(BQ) Part 1 book Epigenetics and dermatology presents the following contents: Introduction to epigenetics, laboratory methods in epigenetics, epigenetics and fibrosis, epigenetic modulation of hair follicle stem cells, epigenetics and the regulation of inflammation,...
EPIGENETICS AND DERMATOLOGY EPIGENETICS AND DERMATOLOGY QIANJIN LU Professor and Director, Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The 2nd Xiangya Hospital, Central South University, Changsha, China CHRISTOPHER C CHANG Professor of Medicine and Associate Director, Allergy and Immunology Fellowship Program, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, California, USA BRUCE C RICHARDSON Professor of Medicine, Epigenetic Research Team Leader, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright r 2015 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-800957-4 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For Information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by MPS Limited, Chennai, India www.adi-mps.com Printed and bound in the United States of America Dedication To our patients who suffer from skin diseases May this book be a seed for future research and development of novel treatments to help alleviate dermatological illness of all forms, from allergic diseases to autoimmune skin diseases and cancer We hope that epigenetics will provide potential cures and personalized approaches for many of these diseases QL, CC, and BR List of Contributors Nezam Altorok Division of Rheumatology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH Jack L Arbiser Department of Dermatology, Emory School of Medicine, Winship Cancer Institute, Atlanta, GA; Department of Dermatology, Atlanta Veterans Affairs Medical Center, Decatur, GA Michael Y Bonner Department of Dermatology, Emory School of Medicine, Winship Cancer Institute, Atlanta, GA Wesley H Brooks Tampa, FL Department of Chemistry, University of South Florida, Christopher Chang Division of Rheumatology, Immunology, University of California, Davis, CA Allergy and Clinical Jessica Charlet Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA Frederic L Chedin Department of Molecular and Cellular Biology, University of California, Davis, CA Hui-Min Chen Department of Molecular and Cellular Biology, University of California, Davis, CA; Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA Suresh de Silva Center for Retrovirology Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio Pierre Gazeau EA2216, INSERM ESPRI, ERI29, European University of Brittany and Brest University, Brest, France; SFR ScInBioS, LabEx IGO “Immunotherapy Graft Oncology,” and “Re´seau E´pige´ne´tique du Cance´ropole Grand Ouest,” France; Laboratory of Immunology and Immunotherapy, CHU Morvan, Brest, France M Eric Gershwin Division of Rheumatology, Immunology, University of California, Davis, CA Allergy and Clinical Yixing Han Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD Christian M Hedrich Pediatric Rheumatology and Immunology, Children’s Hospital Dresden, University Medical Center “Carl Gustav Carus, Technische Universitaăt Dresden, Dresden, Germany Yu-Ping Hsiao Department of Medical Education, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan xiii xiv LIST OF CONTRIBUTORS Jared Jagdeo Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY; Department of Dermatology, University of California at Davis, Sacramento, CA; Dermatology Service, Sacramento VA Medical Center, Mather, CA Yi-Ju Lai Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Christelle Le Dantec EA2216, INSERM ESPRI, ERI29, European University of Brittany and Brest University, Brest, France; SFR ScInBioS, LabEx IGO “Immunotherapy Graft Oncology,” and “Re´seau E´pige´ne´tique du Cance´ropole Grand Ouest,” France Chih-Hung Lee Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Jeung-Hoon Lee Department of Dermatology, College Chungnam National University, Daejeon, South Korea of Medicine, Yungling Leo Lee Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan Patrick S.C Leung Division of Rheumatology, Immunology, University of California, Davis, CA Allergy and Clinical Gangning Liang Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA Jieyue Liao Department of Dermatology, Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, PR China Bin Liu Department of Rheumatology and Immunology, The Affiliated Hospital of Medical College Qingdao University, Qingdao City, Shandong Province, PR China; Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA Fu-Tong Liu Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Yu Liu Department of Dermatology, Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, PR China Alexander Lo SUNY Downstate College of Medicine, Brooklyn, NY Marianne B Løvendorf Department of Dermato-Allergology, Hospital, University of Copenhagen, Hellerup, Denmark Gentofte Qianjin Lu Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan, PR China Anjali Mishra Comprehensive Cancer