Đang tải... (xem toàn văn)
(BQ) Part 2 book Epigenetics and dermatology presents the following contents: Epigenetics and systemic sclerosis, epigenetics of allergic and inflammatory skin diseases, epigenetics and other autoimmune skin diseases, epigenetics and infectious skin disease, epigenetics of melanoma, epigenetics and aging,...
C H A P T E R 12 Epigenetics and Systemic Sclerosis Nezam Altorok1 and Amr H Sawalha2,3 Division of Rheumatology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH 2Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 12.1 INTRODUCTION Scleroderma is a term that encompasses most forms of thickened and sclerotic skin, including both localized (morphea, linear scleroderma, etc.) and systemic sclerosis (SSc) (limited, diffuse) variants SSc is a complex multisystem autoimmune disease that is characterized by three pathological hallmarks: activation of the immune system, vascular injury, and fibrosis of the skin and internal organs [1] There are two major subsets of SSc: diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) that are distinguished by the extent of skin thickening; lcSSc is characterized by skin thickening that is confined to the extremities distal to the elbows and knees with or without facial involvement, whereas dcSSc is characterized by skin thickening that involves areas proximal to the elbows and knees, including the trunk [2] Besides the extent of skin involvement, the two subsets of SSc have different patterns of organ involvement, autoantibody profiles, and survival rates For instance, patients with lcSSc are at risk for developing subcutaneous calcinosis, telangiectasia, malabsorption, digital ulcers, and pulmonary hypertension, whereas patients with dcSSc are at high risk for interstitial lung disease, renal failure, diffuse gastrointestinal disease, and Epigenetics and Dermatology 249 © 2015 Elsevier Inc All rights reserved 250 TABLE 12.1 12 EPIGENETICS AND SYSTEMIC SCLEROSIS Examples of Environmental Agents Linked to SSc Occupational exposures Welding; silica dusts; toxic oil; xenobiotics; pesticides; ultraviolet light exposure; organic solvents; epoxy resins; benzene; trichloroethylene; xylene; urea formaldehyde; and vinyl chloride Infectious agents Human cytomegalovirus Diet L-Tryptophan Drugs Methysergide; pentazocine; cocaine; talc; heroin; bleomycin; ethosuximide; vitamin K; and amphetamines myocardial involvement Anti-topoisomerase I (Scl-70) and anti-RNA polymerase antibodies are common in dcSSc, and anti-centromere antibodies are more common in the lcSSc subset Despite significant efforts, the identity of the initial trigger(s) of SSc remains a major challenge Current hypotheses suggest a possible infectious or perhaps chemical agent that activates the immune system that, in turn, causes vascular injury/dysfunction and persistent activation of fibroblasts [3] The end product of this interaction is deposition of collagens and extracellular matrix (ECM) glycoproteins in organs, which cause organ damage and dysfunction Over the last few years it became evident that substantial epigenetic aberrancies are present in SSc These findings stem from candidate gene and epigenome-wide studies and are supported by the striking geographic clustering of SSc [4] These observations suggest a role for an epigenetic program in the pathogenesis of SSc, driven by epigeneticÀenvironmental factors The environmental factors that are involved in the pathogenesis of SSc are by large uncharacterized However, epidemiological and experimental data have linked a number of occupational exposures to the development of SSc (Table 12.1) In this chapter, we briefly discuss the pathogenesis of SSc; we then explore evidence for epigenetic aberrancies in DNA methylation, histone code, and altered expression of microRNAs (miRNAs) across different cell types that are involved in the pathogenesis of SSc 12.2 PATHOGENESIS OF SSc The current paradigm suggests that the pathogenesis of SSc is based upon a complex interaction between activation of the immune system and vascular damage, in association with fibroblast activation, which leads to progressive tissue fibrosis [5] IMMUNOLOGIC SKIN DISEASES 12.2 PATHOGENESIS OF SSc 251 Activation of the immune system SSc is a connective tissue disorder that is characterized by chronic deregulation of the immune system It appears that the most prominent effect of immune system deregulation occurs in the early phases of SSc, based on the observation that there are significant inflammatory cell infiltrates in the skin in the early phases of SSc [6] In addition, there is significant upregulation of growth factors and cytokines in skin and sera samples, respectively, from patients with SSc [7] Moreover, SSc is characterized by the presence of disease-specific circulating autoantibodies These observations suggest that activation of the immune system is a key feature in SSc a T lymphocytes in SSc T lymphocytes contribute to the pathogenesis of SSc Although the total number of peripheral blood T lymphocytes in SSc is not increased and in fact may be lower than that in healthy people, there is evidence for activation of circulating T lymphocytes in SSc [8] In addition, there is evidence for T-lymphocyte infiltration in lung and skin tissues in the early phases of SSc [9] b B lymphocytes B cells, among other immune cells, are activated in SSc, as manifested by the presence of circulating antibodies, hypergammaglobulinemia, stimulation of polyclonal B cells, and overexpression of CD 19 molecules on naăve and memory B lymphocytes [10] Although the number of naăve B cells is increased in SSc, the number of memory B cells is reduced, but they are activated [11] Human B lymphocytes are a source of transforming growth factor-β (TGF-β) and express receptors for TGF-β [12], and B lymphocytes secrete IL-6 TGF-β and IL-6 may activate fibroblasts and induce upregulation of collagen production c Other immune cells In SSc, several cell types contribute to activation of the immune system; for example, dendritic cells, macrophages, and natural killer cells play an important role in the production of type I interferon, which is upregulated in SSc [13] Vascular injury/dysfunction Vascular damage occurs early in the course of SSc as suggested by the presence of Raynaud’s phenomenon There is evidence for abnormal microvascular endothelial cell (MVEC) function and structure in SSc [14] MVEC dysfunction leads to a host of changes in the blood vessels, including obliterative vasculopathy, that eventually results in a state of chronic tissue ischemia [3] IMMUNOLOGIC SKIN DISEASES 252 12 EPIGENETICS AND SYSTEMIC SCLEROSIS Role of fibroblasts in SSc Fibroblasts play an important role in the pathogenesis of SSc, especially considering that fibroblasts are the most proximate cell for collagen production In comparison to normal fibroblasts, SSc fibroblasts produce more collagen [15] and are characterized by increased proliferation and decreased apoptosis in vitro [16] Moreover, SSc fibroblasts exhibit increased responsiveness to TGF-β [17], and in response overexpress α-smooth muscle actin (α-SMA), which is a marker of myofibroblasts Additionally, fibroblasts play a role in activation of the immune system via production of numerous cytokines and chemokines and upregulation of adhesion and costimulatory molecules Fibroblasts are frequently detected near small blood vessels surrounded by inflammatory cellular infiltrate in the early stages of SSc [18] These observations highlight an important role for fibroblasts in the pathogenesis of SSc that goes beyond collagen production and expansion of ECM, to