem cells and their environment, which are manifested through dynamic changes in chromatin landscapes that orchestrate stem cell plasticity and allow stem cells to survive outside their native niche (reviewed in Adam and Fuchs, 2016Adam R.C. Fuchs E. The yin and yang of chromatin dynamics in stem cell fate selection.Trends Genet. 2016; 32: 89-100Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Fuchs, 2016Fuchs E. Epithelial skin biology: three decades of developmental biology, a hundred questions answered and a thousand new ones to address.Curr Top Dev Biol. 2016; 116: 357-374Crossref PubMed Scopus (96) Google Scholar). Prof. Fuchs has also reported about recent insights into the biology of enhancers in skin epithelial stem cells and how pioneer transcription factors regulate superenhancer assembly in normal and malignant keratinocytes (Adam et al., 2015Adam R.C. Yang H. Rockowitz S. Larsen S.B. Nikolova M. Oristian D.S. et al.Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice.Nature. 2015; 521: 366-370Crossref PubMed Scopus (260) Google Scholar, Yang et al., 2015Yang H. Schramek D. Adam R.C. Keyes B.E. Wang P. Zheng D. et al.ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas.eLife. 2015; 4: e10870Crossref PubMed Scopus (55) Google Scholar). Nuclear compartmentalization of the genes, enhancer elements, and transcription machinery play essential roles in the control of gene expression (Bickmore and van Steensel, 2013Bickmore W.A. van Steensel B. Genome architecture: domain organization of interphase chromosomes.Cell. 2013; 152: 1270-1284Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, Cremer et al., 2015Cremer T. Cremer M. Hubner B. Strickfaden H. Smeets D. Popken J. et al.The 4D nucleome: evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.FEBS Lett. 2015; 589: 2931-2943Crossref PubMed Scopus (150) Google Scholar, Dekker and Mirny, 2016Dekker J. Mirny L. The 3D genome as moderator of chromosomal communication.Cell. 2016; 164: 1110-1121Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar). Prof. Peter Fraser (Babraham Institute, Cambridge, UK) reported on the progress in the further development of chromatin conformation capture technology that allows identification of spatial chromatin interactions in the nucleus. Fraser’s laboratory developed a promoter-capture Hi-C technology to identify distal sequences interacting with annotated gene promoters in 17 primary human hematopoietic cell types and several mouse cell types. In his talk, Peter Fraser reported that more than half of the identified interactions are cell type- or lineage-specific and preferentially link actively transcribed promoters with distal active enhancers. These population studies provide useful information on the range of genome interactions with exciting insights into human genetic variation and disease (Gilbert and Fraser, 2015Gilbert D.M. Fraser P. Three dimensional organization of the nucleus: adding DNA sequences to the big picture.Genome Biol. 2015; 16: 181Crossref PubMed Scopus (3) Google Scholar). Drs. Mike Fessing and Andrei Mardaryev (University of Bradford, UK) presented the data on the higher-order chromatin organization of the epidermal differentiation complex locus in keratinocytes (Botchkarev et al., 2012Botchkarev V.A. Gdula M.R. Mardaryev A.N. Sharov A.A. Fessing M.Y. Epigenetic regulation of gene expression in keratinocytes.J Invest Dermatol. 2012; 132: 2505-2521Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, Fessing, 2014Fessing M.Y. Gene regulation at a distance: higher-order chromatin folding and the coordinated control of gene transcription at the epidermal differentiation complex locus.J Invest Dermatol. 2014; 134: 2307-2310Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, Fessing et al., 2011Fessing M.Y. Mardaryev A.N. Gdula M.R. Sharov A.A. Sharova T.Y. Rapisarda V. et al.p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis.J Cell Biol. 2011; 194: 825-839Crossref PubMed Scopus (129) Google Scholar, Mardaryev et al., 2014Mardaryev A.N. Gdula M.R. Yarker J.L. Emelianov V.U. Poterlowicz K. Sharov A.A. et al.p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells.Development. 