Center and Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio Kathrin Muegge Basic Science Program, Leidos Biomedical Research, Inc., Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, Frederick, MD; Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD xv LIST OF CONTRIBUTORS Sreya Mukherjee Tampa, FL Department of Chemistry, University of South Florida, Nina Poliak Division of Allergy and Immunology, Nemours/AI duPont Hospital for Children, Wilmington, DE Pierluigi Porcu Comprehensive Cancer Center and Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio Jianke Ren Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD Yves Renaudineau EA2216, INSERM ESPRI, ERI29, European University of Brittany and Brest University, Brest, France; SFR ScInBioS, LabEx IGO “Immunotherapy Graft Oncology,” and “Re´seau E´pige´ne´tique du Cance´ropole Grand Ouest,” France; Laboratory of Immunology and Immunotherapy, CHU Morvan, Brest, France Bruce C Richardson Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI Sabita N Saldanha Department of Biological Sciences, Alabama State University, Montgomery, AL Amr H Sawalha Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI Melissa Serravallo Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY Lone Skov Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Minoru Terashima Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD Shannon Doyle Tiedeken Department of Pediatrics, Thomas Jefferson University, Nemours/A.I duPont Hospital for Children, Wilmington, DE Kuan-Yen Tung Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan Xin Sheng Wang Department of Urology, The Affiliated Hospital of Medical College Qingdao University, Qingdao City, Shandong Province, PR China Louis Patrick Watanabe Department of Biology, University of Alabama at Birmingham, Birmingham, AL Henry K Wong Comprehensive Cancer Center and Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio Haijing Wu Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China Li Wu Center for Retrovirology Research, Department Biosciences, The Ohio State University, Columbus, Ohio of Veterinary xvi LIST OF CONTRIBUTORS Ruifang Wu Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China Weishi Yu Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD Ming Zhao Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China Preface Epigenetics—the word epigenetics has been used since the 1940s, when Dr Charles Waddington used the term to describe how gene regulation impacts development In those days, before we even knew the structure of DNA, Dr Waddington also coined the term chreode, to describe the cellular developmental process which leads to the paths that cells take toward development, a sort of cellular destiny Now, some 70 plus years later, the term epigenetics has taken on a different meaning, though not necessarily a discordant philosophy, and is used to describe the study of how genes are regulated without a change in DNA sequence The concept of epigenetics embodies a broad range of cellular and biological phenomena, but the premise is based on the fact that gene expression may be altered in the absence of mutations or deletions, or other changes in DNA sequence, leading to different states of health and disease How this is achieved is through the mechanisms of epigenetics, which includes DNA methylation and alterations in histone structure MicroRNAs, which are short sequences of noncoding RNA that bind to promoter regions of genes to affect translation, have also been classified by some as an epigenetic phenomenon, but this is not without controversy The skin is the largest organ in the body It is a dynamic, living, immunologic structure that possesses many functions, serving as a protective barrier to the outside world and a homeostatic system to support life It is also an immune organ, and while it protects us from the dangers of microbes, pollutants, and toxins, it also participates in how we identify safety from hazardous exposures, thus acting as a medium for the development of tolerance The systems in the skin are complex, involving numerous cell types and signaling molecules, and the pathways that govern the regulation of skin function add an additional layer of complexity Thus, much can go wrong Therefore, diseases of the skin range from neoplasms to infections to autoimmune diseases and allergic conditions Solving the mysteries of skin function will help us find new ways to restore skin “health” or “normalcy.” Epigenetics will no doubt play a significant role in these endeavors The first application of epigenetics was in cancer diagnosis and treatment Interestingly, research scientists, pharmacologists, and physicians xvii TABLE 11.1 Identified Methylated Genes from Different Clinical Specimens of Psoriasis Patients from High-Throughput Data Analysis Author [Reference] Specimen source Hypermethylated genes Hypomethylated genes Gene ontology Gervin et al [55] CD4 cells from PBMCs IL13, CSF2, TNFSF9 