involve activation of the immune system The TGF-β signaling pathway is the most potent stimulus for myofibroblast differentiation as demonstrated by a robust fibrotic response upon exposure of fibroblasts to TGF-β, along with upregulation of matrix gene expression, and myofibroblast transformation [19] Other fibrotic pathways are also important in SSc, such as the Wnt/β-catenin, Hedgehog, and JaggedÀNotch signaling pathways Collagen gene transcription in fibroblasts is modulated by several profibrotic cytokines and transcription factors Friend leukemia integration-1 (Fli-1) is one of the transcription factors that repress expression of collagen [20] Fli-1 is among the transcription factors that are underexpressed in SSc fibroblasts SMAD3 is a profibrotic factor in the TGF-β downstream signaling cascade [21], whereas SMAD7 is an inhibitory factor that modulates TGF-β signaling [22] There is convincing evidence suggesting that deregulation of these factors and pathways in SSc fibroblasts results in an imbalance that favors increased collagen expression and tissue fibrosis 12.3 GENETIC FACTORS IN SSc Genome-wide and candidate-gene association studies have identified several genetic susceptibility loci in SSc (PTPN22, STAT4, IRF5, TNFSF4, SOX5, CD247, TBX21, CTGF, BANK1, FAM167A, HGF, C8orf13-BLK, KCNA5, NLRP1, CD226, IL2RA, IL12RB2, TLR2, and HIF1A, as well as several loci in the HLA region) [23,24] However, it appears that genetic factors account for a small proportion of SSc heritability [25] Concordance rate calculations between twin pairs help in identifying the IMMUNOLOGIC SKIN DISEASES 12.4 EPIGENETIC ABERRANCIES IN SSc 253 respective contributions of genetics and the environment in disease pathogenesis Studies have demonstrated low concordance rates in SSc monozygotic twins, which are not different from the rates seen in dizygotic twins (B5%) [25] Indeed, these observations underscore a prominent role for epigeneticÀenvironmental factors in the pathogenesis of SSc 12.4 EPIGENETIC ABERRANCIES IN SSc In general, epigenetic mechanisms regulate several aspects of chromatin structure and function, including regulation of the chromatin configuration and accessibility of the transcriptional machinery to gene regulatory regions In this section, we will explore the evidence supporting the role of aberrancies in the three epigenetic programs (DNA methylation, histone code modification, and altered expression of miRNAs) involved in the pathogenesis of SSc Fibroblasts It is not surprising to see that most of the studies that have evaluated epigenetics in SSc used dermal fibroblasts, because the skin is the most common tissue involved in SSc and is easily accessible for biopsy a DNA methylation aberrancies in fibroblasts The evidence is expanding regarding the role of DNA methylation aberrancies in the pathogenesis of SSc Genome-wide methylation studies and studies that evaluated candidate-gene DNA methylation have provided new insights into the role of DNA methylation in the pathogenesis of SSc Altered DNA methylation maintenance factors in SSc Similarly to the situation with other autoimmune diseases, the molecular mechanism by which DNA methylation is regulated in patients with SSc is still elusive, but there is evidence of altered levels of epigenetic maintenance mediators—specifically, increased expression levels of DNMT1 in cultured SSc fibroblasts, increased expression of methyl-CpG DNA-binding protein (MBD-1), MBD-2, and methyl-CpGbinding protein (MeCP-2) in SSc fibroblasts [26] Theoretically, these observations may explain the ability of cultured fibroblasts to maintain SSc phenotype over multiple generations by cellular epigenetic inheritance TGF-β signaling pathway TGF-β is considered one of the master-regulators of fibrosis It is generally accepted that activation of the TGF-β signaling pathway in SSc leads to a cascade of fibroblast activation [27] IMMUNOLOGIC SKIN DISEASES 254 12 EPIGENETICS AND SYSTEMIC SCLEROSIS and promotes the transition of fibroblasts and precursor cells toward persistently activated fibroblast phenotype, and upregulation of collagen and ECM [28] Genome-wide DNA methylation studies have shed light on altered DNA methylation in genes that are important in activation of the TGF-β signaling pathway For instance, ITGA9, which encodes for α integrin 9, is hypomethylated and overexpressed in SSc fibroblasts compared to controls [29] Integrins are a family of transmembrane receptors that bind extracellularly to the ECM and intracellularly to the cytoskeleton, thereby “integrating” the extracellular environment with the cell interior to control cell behavior [30] There is an interesting bidirectional interaction between integrins and TGF-β signaling in fibrosis, with TGF-β inducing integrin expression and several integrins directly controlling TGF-β activation including regulation of TGF-β downstream signaling pathway components [31] Upregulation of integrins has been demonstrated in SSc fibroblasts [32À34] and lung fibroblasts from patients with lung fibrosis [35] There is evidence that integrins contribute to fibroblast activation, persistent myofibroblast phenotype [36], and activation of TGFβ in fibrotic diseases [37] Moreover, in the same study, ADAM12 was hypomethylated and overexpressed in SSc fibroblasts ADAM12 contributes to the process of fibrosis through enhancing TGF-β signaling [38À41] Thus, in light of these observations, there appears to be a role for DNA methylation in upregulation of ITGA9 and ADAM12 that in turn contributes to persistent activation of the TGF-β pathway, which leads to tissue fibrosis in SSc Epigenetic aberrancies in transcription factors that are involved in collagen gene expression As set forth, there is an imbalance between profibrotic and antifibrotic factors in SSc There is evidence that levels of Fli-1, which is a transcription factor encoded by the FLI1 gene, are significantly reduced in SSc fibrotic skin and cultured SSc fibroblasts compared with healthy controls [20] Fli-1 is a negative regulator of collagen production by fibroblasts Therefore, it appears that reduced levels of Fli-1 may be responsible for increased collagen synthesis and accumulation in patients with SSc Of interest, studies have demonstrated heavy methylation of the promoter region of FLI1 in SSc fibroblasts [26] Indeed, exposure of SSc fibroblasts to 5azacytidine (5-AZA), a universal demethylating agent (DNMT1 inhibitor), resulted in reduced type I collagen production in vitro These observations demonstrate that DNA methylation IMMUNOLOGIC SKIN DISEASES 12.4 EPIGENETIC ABERRANCIES IN SSc 255 aberrancies contribute to excessive collagen production in SSc fibroblasts It is difficult to draw conclusions regarding the potential for 5-AZA as a treatment modality in fibrosis based on this evidence, as other profibrotic factors could be overexpressed due to the global demethylation effect of 5-AZA on the genome, and, hence, there is a risk of paradoxical activation of the fibrotic process or autoimmunity Furthermore, there is evidence for DNA methylation aberrancies in genes encoding transcription factors that are indirectly involved in collagen production RUNX1 and RUNX2 are transcription factors that induce expression of SOX5 and SOX6, which leads to the induction of type II collagen expression [42,43] RUNX3, another member of the RUNX family, is also likely to contribute to collagen synthesis in association with RUNX2 [44] Hypomethylation of RUNX1, RUNX2, and RUNX3 associated with overexpression of at least RUNX3 in dcSSc and lcSSc has been established [29] These data indicate that alteration of DNA