2014; 141: 101-111Crossref PubMed Scopus (62) Google Scholar). These talks conclude that spatial interactions within and between lineage-specific gene loci in keratinocytes are essential for coordinated regulation of gene expression, implicating their role in governing epithelial differentiation and function. Dr. Christina de Guzman Strong (Washington University, St. Louis, MO) identified previously dynamic chromatin remodeling and activation of the epidermal differentiation complex locus with respect to an epidermal-specific enhancer, 923, thus enabling enhancer-centric studies to elucidate transcriptional activation (Oh et al., 2014Oh I.Y. Albea D.M. Goodwin Z.A. Quiggle A.M. Baker B.P. Guggisberg A.M. et al.Regulation of the dynamic chromatin architecture of the epidermal differentiation complex is mediated by a c-Jun/AP-1-modulated enhancer.J Invest Dermatol. 2014; 134: 2371-2380Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Data presented in her talk show that intraepidermal differentiation complex chromatin contacts are enriched with respect to the 923 enhancer and Flg promoter and that transchromatin interactions enriched in loci are involved in the control of gene expression and epidermal function. Dr. Huiqing Jo Zhou (Radboud University, Nijmegen, The Netherlands) reported on epigenome profiling of differentiating human primary epidermal keratinocytes and characterized a catalog of dynamically regulated genes and p63-bound enhancers that are relevant for epidermal development and related diseases (Kouwenhoven et al., 2015Kouwenhoven E.N. Oti M. Niehues H. van Heeringen S.J. Schalkwijk J. Stunnenberg H.G. et al.Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation.EMBO Rep. 2015; 16: 863-878Crossref PubMed Scopus (95) Google Scholar). Dr. Zhou concluded that p63 bookmarks the genomic loci as a placeholder and functions as a pioneer factor, recruiting other co-regulators to modify the chromatin environment and regulate genes through temporal- and spatial-specific active enhancers during epithelial and epidermal development. Noncoding RNAs, including microRNAs, play pivotal roles in the control of gene expression (Botchkareva, 2012Botchkareva N.V. MicroRNA/mRNA regulatory networks in the control of skin development and regeneration.Cell Cycle. 2012; 11: 468-474Crossref PubMed Scopus (48) Google Scholar, Wang and Chang, 2011Wang K.C. Chang H.Y. Molecular mechanisms of long noncoding RNAs.Mol Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (3246) Google Scholar, Yi and Fuchs, 2012Yi R. Fuchs E. A miR image of stem cells and their lineages.Curr Top Dev Biol. 2012; 99: 175-199Crossref PubMed Scopus (14) Google Scholar). Dr. Rui Yi (University of Colorado, Boulder, USA) reported on his studies of the role of microRNA-mediated mechanisms in the control of skin development, including general factors of microRNA biogenesis such as Dgcr8, Xpo5, Dicer, and Argonaute, as well as individual microRNAs such as miR-203/205/200s (Jackson et al., 2013Jackson S.J. Zhang Z. Feng D. Flagg M. O'Loughlin E. Wang D. et al.Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation.Development. 2013; 140: 1882-1891Crossref PubMed Scopus (61) Google Scholar, Wang et al., 2013Wang D. Zhang Z. O'Loughlin E. Wang L. Fan X. Lai E.C. et al.MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway.Nat Cell Biol. 2013; 15: 1153-1163Crossref PubMed Scopus (101) Google Scholar). He also presented the results of his recent work showing that adaptive expression of a Foxc1-Nfatc1-bone morphogenic protein network in the activated hair follicle stem cells is required to reinforce the quiescent cellular state and maintain the stem cell identity, illustrating an unexpectedly dynamic response by quiescent stem cells to self-renewal (Wang et al., 2016Wang L. Siegenthaler J.A. Dowell R.D. Yi R. Foxc1 reinforces quiescence in self-renewing hair follicle stem cells.Science. 