CCL1, TNFSF11 Immune response, inflammatory response Han et al [56] CD41 cells from PBMCs SLITRK4, EMD, ZIC3, CXorf40A, HDAC6, IKBKG À Autoimmunity, T-cell polarization, immune system Hou et al [57] Skin mesenchymal stem cells CACNA2D3, CBX4, SRF NRP2, S100A10, TCL1B, VASH1 Cell communication, surfaceÀreceptor signaling pathway, regulation of transmission of nerve impulse, cell migration Roberson et al [58] Skin biopsy KYNU, OAS2, S100A12, SERPINB3 C10orf99, IFI27, SERPINB4 Apoptosis, chronic inflammation, immune response, cellÀcell signaling, cell membrane organization, endosome transport Zhang et al [59] Skin biopsy PDCD5 TIMP2 Antiapoptosis, regulation of cell migration, cell cycle, cell communication, signal transduction 11.5 HISTONE MODIFICATION 235 T cells by antigen-presenting cells [61] Cytokine production by T-cell subsets and aberrant proliferation of keratinocytes promotes formation of plaque, which is a characteristic of psoriasis [62À64] In the studies of DNA methylated genes in the pathogenesis of psoriasis, the methylation level of some antiapoptotic genes was significantly altered in the psoriatic skin Chen et al [65] showed that the p16INK4a gene promoter was methylated in 30% of psoriasis patients The PASI score was higher in patients who did not exhibit p16INK4a methylation Hypermethylation of p16INK4a gene promoter leads to reduced p53 levels in keratinocytes as well as to excessive keratinocyte proliferation [65] Another example of aberrant DNA methylation in psoriasis is of SHP-1, which serves as a regulator in growth and proliferation processes The SHP-1 promoter region was found to be significantly demethylated in keratinocytes from psoriatic lesional skin [66] A previous study on lymphoma proved that downregulation of STAT3 mRNA expression results in SHP-1 demethylation [67] A study reported by Sano et al [68] determined that upregulation of STAT3 is an important mechanism in the pathogenesis of psoriasis Hence, STAT3 may act differently on the SHP-1 promoter in epithelial cells Whether the additional tissue-specific factor that triggers the opposite outcome is hypomethylation or hypermethylation remains to be determined Two studies employed high-proliferative-potential colony-forming cell (HPP-CFC) assay to investigate the relationship between antiapoptotic genes and proliferation/differentiation in hematopoietic stem cells (HSCs) [69,70] The promoter regions of p15 and p21 are hypomethylated in psoriasis, and colony counts of HPP-CFCs in the bone marrow of psoriatic patients are significantly lower than those in healthy controls [69] In addition, the lower colony-formation capability of HPP-CFCs from bone marrow hematopoietic progenitor cells in psoriasis patients is closely associated with the methylation levels of p16 in HPP-CFCs cells [70] 11.5 HISTONE MODIFICATION In eukaryotes, DNA is packaged into nucleosomes that consist of two copies each of the histone proteins H2A, H2B, H3, and H4 There are three conditions in histone modification, which include the permissive (active promoter) status, repressive (inactive promoter) status, and poised (accessible promoter) status In addition, methylation, acetylation, phosphorylation, and ubiquitination of histone tails occur at specific sites and residues, and control of gene expression occurs by regulating DNA accessibility to RNA polymerase II and other transcription factors Histone modifications influence the transcription process and reflect the transcriptional states of IMMUNOLOGIC SKIN DISEASES 236 11 EPIGENETICS IN PSORIASIS the underlying genes [71,72] For example, tri-methylation of histone H3 tails with lysine (H3K4) is strongly associated with transcriptional activation, and tri-methylation of H3K27 is frequently associated with gene silencing [73] Methylation of H3K9 and H3K27 has also been reported to be the key regulator in red eye pigmentation of Drosophila (position-effect variegation) [74À76], long-term gene silencing (polycomb silencing) [76À78], and X-chromosome inactivation [79] In addition, these two modified histones possess certain characteristics of a prototype-guided information duplication system However, whether methylation of histone tails is inherited during mitotic divisions remains unclear In addition to methylation, acetylation of histone tails is also considered to result in gene activation, whereas histone deacetylation is believed to result in gene silencing and is, therefore, considered a repressive marker Acetylation of histone tails is catalyzed by histone acetyltransferases (HATs), and the acetyl groups are removed from the histone tails by deacetylases An emerging paradigm for epigenetic modification indicates association between DNA methylation and histone modification DNMT3L is a regulatory factor related (in sequence) to the mammalian de novo DNMT3A and DNMT3B DNMT3L was demonstrated to catalyze methylation of H3K4 via recruitment or activation of DNMT3A2 [80] Cedar and