methylation could affect expression of transcription factors that play a role in collagen production by SSc fibroblasts DNA methylation aberrancies in collagen and ECM-protein encoding genes Tissue fibrosis is the most prominent clinical manifestation in SSc Fibrosis is the result of excessive production of collagen and ECM components, or defective remodeling of the ECM Studies have confirmed hypomethylation and overexpression of two collagen genes (COL23A1, COL4A2) in dcSSc and lcSSc fibroblasts compared to control fibroblasts [29], in addition to hypomethylation of several collagen genes in each subset separately [29] Moreover, TNXB was hypomethylated in dcSSc and lcSSc fibroblasts [29] TNXB encodes a member of the tenascin family of ECM glycoproteins, which are involved in matrix maturation [45] The Wnt/β-catenin signaling pathway There is an increasing interest in the role of the Wnt/ β-catenin signaling pathway as one of the profibrotic pathways in SSc Studies have demonstrated persistent activation of the Wnt/β-catenin pathway as demonstrated by localization of β-catenin in fibroblast-like cells present in affected tissues [46] Moreover, stimulation of normal fibroblasts with Wnt ligands results in β-catenin-mediated expression of collagen and other matrix genes, and enhanced myofibroblast differentiation and increased cell migration as expected in SSc [47,48] In SSc, canonical Wnt signaling is activated by overexpression of Wnt IMMUNOLOGIC SKIN DISEASES 256 12 EPIGENETICS AND SYSTEMIC SCLEROSIS proteins and by downregulation of the endogenous Wnt antagonists The intensity and duration of Wnt/β-catenin signaling is normally tightly regulated by endogenous inhibitors There is evidence of reduced expression of the endogenous Wnt antagonists, DKK1 and SFRP1, due to hypermethylation of the promoter region of DKK1 and SFRP1 in SSc fibroblasts [49] On the other hand, there is evidence of hypomethylation of genes representative of the Wnt/β-catenin pathway in SSc—specifically, we demonstrated recently hypomethylation of CTNNA2 and CTNNB1 in dcSSc fibroblasts, and CTNNA3 and CTNND2 in lcSSc fibroblasts compared to control fibroblasts [29] These findings suggest that DNA methylation aberrancies contribute to decreased expression of Wnt antagonists and increased expression of Wnt ligands and probably contribute to chronic activation of Wnt/β-catenin pathway signaling in SSc Cadherins Cadherins are a group of transmembrane glycoproteins that mediate calcium-dependent homophilic cell-to-cell adhesion at adherens junctions [50] Microarray studies have demonstrated overexpression of CDH11, which encodes cadherin-11, in fibroblasts from patients with SSc [51,52] Moreover, Cdh11deficient mice developed less fibrosis in bleomycin-induced fibrosis [53] There is evidence for hypomethylation of CDH11 in dcSSc fibroblasts in comparison to fibroblasts from healthy controls [29] It is possible that hypomethylation of CDH11 contributes to its overexpression, which facilitates the differentiation of resident tissue fibroblasts into myofibroblasts in SSc The methylome in dcSSc versus lcSSc fibroblasts Recently, a genome-wide DNA methylation study demonstrated an interesting difference in DNA methylation aberrancies between dcSSc and lcSSc subsets in reference to healthy fibroblasts The study demonstrated 3528 differentially methylated CpG sites in SSc, of which there were only 203 (B6%) CpG sites differentially methylated in both dcSSc and lcSSc This finding suggests an interesting divergence of the DNA methylome at the genome-wide level between dcSSc and lcSSc that reflects heterogeneity at the epigenome level in scleroderma subsets [29] Therefore, it is prudent to evaluate DNA methylation aberrancies and probably other epigenetic mechanisms in SSc in subset-specific approaches b Histone modification aberrancies in SSc fibroblasts We have discussed DNA hypermethylation and repression of FLI1 in SSc fibroblasts early in this chapter It is interesting to note that there is also significant reduction of histone H3 and H4 IMMUNOLOGIC SKIN DISEASES 12.4 EPIGENETIC ABERRANCIES IN SSc 257 acetylation in the promoter region of the FLI1 gene in SSc fibroblasts compared to healthy fibroblasts [26] Moreover, trimethyl histone H3 on lysine 27 (i.e H3K27me3), which is a potent repressor mark for target gene transcription, is increased in SSc fibroblasts in comparison with controls [54] Altogether, these observations indicate that there are defects in the histone code in SSc, and that cross-talk between DNA methylation and histone modification changes can be involved in the pathogenesis of SSc, as demonstrated by FLI1 repression in SSc fibroblasts c miRNA expression aberrancies in fibroblasts Briefly, miRNAs are small noncoding RNAs (generally 19À25 nucleotides in length) that play important regulatory roles mainly by cleavage or translational repression of targeted mRNAs Many miRNAs are reported to be differentially expressed in SSc, suggesting that miRNA dysregulation plays a role in the pathogenesis of SSc miRNA regulation of the TGF-β signaling pathway TGF-β mediates fibrosis positively by activating its downstream mediators, SMAD2 and SMAD3, but negatively via its inhibitory factor SMAD7 miR-21, which is upregulated in SSc fibroblasts [55], targets SMAD7 Overexpression of miR21 in SSc fibroblasts decreases levels of SMAD7, whereas knockdown of miR-21 increases SMAD7 expression [56,57] Therefore, miR-21 probably exerts a profibrotic effect by negatively regulating SMAD7 in SSc fibroblasts Altered expression of several other miRNAs in SSc with putative targets in the TGF-β downstream pathway (such as miR145, miR-146, and miR-503) has also been demonstrated (Table 12.2) miRNAs directly target collagen genes in SSc miR-29 underexpression was reported in skin fibroblasts from patients with SSc, as well as fibroblasts from the mouse model of bleomycin-induced skin fibrosis [65] It was demonstrated that induced expression of miR-29 in SSc fibroblasts reduces the expression of its target genes, and collagen type I and type III Other potential targets for miRNA-29 include profibrotic molecules such as platelet-derived growth factor B (PDGF-B) and thrombospondin Of significant interest, the stimulatory effects of TGF-β and PDGF-B on collagen synthesis were reduced by inducing the expression of miR-29 [65] On the other hand, downregulation of miR-29 leads to further upregulation of TGF-β and PDGF-B Taken together, these data argue for an antifibrotic role of miR-29 in SSc IMMUNOLOGIC SKIN DISEASES 258 TABLE 12.2 Gene/pathway 12 EPIGENETICS AND SYSTEMIC SCLEROSIS Summary of Key Epigenetic Aberrancies Reported in SSc Epigenetic defect Cell type Putative target/ mechanism of action in SSc References DNA METHYLATION COL4A2yz, COL23A1yz, COL8A1y, COL16A1y, COL29A1y, COL1A1z, COL6A3z, COL12A1z Hypomethylation Fibroblasts Likely contributes to overexpression of collagen genes [29] PAX9yz Hypomethylation Fibroblasts Hypomethylation of PAX9 may contribute to the process of fibrosis by overexpression of pro-α chain of type I collagen [29] TNXByz Hypomethylation Fibroblasts Unclear; possible overexpression of ECM glycoproteins [29] ITGA9yz Hypomethylation Fibroblasts Hypomethylation of ITGA9 contributes to ITGA9 overexpression in SSc ITGA9 plays an integral role in myofibroblast differentiation and activation of TGF-β signaling pathway [29] RUNX1yz, RUNX2yz, RUNX3yz Hypomethylation Fibroblasts Indirectly induce expression of type II collagen by increasing expression of SOX5 and SOX6 [29] ADAM12yz Hypomethylation Fibroblasts ADAM12 overexpression in SSc contributes to fibrosis