2016; 351: 613-617Crossref PubMed Scopus (86) Google Scholar). Dr. Michaela Frye (University of Cambridge, UK) spoke about the role of RNA modifications in the control of cell differentiation. Studies from Frye’s laboratory showed that cytosine 5 methylation is a common posttranscriptional modification in transfer RNA and that hypomethylation of transfer RNAs causes the up-regulation of cellular stress pathways and a global reduction of protein synthesis (Blanco and Frye, 2014Blanco S. Frye M. Role of RNA methyltransferases in tissue renewal and pathology.Curr Opin Cell Biol. 2014; 31: 1-7Crossref PubMed Scopus (81) Google Scholar). Data obtained in Frye’s laboratory show that activation of stress response pathways drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumorigenesis (Blanco et al., 2016Blanco S. Bandiera R. Popis M. Hussain S. Lombard P. Aleksic J. et al.Stem cell function and stress response are controlled by protein synthesis.Nature. 2016; 534: 335-340Crossref PubMed Scopus (244) Google Scholar). Dr. Markus Kretz (University of Regensburg, Germany) continued the discussion on the role of noncoding RNAs in the control of epidermal differentiation. Using human organotypic epidermis as a model system, Kretz’s laboratory aims to understand how long noncoding RNAs help regulate the intricate balance between progenitor cells undergoing continual regeneration and highly differentiated cells forming the mature tissue environment and how this balance is affected during cancer progression. Kretz’s recent work shows that several long noncoding RNAs play important roles in regulating the homeostasis of normal epidermal tissue and might also be implicated in its neoplastic progression (Thorenoor et al., 2016Thorenoor N. Faltejskova-Vychytilova P. Hombach S. Mlcochova J. Kretz M. Svoboda M. et al.(Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer.Oncotarget. 2016; 7: 622-637Crossref PubMed Scopus (63) Google Scholar). Dr. Anna Mandinova (Harvard University, Charlestown, MA) reported that YBX1 mRNA binding protein negatively controls the translation of a senescence-associated subset of cytokine mRNAs in epidermal progenitor cells, thus suggesting YBX1 as a critical posttranscriptional effector required for maintenance of epidermal tissue homeostasis. Dr. Eleonora Candi (University of Rome, Italy) spoke about the role of noncoding transcripts with ultraconserved element in keratinocytes differentiation (Marini et al., 2016Marini A, Lena AM, Panatta E, Ivan C, Han L, Liang H, et al. Ultraconserved long non-coding RNA uc.63 in breast cancer. Oncotarget 2016; August 2016.Google Scholar). Candi’s laboratory identified ultraconserved element 291 as a crucial player, with knockdown results in enhanced proliferation and significant reduction of the terminal differentiation program. These results indicate that noncoding transcripts with ultraconserved element have a key role in driving keratinocyte terminal differentiation. Prof. Daniel Aberdam (University of Paris, France) spoke about progress in showing an important role of exosomes as mRNA and microRNA transporting elements in intercellular communications and signaling (Erbani et al., 2016Erbani J. Aberdam D. Larghero J. Vanneaux V. Pluripotentstem cells and other innovative strategies for the treatment of ocular surface diseases.Stem Cell Rev. 2016; 12: 171-178Crossref PubMed Scopus (15) Google Scholar). Normal human keratinocytes release exosomal microRNAs that modulate pigmentation of melanocytes, and the cutaneous wound healing response can be modulated by exosomes derived from mesenchymal stem cells through the activation of the Wnt pathway, angiogenesis, and extracellular matrix remodeling. These data show a potential for using exosomes as a novel approach for modulating gene expression in distinct skin cell populations and managing skin disorders. Spatial genome organization and expression of many components of epigenetic regulatory machinery are markedly changed during aging (Chandra and Kirschner, 2016Chandra T. Kirschner K. Chromosome organisation during ageing and senescence.Curr Opin Cell Biol. 2016; 40: 161-167Crossref PubMed Scopus (36) Google Scholar). Prof. Peter Adams (University of Glasgow/Beatson Institute for Cancer Research, Scotland) discussed the role for cellular senescence as a stable proliferation arrest implicated in tumor suppression and aging. In melanocytes, diverse senescence can contribute to tumor suppression, a debilitating congenital syndrome (congenital melanocytic nevus syndrome) and cell aging. Dissecting the mechanisms of cell senescence in