by inducing TGF-β signaling pathway [29] (Continued) IMMUNOLOGIC SKIN DISEASES 490 INDEX Chromosome open reading frame (C2orf3), 44t Chronic urticaria (CU), 297À299 CI-994, 427 Cirrhosis, liver fibrosis and, 54À55 Clinically amyopathic DM (CADM), 318 C-myc oncogene, 329 COL1A1 gene, 398 COL4A2 gene, 255 COL23A1 gene, 255 Cold urticaria, 299 Collagen gene, 385 DNA methylation aberrancies in, 255 epigenetic aberrancies in transcription factors in, 254À255 miRNAs target in SSc, 257À261 Combined bisulfite and restriction analysis (COBRA), 10 Comorbidities, psoriasis-related, 229 Connective tissue disease (CTD), 186À187, 316 Connective tissue growth factor (CTGF), 385 CpG dinucleotides, 369À370, 444 CpG islands (CGI), 14, 344, 412, 421 hypermethylation of, 231 CpG methylator phenotype (CIMP), 344À346 CpG sites, 3À4, 13À14, 280 Crotonylation, 120t CTCF (11-zinc finger protein), 99 CTNNA2, 255À256, 258t CTNNA3, 255À256, 258t CTNNB1, 255À256, 258t CTNND2, 255À256, 258t Cutaneous leukocyte antigen (CLA), 364 Cutaneous malignant melanoma (CMM) See Melanoma Cutaneous squamous cell carcinoma, 188À190 Cutaneous T-cell lymphoma (CTCL), 192À194, 363 Cyclin D1 (CCND1), 190À191 Cytidine, DNA methylation of, 472f Cytokines, 449 Cytosine, 3À4 demethylation, 211À212 Cytosine-phosphate-guanosin dinucleotides (CpGs), 86 Cytotoxic T lymphocyte-associated protein 4, 185 Cytotoxic T-cell lymphocyte antigen 4, 281 D D816V c-kit mutation, 294 Darier sign, 296 De novo DNA methyltransferases, 344 Decitabine, 126, 352, 449t Deimination, 120t Dermal epidermal junction (DEJ) zone, 395À396 Dermatomyositis (DM) epigenetic in, 316À318 Gottron’s papules, 318 miRNAs in, 313t, 318 PCR analysis, 318 Dermatopontin, expression of, 398 Desmoplastic melanoma, 341 Diacetylspermine (DASp), 420À421 DIANA-microT, 29 Dicer, 80À81, 101, 179f Dickkopf-1, 62À63 Diet autoimmune diseases, 469À470 and lupus, 218À219 and nutrition, 264À265 Differentially methylated regions (DMRs), 289 Digital ulcer, systemic sclerosis and, 55 Dihydrouridine synthase 3-like (DUS3L), 44t Dimethylarginine dimethylaminohydrolase (DDAH2), 389 and keratinocytes regulation, 385 2,4-Dinitrofluorobenzene (DNFB), 186 Diphenylcyclopropenone (DPCP), 186 DKK1, 63À64, 255À256, 258t DNA demethylation, 211f and environmental factors, 479 of T cells, 216À217 environmental causes, 217À219 DNA hypermethylation, 117, 320, 344À346, 448 DNA hypomethylation, 46À47, 117, 317, 343À344, 425À426 DNA methylation, 3À4, 44t, 56À57, 78À79, 78t, 86, 103, 145, 258t, 307, 369À370, 444À453 aberrancies in collagen and ECM-protein encoding genes, 255 in fibroblasts, 253À256 aberrancies in T-lymphocytes, 262À263 alterations in nitric oxide synthesis, 261À262 INDEX altered maintenance factors in SSc, 253 analysis, 7À16 animal studies involving modulation of, 115À116 in atopic dermatitis, 279À280 and autoimmune disease, 471À473, 475t and cancer, 370À372 environmental factors, influence of, 476f epigenetic therapy in autoimmune diseases, 449À453 genome-scale, 13À16 microarray-based analysis of DNA methylation changes, 14À15 next-generation sequencing techniques, 16 histone acetylation enzymes/histone deacetylation enzymes, 445 histone deacetylation enzyme inhibitors, 446 histone methyltransferases/histone demethylases, 446À447 histone modification, 444À445 human cancer and, 117 importance of, 45À46 keratinocyte differentiation and, 41 and liver fibrosis, 61À62, 61f and lung fibrosis, 58À60, 59f lupus, 210À217, 220 and gender, 219À220 5mC from cytosine, methods to distinguishing, 8f bisulfite conversion technique and derivatives, 9À11 immunoprecipitation-based methods, 11À12 mass spectrometry-based methods, 12À13 restriction endonuclease-based analysis, 8À9 in MVEC apoptosis, 262 and overall aging in skin, 388À389 in psoriasis, 231À235, 289, 290f epigenomic profiling, 231À232 profiling, 232À233 of specific genes, 233À235 regulation of, 115À119, 116t DNA methyltransferase DNMT3a, 117À118 and systemic sclerosis, 63À65, 64f targeting, 352À353 T cell DNA methylation See T cell DNA methylation 491 and T cell gene expression, 212À213 TET proteins and use of epigenetic therapy in cancer, 447À449 DNA methyltransferases (DNMTs), 3À4, 56À57, 86, 310, 311t, 315À316, 370À371, 411À412, 471À472 and autoimmunity, 477À479 DNMT1, 46, 56À57, 63À64, 78À79, 78t, 103À104, 279, 330À331, 370, 379À380, 411À412 atopic dermatitis, 279 mRNA levels of, 232À233 DNMT3a, 56À57, 93À94, 115, 116t, 379À380 DNMT3b, 56À57, 115, 379À380 DNMT3L, 56À57, 236 DNA modifications on hair follicle stem cells, 78À79, 78t DNA repair Ku70, 147 signaling, sirtuins in, 149À150, 158t Dnmt1, 115À116, 145, 211À212, 216, 218, 221, 253, 262 DOT1L, histone methyltransferase, 122 DPP4 gene, 422 Dr3 protein, 421 Drosha, 101, 179f Drosophila cells, 19 Drug-induced lupus (DIL), 214À215, 469À470 E E4BP4, expression of, 420 E6 associated protein (E6AP), 334 E-cadherin, 47t ECM-protein encoding genes, DNA methylation aberrancies in, 255 Effector T cells, 87À88 Eland, 22 Embryonic stem cells (ESCs), 79À80 Enhancer of zeste homologue (EZH2), 390 Environmental factors, 469À471 drugs and diet, 469À470 epigenetics and, 473 infectious agents, 469 respiratory exposures, 470 EperstainÀBar virus (EBV), 320 Epidermal differentiation complex (EDC) gene, 39À41 Epidermis, defined, 42 492 INDEX Epigenetic modulation, 42 defined, 41 histologic analysis of epidermal sample, 43f in keratinocyte differentiation, 41À45 Epigenetic regulation on hair follicle stem cells, 77À81, 78t of IL-10, 95À98, 97f Epigenetic therapy, for cancer, 126À127 Epigenetics, 54, 77À78 biology of, 56À58 DNA methylation, 56À57 histone modifications, 57À58 defined, 3, 56, 113, 230À231, 379À380, 409À410 DNA methylation analysis, 7À16 genome-scale, 13À16 principles to distinguishing 5mC from cytosine, 8À13 and fibrosis, 58À65 histone modification analysis, 19À24 laboratory methods in, and liver fibrosis, 61À63, 61f DNA methylation and, 61À62 histone modifications and, 62À63 and lung fibrosis, 58À61, 58t DNA methylation and, 58À60 histone modifications and, 60À61 mechanism in, 4À5 microRNAs analysis, 25À30 recent advances in, 114 role in pathogenesis, and skin diseases, 45À48 and systemic sclerosis, 63À65 DNA methylation and, 63À65 histone modifications and, 65 techniques used for 5hmC mark detection, 16À19 Epigenome-wide association studies (EWAS), 428, 473À475 Epigenomic profiling in psoriasis, 231À232 EpithelialÀmesenchymal transition (EMT), 349À350 Epithelium, stratified, 39À41 EpsteinÀBarr virus (EBV), 329 ERK, 341À342 ERK1, 96À97 ERK2, 96À97 ETS (E-twentysix), 92À93 Euchromatin, 61f, 414À415 EX-527, 164t EZH2, histone lysine 27 methyltransferases, 122À123 F Fas promoter, 60À61 F-box and leucine-rich repeat protein 17 (FBXL17), 44t 5fC (5-formylcytosine), 16À19 FceR1G promoter, 279À280 FHIT, 47t Fibroblast growth factor receptor (FGFR2), 239À240 Fibroblasts, 37 DNA methylation aberrancies in, 253À256 methylome in diffuse cutaneous vs limited cutaneous, 256 miRNA expression aberrancies in, 257À261 role in systemic sclerosis, 252 Fibrosis autoimmunity and, 65À66 defined, 53À54 epigenetic regulations in, 59f epigenetics and, 58À65, 58t incidence and prevalence of, 54À55 Filaggrin, 280, 283 null mutation of, 278 FLI1 gene, 254À255, 258t Fluorescence correlation spectroscopy method, 27À28 Follicular epithelial stem cell, 75À76 Forkhead box (FOX) family of transcription factors, 146À147 Forkhead box P3 (Foxp3), 92À93 Formylation, 120t 14À13À3s gene, 47t Friend leukemia integration-1 (Fli-1), 252 G G9A, 121t, 124 GATA3, 367 GATA-binding factor (GATA)3, 90 Gene expression, in keratinocyte differentiation, 39À41 Gene ontology (GO) analysis, 232À233 Generalized vitiligo See Nonsegmental vitiligo (NSV) Genetic factors, in systemic sclerosis, 252À253 Genetics role, in disease, Genome wide linkage analysis, 279 INDEX Genome-scale DNA methylation analysis, 13À16 microarray assays in DNA methylation detection, comparison of, 15t microarray used in DNA methylation profiling, 14À15 next-generation sequencing techniques, 16, 17t sample preparation, 14 Genome-wide association studies (GWAS), 279, 428, 473À475 Germ line mutations, 342À343 Global hypomethylation, 389 β-Glucosyltransferase (β-GT), 16À19 Glutathione S-transferase PI (GSTP 1) hypermethylation, 448 Glycyl-l-histidyl-l-lysine (GHK), 397 5-gmC (β-glucosyl-5hydroxymethylcytosine), 16À19 Graft-versus-host disease, 214 Guttate psoriasis, 288, 293 H H3 lysine 27 trimethylation (H3K27me3), 390 H3 phoyphorylation at position serine 10 (H3S10p), 96À97 H3K methylation, 258t H3K27me3, 42, 78t, 79À80, 89À90, 258t, 420 H3K36me3, 123 H3K4 methylation, 62À63, 315À316 H3K4 trimethylation, 89À90 H3K4me3, 78t, 79À80 H3K79me2, 78t, 79À80 H4 acetylation, 258t, 320 Hair follicle (HF), 75À76 Hair follicle stem cells (HF-SCs), 75À76 applications of, 77 characteristics of, 76À77 epigenetic regulation on, 77À81, 78t DNA modifications, 78À79, 78t histone modifications, 78t, 79À80 microRNAs on, 78t, 80À81 identification of, 76 HDAC, 127 HDAC inhibitors (HDACi), 236À237, 347À348, 353, 393, 445À446, 449, 451À452 HDAC-7 gene, 65 Heavy metals and autoimmune disorders, 471 493 HELP (HpaII tiny fragment enrichment by ligation-mediated PCR), 15t Hematopoietic stem cells, 235 Hepatic encephalopathy, cirrhosis in, 54À55 Hepatic stellate cells, 61À62 epigenetic regulations in, 61f Herpes simplex viruses, 329À332 HSV1 AND -2 AND VZV, 332À333 human papilloma virus (HPV), 333À334 KSHV (HHV8), 331À332 HHV8 (KSHV), 329, 331À332 Hierarchical clustering, 38À39, 40f High-proliferative potential colony-forming cell (HPP-CFC) assay, 235 Histamine, 297 Histone lysine trimethylation (H3K4me3), 393 Histone lysine trimethylation (H3K9Me3), 60À61, 86 Histone lysine 18 acetylation (H3K18ac), 86 Histone lysine 27 methylation (H3K27me), 390À391 Histone lysine 27 trimethylation (H3K27me3), 86, 393À394 Histone acetylation, 4, 41, 57À58, 127, 392À393 Histone acetylation enzymes/histone deacetylation enzymes, 445 Histone acetyltransferases (HATs), 4, 141À142, 145À146, 235À237, 347, 414, 445À447 Histone deacetylase inhibitors (HDACi), 42À43, 138, 142, 331À332, 392, 449 Histone deacetylases (HDACs), 4, 236À237, 414, 444À447, 451 Histone deacetylation, 41, 57À58, 446 Histone deacetyltransferases (HDACs), 347À348 Histone demethylases (HDMs), 142 Histone H3 tail with lysine (H3K4), trimethylation of, 235À236 Histone H4 at lysine 20 (H4K20me3), 390 Histone methylation, 57À58, 58t, 333, 390À392 in HF-SCs, 79À80 INK4 loci, 390À391 p53 and Rb, 391À392 p63, 392 Histone methyltransferases (HMTs), 122À124, 142, 446À447 494 INDEX Histone modification, 57À58, 58t, 120t, 141À145, 235À237, 258t, 307, 311t, 444À445 aberrancies in SSc fibroblasts, 256À257 and autoimmune disease, 471À473 in B-lymphocytes, 263 challenges for, 24 ChIP-on-chip technique, 20À21 ChIP-seq, 21À23 advantages of, 23 motif finding, 22À23 peak calling, 22 read aligner, 22 workflow, 21 chromatin immunoprecipitation (ChIP), 19À20 enzymes in cancer, 121t EZH2, histone lysine 27 methyltransferases, 122À123 and gene expression, 25f on hair follicle stem cells, 78t, 79À80 histone lysine methyltransferases, 122 histone methyltransferases and demethylases, 123À124 keratinocyte differentiation and, 41 and liver fibrosis, 62À63 and lung fibrosis, 60À61 and lupus, 220À221 MLL, 122 in psoriasis, 236À237 in systemic lupus erythematosus, 47À48 and systemic sclerosis, 65 targeting, 353À354 Histone posttranslational modifications and chromatin remodeling, 347À349 Histone proteins, 86 HLA genes, 63À64 HLA-Cw6 allele and psoriasis, 230 HpaII-MspI, 8À9 HSV1 and -2 and VZV infection, 332À333 Human cancer and DNA methylation, 117 Human diploid fibroblasts (HDFs), 388 Human imprinting disorders, epigenetics in, 456 Human papillomavirus (HPV), 156À157, 333À334 HumanMethylation27 BeadChip microarray analysis, 389 Huntington’s disease (HD), 454t, 455 Hutchinson-Gilford progeria syndrome (HGPS) skin fibroblasts, 390 Hydeoxymethylation, 116t Hydralazine, 103 and drug-induced lupus, 470 50 -Hydroxymethylcytosine (5hmC) mark detection, 3À4, 7À8, 16À19, 81À82, 118À119 Hypermethylation of CpG islands, 231 Hyperproliferative skin disease, sirtuins in, 155 Hypomethylation in development of MF/ SS, 371 Hypothetical protein LOC151278 (FL00003#J32447), 44t Hypoxia, 265 -inducible factor (HIF), 265 in pulmonary fibrosis, 58À60 Hyroxylation, 120t I Idiopathic pulmonary fibrosis (IPF), 54, 58t IFN regulatory factor (IRF)4, 90 IFN/Ifn genes, 89À90 IGF-BP3, 47t Igh, 98À99 Igγ, 98À99 Igκ, 98À99 IL-1 receptor-associated kinase (IRAK-1), 238À239 IL2, 93À94 IL-4-induced Stat6, 90 IL-9, 90 IL-10, 90, 97À98, 221 epigenetic regulation of, 95À98, 97f IL-17, 95 dermatomyositis, 317À318 in pathogenesis of atopic dermatitis, 283 IL-17A gene, 93À94, 421À422 IL19, 97À98 IL-21, 90À92 IL-22, 90À92 IL-23, 90À92 IL-26, 90À92 Illumina Solexa Genome Analyzer, 21À22 Illumina/Solexa, NGS platform, 16, 17t Immune regulation influence of environmental factors on, 103À104 X chromosome for, 102 Immune system, activation of, 251 Immunoprecipitation-based methods, 11À12 methylated-CpG island recovery assay (MIRA), 12 INDEX methyl-binding (MB)-PCR, 12 Imprinting control regions (ICRs), 456 Indolent mastocytosis (ISM), 295À296 Infectious agents, 469 Infectious skin disease, epigenetics and, 327 herpes simplex viruses, 329À332 HSV1 AND -2 and VZV, 332À333 KSHV (HHV8), 331À332 human papilloma virus (HPV), 333À334 Inflammation, defined, 85 Inflammatory bowel disease (IBD), 449À451 Inflammatory skin diseases microRNAs in, 181À187 allergic contact dermatitis (ACD), 186 atopic dermatitis (AD), 185 connective tissue diseases, 186À187 psoriasis, 181À185 sirtuins, 153À155, 158t INK4 loci, 390À391 Interferon (IFN), 65À66 Interleukin-1 (IL-1), 65À66 Interleukin-4 (IL-4), 65À66 Interleukin-6 (IL-6), 65À66 Interleukin-10 (IL-10), 95À98, 310 Interleukin-13 (IL-13), 65À66 Intronic enhancer (I-SRE), 96 Introns, 231 Isoschizomers, 8À9 ITGA9, 253À254 ITGAL, 452 J JARID1C, 123 Jarid2, 78t, 79À80 JMJD3, 42 K K15-positive stem cells, 78À79 Kaposi’s sarcoma (KS), 331 KDM1A/LSD1/BHC110/AOF2, 121t KDM1B/LSD2, 121t KDM6A/UTX, 121t Keratinocyte differentiation calcium treatment for, 38À39 calcium-inducible genes in, 40f epigenetic modulation in, 41À45, 43f gene expression in, 39À41 Keratinocyte proliferation and differentiation, 181À183 Kinases, 142 KIR expression, 367À368 495 KIT (tyrosine kinase receptor), 294 KMT2A (MLL1), 121t KMT2B (MLL2), 121t KMT2C (MLL3), 121t KMT3A (SETD2), 121t KMT3B (NSD1), 121t KMT6 (EZH2), 121t KSHV (HHV8), 331À332 L Latency associated transcript (LAT), 332À333 Lentigo maligna melanoma (LLM), 340À341 LFA-1 gene, 213, 230 Lichen simplex chronicus (LSC), 48 Life Technologies/SOLiD, NGS platform, 16, 17t LINE-1 methylation, 48 Liver fibrosis, 54À55, 58t DNA methylation, 61À62, 61f epigenetics and, 61À63, 61f histone modifications and, 62À63 Long noncoding RNAs (lncRNAs), 5, 368 Luciferase reporter assays, 30 Lung fibrosis DNA methylation and, 58À60, 59f histone modifications and, 60À61 Lupus See Systemic lupus erythematosus (SLE) Lyko group study, 388À389 Lymphocyte genes, 370 Lysine methylation, 120t Lysine-specific demethylase-1 (LSD1), 123À124, 333 M MAGE genes, 343À344 MALDI-TOF mass spectrometry, 12À13 with base-specific cleavage, 13 with primer extension, 13 Malignant melanoma (MM) management of, 351 microRNAs in, 190À192 Malignant skin diseases microRNAs in, 187À194, 189f basal cell carcinomas (BCCs), 187À188 cutaneous squamous cell carcinoma, 188À190 cutaneous T-cell lymphoma (CTCL), 192À194 malignant melanoma, 190À192 496 INDEX Mammalian target of rapamycin (MTORC1), 331 Mapping and Assembly with Qualities (Maq) aligner, 22 Mass spectrometry-based methods, 12À13 MALDI-TOF mass spectrometry with base-specific cleavage, 13 with primer extension, 13 MassARRAY EpiTYPER, 12À13 Mastocytosis, 294À297 biomarkers of, 297 classification of, 296t diagnosis, 296À297 epidemiology, 294 epigenetics, 295 genetics, 294 Matrix metalloproteinases (MMPs), 152, 289 MBD2 gene, 232À233 MDScan program, 22À23 5-MeC, 421 MeCP2, 61À63, 115, 118À119, 232À233 MeDIP (methylated DNA immunoprecipitation), 11À12, 15t MeDIP-seq technology, 16, 289 MEIS1, 123 Melanin, 37, 340 Melanocytes, 37, 310À312, 340, 386 Melanoma, 3À4, 190À191, 339, 386, 453 epigenetic alterations of, 343À351 DNA hypermethylation, 344À346 DNA hypomethylation, 343À344 histone posttranslational modifications and chromatin remodeling, 347À349 noncoding RNAs, 349À351 polycomb group proteins (PcGs), 349 epigenetic drugs used in, 352t epigenetic drug treatment in, 352À354 targeting DNA methylation, 352À353 targeting histone modifications, 353À354 etiology and pathogenesis of, 341À351 genes showing DNA hypermethylation in, 345t genes showing DNA hypomethylation in, 343t genetic alterations of, 341À343 germ line mutations, 342À343 sporadic mutations, 341À342 genetic drug treatment in, 351 incidence and etiology of, 339 misregulated miRNAs in, 350t origin and heritability of, 340 progression and subtypes, 340À341 MEME program, 22À23 Merkel cell carcinoma (MCC), 194 Mesenchymal cell, 75À76 Mesenchymal stem cells (MSCs), 232À233 and dermal fibroblasts, 386À387 Methionine, 103À104 Methotrexate (MTX), 184, 479À480 Methylated CpG-binding proteins, 16À19, 456 Methylated DNA immunoprecipitation (MeDIP), 11À12 Methylation of arginine, 4, 446À447 DNA See DNA methylation H3K4 methylation, 62À63, 315À316 H3K methylation, 258t histone, 57À58, 58t, 333, 390À392 histone lysine 27, 390À391 hydeoxymethylation, 116t LINE-1, 48 lysine, 120t Methylation-sensitive amplified polymorphism (MSAP) method, Methylation-sensitive high-resolution melting (Ms-HRM), 11 Methylation-sensitive melting curve analysis (Ms-MCA), 10À11 Methylation-sensitive restriction enzymes (MRE-seq) methods, 16 Methylation-sensitive single-nucleotide primer extension (Ms-SNuPE), 10 Methyl-binding (MB)-PCR, 12 Methyl-CpG immunoprecipitation (MCIp), 11À12 Methyl-CpG island recovery assay (MIRA), 12 Methyl-CpG-binding domain (MBD) protein, 56, 115, 411 Methyl-CpG-binding domain protein 3like-1 (MBD3L1) protein, 12 Methyl-CpG-binding proteins, 3À4, 471À472 5-Methylcytosine (5mC), 3À4, 7À8 from cytosine, methods to distinguishing, 8f bisulfite conversion technique and derivatives, 9À11 immunoprecipitation-based methods, 11À12 mass spectrometry-based methods, 12À13 restriction endonuclease-based analysis, 8À9 INDEX Methyl-DNA-binding domain proteins (MBDs), 310, 311t O-6-Methylguanine-DNA methyltransferase (MGMT), 45À46, 47t, 447À448 MethyLight technology, 11 Methylome, in fibroblasts, 256 Methyltransferases, 116t, 379À380 Micrococcal nuclease (mNase) digestion, 24 Microphthalmia-associated transcription factor (MITF), 343, 386 MicroRNA-22, 452À453 MicroRNA-34a, 47t MicroRNA-126, 452 MicroRNA-146b, 452À453 MicroRNA-155, 452À453 MicroRNA-214, 452À453 MicroRNA-221, 452À453 MicroRNAs (miRNAs), 4À5, 25À30, 177À181, 237, 258t, 308, 380, 388, 394À396, 451À452 See also Noncoding RNA (ncRNAs) aberrancies in fibroblasts, 257À261 aberrant expression in MVEC, 262 associated in the aging of skin, 394t biogenesis, 178, 179f as biomarkers, 194À195 clinical applications of, 194À196 collagen genes in SSc, 257À261 in dermatomyositis, 313t detection, 26À28 microarray, 26 next-generation sequencing (NGS), 26À27 Northern blot analysis, 27 RT-PCR, 27 discovery, 177À178 function, 179À180 general analysis pipeline for, 26f on hair follicle stem cells, 78t, 80À81 importance in skin diseases, 195À196 in inflammatory skin diseases, 181À187 allergic contact dermatitis (ACD), 186 atopic dermatitis (AD), 185 connective tissue diseases, 186À187 psoriasis, 181À185 interference keratinocyte differentiation and, 41 and lupus, 221 in malignant skin diseases, 187À194 basal cell carcinomas (BCCs), 187À188 497 cutaneous squamous cell carcinoma, 188À190 cutaneous T-cell lymphoma (CTCL), 192À194 malignant melanoma, 190À192 MiRNA-150, 102 MiRNA-181, 102 in normal skin, 180À181 in pathogenesis of dermatomyositis, 318 in pathogenesis of psoriasis, 290 posttranscriptional regulation of inflammation through, 101À102 in psoriasis, 290À291 recognition elements (MREs), 29 regulation of TGF-β signaling pathway, 257 in skin diseases, 177 target prediction, 28À30 DIANA-microT, 29 PicTar, 29 TargetScan, 28À29 tools for, 28t target validation and functional analysis gain-of-function and loss-of-function experiments, 30 luciferase reporter assays, 30 in vitiligo, 313t Microvascular endothelial cells (MVECs), 251, 261À262 DNA methylation in, 262 miRNA aberrant expression in, 262 MiR let-7a, 257À261, 258t MiR-7, 258t, 317 MiR-18b, 78t, 80À81, 190À191 MiR-21, 181À184, 186, 188À192, 240, 258t, 291À292, 385 MiR-26b, in psoriasis, 240À241 MiR-29, 257À261, 258t MiR-29a, 186À187 MiR-31, 190À191, 240À241, 290 MiR-99a, 181À183, 258t, 368 MiR-99a, 240À241 MiR-106b, in psoriasis, 240À241 MiR-125b, 78t, 80À81, 181À183, 188À190, 239À240 MiR-126, in psoriasis, 192À193, 221, 240À241 MiR-129-5p, 258t MiR-142, 258t, 266À267 MiR-142-3p, 186À187, 221, 240À241, 295 MiR-145, 257, 258t 498 INDEX MiR-146, 257, 258t, 266À267 MiR-146a, 48, 185, 238À239, 239f, 281, 291, 429À430 MiR-150, 258t MiR-152, 258t, 262, 395 MiR-155, 185, 192À193, 281, 368 MiR-196a, 258t MiR-203, 180À183, 188À190, 238, 239f, 290À291, 395 MiR-221, 190À191, 240À241, 295 MiR-222, 238, 240À241 MiR-223, 184, 193, 240À241, 281, 292, 318 MiR-424, 184, 240À241 MiR-503, 219, 258t MIRA (methylated-CpG island recovery assay), 12, 15t MiRBase tool, 28t Mitochondrial ribosomal protein L36 (MRPL36-NDUFS6), 44t Mitogen-activated protein (MAP) kinase activation, 330À331 MLH1 (MutL Homologue 1) gene, 47t, 117 MLL (mixed lineage leukemia) gene, 118, 122 Model-based analysis of ChIPseq (MACS), 22 Molecular basis of epigenetics, 411À415 DNA methylation, 411À413 histone modifications, 413À415 Monomethylated H3 at lysine (H3K4me1), 119 Motif discovery algorithm programs, 22À23 Multiple sclerosis (Ms), 423À424, 449 Mycosis fungoides and Se´zary syndrome (MF/SS) clinical overview, 364À365 molecular gene expression differences in, 366À368 molecular immunopathology of, 365À366 noncoding RNAs in, 368 novel genes expressed in, 367À368 potential genetic and epigenetic mechanisms in, 369À372 DNA methylation, 369À370 DNA methylation and cancer, 370À372 protein markers in, 367 Myelin basic protein (MBP), 423 Myelodysplastic syndrome (MDS), 117À118, 448 Myofibroblastic transdifferentiation (MTD), 62 N National Center for Health Statistics at the Centers for Disease Control and Prevention, 54À55 Necdin gene, 47t, 62À63 Neurological diseases epigenetics in, 453À456 potential epigenetic therapies in, 454t Next-generation sequencing (NGS) techniques, 16, 17t, 26À27, 181À183 NFAT (Nuclear factor of activated T cells), 92À93 N-hydroxysuccinamide (NHS), 26 Nicotinamide (NAM), 140 Nicotinamide adenine dinucleotide (NAD ), 138, 236À237 Nodular melanoma (NM), 190À191, 340À341 Noncoding RNA (ncRNAs), 4À5, 237À241, 349À351 miR-21, 240 miR-26b, 240À241 miR-31, 240À241 miR-99a, 