melanocytes is yielding insights to combat melanoma, treat congenital melanocytic nevus syndrome, and promote healthy aging (Rai and Adams, 2012Rai T.S. Adams P.D. Lessons from senescence: chromatin maintenance in non-proliferating cells.Biochim Biophys Acta. 2012; 1819: 322-331Crossref PubMed Scopus (50) Google Scholar). Dr. Eric Shirmer (University of Edinburgh, Scotland) spoke about how spatial genome organization contributes to the regulation of gene expression and the role of tissue-specific nuclear envelope transmembrane proteins that regulate positioning of specific subsets of genes during cell differentiation (Czapiewski et al., 2016Czapiewski R. Robson M.I. Schirmer E.C. Anchoring a leviathan: how the nuclear membrane tethers the genome.Front Genet. 2016; 7: 82Crossref PubMed Scopus (42) Google Scholar). During myogenesis, three muscle-specific nuclear envelope transmembrane proteins with genome organization functions influence the expression levels of 38% of all genes involved in muscle-specific differentiation. In Emery-Dreifuss muscular dystrophy patients, several of these spatial genome organization nuclear envelope transmembrane proteins from muscle serve as strong candidates contributing to the disease progression, suggesting that gene misregulation may contribute significantly to the Emery-Dreifuss muscular dystrophy pathophysiology. Dr. John Connelly (Queen Mary University of London, UK) reported that transmission of mechanical forces to the nucleus play a role in the intracellular positioning, mitosis, and cell motility. Connelly’s laboratory showed that cross-talk between the cytolinker plectin and F-actin controls keratin network organization and the three dimensional nuclear morphology of keratinocytes (Almeida et al., 2015Almeida F.V. Walko G. McMillan J.R. McGrath J.A. Wiche G. Barber A.H. et al.The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes.J Cell Sci. 2015; 128: 4475-4486Crossref PubMed Scopus (34) Google Scholar). Data from Connelly’s laboratory suggest that the biophysical cues may directly regulate chromatin remodeling in keratinocytes and raise interesting questions about the impact on epidermal cell fate and function. Prof. Karima Djabali (Technical University Munich, Germany) spoke about Hutchinson-Gilford progeria premature aging syndrome, which eventuates in the production of a mutant form of the nuclear lamin A (or progerin). Progerin is accumulated in dermal fibroblasts and selected terminally differentiated keratinocytes of aged individuals (McClintock et al., 2007McClintock D. Ratner D. Lokuge M. Owens D.M. Gordon L.B. Collins F.S. et al.The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.PLoS One. 2007; 2: e1269Crossref PubMed Scopus (261) Google Scholar) and is expressed in vascular cells, resulting in vessel wall cell loss and replacement by fibrous tissue. This provides the basis for further study of the potential role of abnormal forms of lamin A in the process of normal skin aging (Eisch et al., 2016Eisch V. Lu X. Gabriel D. Djabali K. Progerin impairs chromosome maintenance by depleting CENP-F from metaphase kinetochores in Hutchinson-Gilford progeria fibroblasts.Oncotarget. 2016; 7: 24700-24718Crossref PubMed Scopus (16) Google Scholar). Dr. Andrey Sharov (Boston University, MA) reported about the role of Lsh, a member of the SNF2 chromatin-remodeling family, which is involved in the control of DNA methylation patterns during embryonic development. Prof. Cord Brakebusch (University of Copenhagen, Denmark) spoke about epigenetic control of IL-23 expression in keratinocytes involving histone methylation, which is regulated by tumor necrosis factor and the actin cytoskeletal organizer N-WASP (Lefever et al., 2010Lefever T. Pedersen E. Basse A. Paus R. Quondamatteo F. Stanley A.C. et al.N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF{beta} pathways.J Cell Sci. 2010; 123: 128-140Crossref PubMed Scopus (28) Google Scholar). These data suggest a novel role for N-WASP in keratinocytes in the initiation of IL-23–dependent skin inflammation. Prof. Honglin Wang (Shanghai Jiao Tong University, China) reported that NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA miR-31, one of the most dynamic microRNAs identified in the skin of psoriatic patients and mouse models (Yan et al., 2015Yan S. Xu Z. Lou F. Zhang L. Ke F. Bai J. et al.NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.Nat Commun. 