240À241 miR-106b, 240À241 miR-125b, 239À240 miR-126, 240À241 miR-142-3p, 240À241 miR-146a, 238À239, 239f miR-203, 238, 239f miR-221, 240À241 miR-222, 240À241 miR-223, 240À241 miR-424, 240À241 transcription of, 86À87, 99À100 Nonmelanoma skin cancer (NMSC), 156, 190À191 Nonsegmental vitiligo (NSV), 308À314 Normal human dermal fibroblasts (NHDFs), 161, 398 Normal-appearing white matter (NAWM), 423À424 Northern blot analysis, 27 NOS3 gene, 258t, 261À262 NRAS gene, 341À342 NSD1, 123 Nuclear factor (NF)-κB, 60À61 Nucleosomes, 57, 104, 113, 115, 124, 220À221, 235À236, 347À349, 389À390, 410, 418, 447, 473, 474f chromatin states and, 474f INDEX Nucleotide-binding oligomerization domain-like receptors (NLRs) in pathogenesis of atopic dermatitis, 281À282 Nutrition, 264À265 O O-acetyl-ADP-ribose (OAADPR), 140 Obesity, epigenetics in, 41, 458À460 O-GlcNAcylation, 120t Oligonucleotides, 14, 26 Oxidative bisulfite sequencing (oxBS-Seq), 16À19 Oxidative stress, 99, 150, 209, 253, 265À266, 386, 391À392, 398, 479 lupus and, 217À218 sirtuins in, 150À151, 158t P P14ARF, 47t, 342 p15 gene, 47t, 235 p16 gene, 42À43, 47t, 48, 235 P16INK4a gene, 228À229, 233À235, 330À331, 387À388, 390À391, 393, 395, 397 p53 gene, 42À43, 46, 146, 330À331, 334, 387À388, 391À392, 395, 447À448 p63 transcription factor, 392, 395 p73, 47t, 146À147 P300, 65, 89À92, 96 Panobinostat, 427 Parkinson’s disease (PD), 454t, 455 Patched1 (PTCH1), 61À62 PDGFC, 258t Peak calling, 22 Pemphigus, 318À319 epigenetic in, 318À320 Peptidyl arginine deaminase type II (PAD2), 423À424 Peripheral blood mononuclear cells (PBMCs), 63À64, 184, 232À233, 236À237, 292, 310, 315À318, 320, 451, 473 Peroxisome proliferator-activated receptor gamma (PPAR-γ), 62À64 Phenylbutazone (PB), 446 β-Phenylsplitomicins, 164t Phosphatase and tension homolog (PTEN), 61À62 Phosphatidic acid phosphatase type domain containing (PPAPDC3), 289 Phosphorylation, 120t, 426À427 499 Photoaging, 149 inflammation in, 152À153 sirtuin modulation of apoptosis in, 151À152 of skin, 387À388 PicTar, 28t, 29 Pleckstrin homology, Sec7 and coiled-coil domains (PSCD2), 43À45, 44t PLS3 gene, 367À368, 371À372 Poly-ADP-ribose polymerase (PADPRP), 103 Polyamine-modulated factor 1-binding protein (PMFBP1) expression level, 420À421 Polycomb group proteins (PcGs), 79À80, 349, 393À394 Polymyositis (PM), 316 Posttranslational modifications, 4, 57, 307, 389À390, 414, 473 Primary Sjogren’s syndrome, 3À4 Pri-miRNA, 178, 179f, 237, 308 Procainamide, 103, 214À215, 469À470 Programmed cell death (PDCD5), 290 Proline isomerization, 120t Promoter array, 14 Promoter hypermethylation, in skin cancer, 46À47, 47t, 447À448 Promyelocytic leukemia zinc finger (PLZF), 190À191 Propionylation, 120t Protein kinase D3 (PRKD3), 44t Protocadherin gamma subfamily A, (PCDHGA3), 44t Psoriasis, 48, 153À154, 181À185, 227, 236À237, 287À293 DNA methylation, 231À235 epigenomic profiling in, 231À232 profiling, 232À233 of specific genes, 233À235 environmental factors of, 228À229 comorbidities, 229 smoking habits, 229 ultraviolet (UV) irradiation, 228À229 epidemiology of, 227, 287 epigenetics, 289À292 epigenetics and genetics in, 230À231 epigenetics and pathogenesis of psoriasis, 230À231 genetics, 288 heritability of, 230 histone modification in, 236À237 miRNAs in, 181À185 500 INDEX Psoriasis (Continued) noncoding RNAs, 237À241 miR-106b, 240À241 MiR-125b, 239À240 miR-126, 240À241 miR-142-3p, 240À241 MiR-146a, 238À239, 239f MiR-203, 238, 239f MiR-21, 240 miR-221, 240À241 miR-222, 240À241 miR-223, 240À241 miR-26b, 240À241 miR-31, 240À241 miR-424, 240À241 miR-99a, 240À241 pathogenesis, 292À293 phenotypes and diagnosis, 293 sirtuin modulation for, 153À154 treatment, 293 Psoriasis area and severity index (PASI) score, 232À235 Psoriasis susceptibility through (PSORS1À9), 288 Psoriasis vulgaris, 3À4, 288À289, 291À293 PTPRG, 47t Pulmonary fibrosis, 54À55 Pyrosequencing, 9À10, 381, 391 Q Quercetin, 164t R Radial growth phase (RGP)-confined melanoma, 340 RANTES protein, 315À316 RARb2, 47t RAR-related orphan receptor (ROR)γ, 90 RAS protein activator like-1 gene (RASAL1), 61À62, 458À459 RASSF1A, 47t, 352À353 Reactive oxidative species (ROS), 148À151, 265À266, 398 Reduced representation bisulfite sequencing (RRBS), 16 ReGenistem Red Rice (R3), 398 Regulatory CD41 T cells, 92À93 Rejuvenation of aged cells, 396 RelapsingÀremitting Ms (RRMS), 423 Renal crisis, systemic sclerosis and, 55 Renal disease, epigenetics in, 458À459 Respiratory exposures and autoimmune diseases, 470 RFX1, 420 Rheumatoid arthritis (RA), 412À413, 420À422, 446, 449 respiratory exposures, 470 Ribosomal RNAs, 5, 147 RNA interference (RNAi) screen, 333, 457À459 RNA22, 29À30 RNA-induced silencing complex (RISC), 178, 308 Roche/454, NGS platform, 16, 17t, 21À22 Romidepsin, 45, 127, 427, 449, 449t, 453 RT-PCR (quantitative reverse transcriptasePCR) analysis, 25, 27 Runx (Runt-related-transcription-factor), 92À93 RUNX1, 254À255 RUNX2, 254À255 RUNX3, 216, 254À255, 416À417 Ruxolitinib, 427 S Saccharomyces cerevisiae, 138 S-adenosyl methionine (SAM), 56, 103, 211À212, 218, 231, 421, 446À447, 471À472, 479À480 S-adenosyl methionine decarboxylase (AMD) expression level, 420À421 S-adenosylhomocysteine (SAH), 211À212, 218 Salermide, 164t Samhd1 gene, 370À371 Schistosoma mansonii, 90 Scleroderma, 46À47, 186À187, 249À250, 452À453, 475t Secreted frizzled-related protein (SFRP1), 422 Sederma, 397 Segmental vitiligo (SV), 308À309 Senescence and aging, 381 Senestem, 397 Serine Protease Inhibitor Kazal-Type (SPINK5) gene, 278 SET7/9 gene, 62À63 SETDB2 gene, 123 Sezary syndrome, 453 SFRP1, 63À64, 255À256, 258t SHP1, 47t SHP-1 demethylation, 235 INDEX Signal peptidase complex subunit homolog (SPCS2), 44t Signaling lymphocytic activation moleculeassociated protein” (SAP), 221 Signal-to-noise ratio (SNR), 29 Silicone implants and autoimmune disorders, 471 Single-nucleotide polymorphisms (SNPs), 14, 15t, 450À451 SIRT1, 138À140, 139t, 142À149, 143t, 151À152, 154, 156À166 role in cell cycle, 155 role in cell proliferation, 155 role in DNA repair, 150, 158t role in psoriasis, 154 role in vitiligo, 154À155 SIRT2, 138À140, 142À144, 143t, 146À151, 157 SIRT3, 138, 142À144, 143t, 146À151 SIRT4, 138À139, 143t SIRT5, 138, 143t SIRT6, 138À140, 142À144, 143t, 147À149 keloid scarring, 156 role in DNA repair, 149À150 SIRT7, 139À140, 143t, 146, 151 Sirtinol, 155, 164t Sirtuin (SIRT1), 392 Sirtuins, 4, 137À138 in apoptosis, 146À147 in autoimmune diseases, 153À155 cell cycle regulation in cell proliferation, 147À148 chromatin structure and function, modification of, 141À146, 143t DNA methylation, 145 histone modification, 141À145 nonhistone substrates, interaction with, 145À146 enzyme reactions, 140 epigenetic mechanisms, 140À141 heritability of epigenetic changes, 141 function, modulators of, 157À166 and related limitations, 157À161 in skin cancer, 161À166 history, 138 in hyperproliferative skin disease, 155 in inflammatory diseases, 153À155 inhibitors, 164t NAM and splitomicin, 161À166 Tenovin-1 and -6, 161 interact with substrates via enzymatic activity, 138À140 501 in skin aging, 148À153 DNA Repair signaling, 149À150 oxidative stress, 150À151 photoaging, inflammation in, 152À153 photoaging, sirtuin modulation of apoptosis in, 151À152 telomere maintenance, 148À153 in skin cancer, 156À157 in skin inflammation, 153À155 in skin repair and scarring, 155À156 targets, 139t Skin cancer, 46 modulation of sirtuin activity in, 161À166 sirtuins in, 156À157 Skin diseases, epigenetics and, 45À48 Skin repair and scarring, sirtuins in, 155À156 SM associated with a hematologic nonmast cell clonal disease (SM-AHNMD), 295À296 SmaI-XmaI, 8À9 Smoking, 470 Smoking habits and psoriasis, 