2015; 6: 7652Crossref PubMed Scopus (152) Google Scholar). Because dysfunctional regulatory T cells have been identified in individuals with psoriasis, Wang’s laboratory showed miR-31 and its target Gprc5a as critical regulators for regulatory T-cells generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional regulatory T cells in skin inflammation and psoriasis (Zhang et al., 2015Zhang L. Ke F. Liu Z. Bai J. Liu J. Yan S. et al.MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3.Nat Commun. 2015; 6: 7639Crossref PubMed Scopus (71) Google Scholar). Prof. J.T. Elder (University of Michigan, Ann Arbor, MI) continued discussion about the genetics and epigenetics of psoriasis (Li et al., 2014Li B. Tsoi L.C. Swindell W.R. Gudjonsson J.E. Tejasvi T. Johnston A. et al.Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms.J Invest Dermatol. 2014; 134: 1828-1838Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). Elder’s laboratory was testing the hypothesis that specific alterations in chromatin structure and gene regulation in skin-homing T cells and myeloid dendritic cells underlie the effects of many psoriasis-associated genetic variants. Data from his laboratory resulted in generation of genetic and epigenetic maps helping identify the regulatory variations underlying psoriasis genetic signals on a genome-wide basis. Dr. Malgorzata Wiench (University of Birmingham, UK) reported on how epigenetic mechanisms contribute to cancer initiation and progression in the context of the role for DNA modifications in the activity of distal regulatory elements in squamous cell carcinomas (Wiench et al., 2011Wiench M. John S. Baek S. Johnson T.A. Sung M.H. Escobar T. et al.DNA methylation status predicts cell type-specific enhancer activity.EMBO J. 2011; 30: 3028-3039Crossref PubMed Scopus (168) Google Scholar). Using genome-wide DNase I hypersensitive sites sequencing methods, Wiench’s laboratory identified squamous cell carcinoma-specific regulatory elements and showed that treatment with 5-aza-cytidine significantly alters the epigenetic landscape in cancer cells. Thus, identification of the DNA demethylation changes could potentially hold therapeutic value for squamous cell carcinoma. Finally, Dr. Oleg Fedorov (Oxford University, UK) spoke about distinct classes of small molecules that modulate the activity of epigenetic regulators in normal and neoplastic cells. The regulation of chromatin structure and gene expression is governed by a multitude of proteins that “write,” “read,” and “erase” histone marks. Fedorov highlighted the recent progress in the field of bromodomain inhibitors and their potential application in multiple disease areas such as inflammation and cancer (Hammitzsch et al., 2015Hammitzsch A. Tallant C. Fedorov O. O'Mahony A. Brennan P.E. Hay D.A. et al.CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.Proc Natl Acad Sci USA. 2015; 112: 10768-10773Crossref PubMed Scopus (160) Google Scholar, Montenegro et al., 2016Montenegro RC, Clark PG, Howarth A, Wan X, Ceroni A, Siejka P, et al. BET inhibition as a new strategy for the treatment of gastric cancer. Oncotarget 2016; June 2016.Google Scholar). The Symposium served as an important step in integrating research in skin and chromatin biology and provided a platform for further analyses of the epigenetic mechanisms that control reorganization of gene expression programs in different skin cell lineages during normal homeostasis and regeneration, as well as during skin aging and inflammatory and neoplastic skin disorders. The Symposium helped bridge the gap between our current knowledge of basic epigenetic mechanisms and understanding on how their alterations contribute to the development of pathological skin conditions, such as psoriasis and cancer. Hopefully, this symposium will help in the further development of skin epigenetics as a novel area of basic and applied cutaneous research and will promote the research toward generation of novel cohorts of epigenetic drugs for the treatment of skin disorders.