229 α-Smooth muscle actin (α-SMA), 252 SNF factors, of chromatin remodeling BRG1 (SMARCA4), 125À126 SNF5, 125 SNF5/INI1 gene, 125 SnuPE ion pair reversed-phase HPLC (SIRPH), 10 Sodium butyrate (NaB), 45 Solute carrier family member (SLC3A2), 420À421 Southern blot analysis, 8À9 SOX2OT, 266 Spastic paraplegia 20, spartin (SPG20), 44t Spermidine/spermine N1-acetyltransferase (SSAT1) expression level, 420À421 Splitomicin, 161À166, 164t Sporadic mutations, 341À342 Squamous cell carcinoma (SCC) microRNAs in, 188À190 STAT (signal transducers and activators of transcription) signaling, 192À193 Stat3, 90À92, 96 Stat4-mediated acetylation, 96 Stat5-mediated histone H3 acetylation, 96 Stress-induced premature senescence (SIPS), 388 Suberoylanilide hydroxamic acid (SAHA), 446 502 INDEX Sumoylation, 4, 120t Superficial spreading melanoma (SSM), 190À191, 340À341 Suppressor of cytokine signaling-3 (SOCS3), 238, 290À291 Suramin, 164t, 353À354 Surface-enhanced Raman scattering (SERS) platform, 27À28 Suv4-20, 390 SUZ12, 121t SYBR Green fluorescent probe, 27 Synovial-infiltrating CD4 T cells, 421À422 Systemic corticosteroids, for atopic dermatitis, 287 Systemic lupus erythematosus (SLE), 3À4, 90, 154, 187, 207, 236À237, 412À413, 416À420, 449, 468À470 background, 209À210 CD4 T cells, 221 DNA methylation, 210À217 and T cell gene expression, 212À213 epigenetic factors in, 46À47 genetic/epigenetic interactions in, 219À220 age, genetic risk, DNA methylation, and lupus, 220 DNA methylation, lupus, and gender, 219À220 histone modifications and, 220À221 interactions of experimentally demethylated T cells with macrophages and B Cells, 213À214 miRNAs and, 221 PKCδ inactivation in, 217 symptoms of, 209À210 T cell DNA demethylation, environmental causes of, 217À219 diet, 218À219 oxidative stress, 217À218 T cell DNA methylation and drug-induced lupus, 214À215 gene expression and idiopathic lupus, 215À216 mechanisms of, 216À217 Systemic mastocytosis (SM), 295À296 Systemic sclerosis (SSc), 55, 58t, 186À187 altered maintenance factors, 253 B-lymphocytes in, 251 clinical relevance of epigenetic aberrancies in, 266À267 DNA methylation and, 63À65, 64f epigenetic aberrancies in, 253À263, 258t fibroblasts, 253À261 lymphocytes, 262À263 MVECs, 261À262 epigenetic dysregulation, 264À266 epigenetics and, 63À65 genetic factors in, 252À253 histone modifications and, 65 pathogenesis of, 250À252 activation of immune system, 251 role of fibroblasts in SSc, 252 vascular injury/dysfunction, 251 T-lymphocytes in, 251 T T cell DNA demethylation, environmental causes of, 211À212, 214À215, 217À219 diet, 218À219 oxidative stress, 217À218 T cell DNA methylation and drug-induced lupus, 214À215 gene expression and idiopathic lupus, 215À216 mechanisms of, 216À217 T helper cell (Th)1, 65À66, 89À90 TaqMan miRNA low-density array (TLDA), 240À241 TargetScan software, 28À29, 28t, 31À32 T-cell differentiation, epigenetic mechanisms during, 87À95, 88f CD41 T-cell phenotype determination, 89À94, 92f generation of CD31CD42CD82DN T cells, 94À95 T-cell receptor (TCR) complex, 98 TCRα, 98 TCRβ, 98 TCR-γ, 98 TCRδ, 98 TenÀeleven translocation (TET) family proteins, 3À4 Tenovin-1, 161, 164t Tenovin-6, 161, 164t TET genes, 372, 384 TET methylcytosine dioxygenase (TET2) and epidermis, 383À384 TET1 (ten-eleven translocation1) gene, 115, 118 TET2 (ten-eleven translocation2) gene, 118, 383À384, 389 TET2 mutation, 118À119, 372 INDEX Tet-assisted bisulfite sequencing (TAB-Seq), 16À19 TGF-β signaling pathway, 252À254 miRNA regulation of, 257 Th1 cells, 65À66, 89À90, 282À283, 292À293, 319, 451À452, 456À457 Th2 cells, 65À66, 90, 212, 281À282 in pathogenesis of atopic dermatitis, 281À282 Th2 genes, 457 Th17 cells, 90À92, 229, 242, 292À293, 317À318 dermatomyositis, 317À318 in pathogenesis of atopic dermatitis, 283 Th22 cells, 292À293 in pathogenesis of atopic dermatitis, 282À283 Thioredoxin domain containing (TXNDC9-EIF5B), 44t Thrombospondin-1, 47t Thy-1 membrane protein, 58À60 Thymic stromal lymphopoietin (TSLP), 280 Thymidine, 9, 13 TIMP1, 63 Tissue inhibitor of metalloproteinase (TIMP2), 289 T-lymphocytes DNA methylation aberrancies in, 262À263 in systemic sclerosis, 251 TNF receptor-associated factor (TRAF-6), 238À239 TNFSF7 gene, 452 TNXB, 255 Tobacco smoking, 470 and DNA methylation, 473 Toll-like receptors (TLRs) in pathogenesis of atopic dermatitis, 281À282 Topical calcineurin inhibitors (TCIs) for atopic dermatitis, 287 Topical corticosteroids (TCS) for atopic dermatitis, 286 Transcription factor Fli1, 63À64 Transforming growth factor-β (TGF-β), 310À312, 385 Transforming growth factor-β1 (TGF-β1), 60À61, 65À66 Transit amplifying (TA) cells, 76 Treatment, epigenetic, 443 in dermatologic diseases, 453À459, 454t 503 in allergy and allergic dermatological diseases, 456À457 in cardiovascular, obesity, renal disease, 457À459 in human imprinting disorders, 456 in neurological diseases, 453À456 DNA methylation, 444À453 in autoimmune diseases, 449À453 in cancer, 447À449 histone acetylation enzymes/histone deacetylation enzymes, 445 histone deacetylation enzyme inhibitors, 446 histone methyltransferases/histone demethylases, 446À447 histone modification, 444À445 Tregs, 92À93, 291À292, 310À312, 314À315 Trichostatin A (TSA), 47À48, 267, 385, 428, 446 Trimethylated H3 at lysine (H3K4me3), 79À80, 119 Trimethylated H3 at lysine (H3K9me3), 119 Trimethylated H3 at lysine 27 (H3K27me3), 42, 79À80, 117, 119, 122À123, 393À394 Tri-methylation of histone H3 tail with lysine (H3K4), 235À236 Trypsin, for epidermal fragmentation, 43À45 Tryptase, 297 Tumorigenesis, 114À116, 119 geneticÀepigenetic cross talk in, 348f Turner syndrome, 102 Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide (YWHAQ), 43À45, 44t U Ubiquitylation, 120t UHRF, 78À79, 78t Ultraviolet (UV) irradiation, for psoriasis treatment, 228À229 Ultraviolet radiation exposures and autoimmune disorders, 471 30 Untranslated region (30 UTR), 29À30, 231 Urticaria, 297À300 diagnosis, 299À300 epidemiology, 298 epigenetics, 298 pathogenesis, 298 phenotypes, 298À299 504 Urticarial pigmentosa (UP), 297 UTX (demethylase of H3K27me3), 123 V Valproate, 428, 451À452 Valproic acid (VPA), 331, 353À354 Vascular injury/dysfunction, 251 Ventral anterior homeobox (VAX1), 44t Vertical growth phase (VGP), 340 VHL (von HippelÀLindau) gene, 117 Vitamin D receptor, 80À81 Vitiligo, epigenetic in, 308À314 Vorinostat, 45, 127, 427, 449t VZV infection, 332À333 W Waddington, C.H., 3, 409À410 WD repeat domain 54 (WDR54), 44t WebMOTIFS program, 22À23 Weeder program, 22À23 Werner syndrome (WS), 149 INDEX Whole-genome microarray platforms, 232À233 Wnt signaling, 62À63 Wnt/β-catenin signaling pathway, 255À256 X X chromosome and DNA methylation, 219 for immune regulation, 102 Xeroderma pigmentosum (XP), 150 X-linked genes in DNA methylation, 219 Z Zest homologue (EZH2), 122À123, 422 Zinc finger, AN1-type domain 2A (ZFAND2A), 44t Zinc finger, HIT type (ZNHIT3), 44t Zinc finger, ZZ-type with EF-hand domain (ZZEF1), 44t Zinc finger and BTB domain containing 11 (ZBTB11), 44t ... scleroderma and diffuse cutaneous scleroderma J Clin Immunol 20 12; 32( 3):514 22 ; PubMed PMID: 22 307 526 Epub 20 12/ 02/ 07 eng Zhu H, Luo H, Li Y, Zhou Y, Jiang Y, Chai J, et al MicroRNA -21 in scleroderma... IRF5, TNFSF4, SOX5, CD247, TBX21, CTGF, BANK1, FAM167A, HGF, C8orf13-BLK, KCNA5, NLRP1, CD 226 , IL2RA, IL12RB2, TLR2, and HIF1A, as well as several loci in the HLA region) [23 ,24 ] However, it appears... 20 14; pii annrheumdis -20 14 -20 5303 [Epub ahead of print.] PubMed PMID: 24 8 122 88 [30] Hynes RO Integrins: bidirectional, allosteric signaling machines Cell 20 02; 110 (6):673À87; PubMed PMID: 122 97042