Bergman showed a bidirectional relationship between histone and DNA methylation They believed that methylation of the histone tail may influence gene silencing Methylation usually occurs on closed chromatin structure during early development; this state is maintained through regulation of DNA methylation and chromatin structure following cell division [81] 11.5.1 Histone Modification in Psoriasis The balance of acetylation and deacetylation of histone tails with lysine residues is tightly regulated by HATs and histone deacetylases (HDACs) Aberrant expression of these two enzymes has been observed in psoriasis Tovar-Castillo et al [82] reported that HDAC-1 mRNA is overexpressed in psoriatic skin as compared with that in normal skin of healthy controls In recent clinical practices, HDAC inhibitors (HDAC-Is) are used to treat chronic immune and inflammatory disorders such as systemic lupus erythematosus (SLE) and psoriasis [83,84] Next, the silent mating type information regulation homologue (HDAC-SIRT1) is a nicotinamide adenine dinucleotide (NAD1)-dependent deacetylase that is involved in cellular metabolisms and cellular stress responses [85] Zhang et al [86] also found that SIRT1 mRNA expression was significantly downregulated in PBMCs from psoriasis patients compared to those from healthy controls In addition, it has been proposed that HDAC-SIRT1 inhibits E2F1 IMMUNOLOGIC SKIN DISEASES 11.6 NONCODING RNAs 237 activity to prevent normal keratinocyte proliferation [87] E2F1 is a member of the E2F family of transcription factors, and activation of E2F signaling is often involved in aberrant cell proliferation or apoptosis [88] 11.6 NONCODING RNAs miRNAs are the most studied class of noncoding RNAs that regulate gene expression by binding to the 30 UTRs of target mRNA, which ultimately leads to mRNA degradation or inhibition of protein translation [89,90] miRNAs are encoded in the genome and are derived from the intergenic regions (encoded as a single gene or gene clusters) or the intron regions pri-miRNA is a 70-nucleotide structure that is transcribed from the nucleus The RNase III enzymes such as Drosha and DGCR8 (double-stranded RNA-binding protein) process pri-miRNA to form pre-miRNA with a stem-loop structure The resulting pre-miRNA is imported in the cytoplasm by the transporter protein Exportin The pre-miRNA is bound and cleaved by Dicer (RNase III enzyme) in the cytoplasm to generate mature miRNA molecules To date, almost 2000 mature miRNAs have been found in the human genome, the information concerning each miRNA being available on the website: http://www.mirbase.org/ miRNAs are considered both oncogenes and tumor suppressor genes, and aberrant miRNA expression has been reported to contribute to the pathogenesis of most malignancies [91] In addition, the role of miRNAs in cardiovascular diseases and liver injury is also well-established and therefore they are regarded as therapeutic targets [92,93] Recently, the miRNA expression microarray platform was comprehensively applied for screening novel miRNAs from different psoriasis specimens In recent years, next-generation sequencing technologies have matured and become capable of assessing epigenetic markers on a genome-wide scale [94] Compared with the array platform, the next-generation sequencing technologies can provide superior data quality; these technologies have been applied to the study of miRNAs (miRNA-seq) and histone markers (ChIP-seq) Some studies have shown that miRNAs play important roles in the regulation of processes during early development, cell proliferation, cell differentiation, cell apoptosis, signal transduction, and organ development [95À99] Aberrant miRNA expression is also involved in the regulation of immune system development and in the pathogenesis of chronic inflammatory diseases [100À102] The first evidence of the involvement of miRNAs in inflammatory diseases was obtained from the miRNA expression microarray data Novel miRNA signature was found to be associated with psoriasis [102] miRNAs are expressed in a nonrandom IMMUNOLOGIC SKIN DISEASES 238 11 EPIGENETICS IN PSORIASIS manner in healthy and psoriatic skin However, in the mRNA expression array data and the pathway signaling of psoriasis, a set of miRNAs was found to be downregulated in psoriasis These findings imply that miRNAs play general roles in the pathogenesis of psoriasis and that some miRNAs are specifically downregulated in psoriatic skin In addition, some genetic regions of interest were found to overlap with the loci identified as being involved in the development of psoriasis and atopic dermatitis [103] In recent years, increasing evidence suggests that miRNAs are also important in the pathogenesis of skin disorders such as psoriasis and atopic eczema 11.6.1 miR-203 in Psoriasis miR-203 is the first miRNA discovered in skin; it is overexpressed in psoriatic skin as compared with that in both normal skin from healthy controls and lesional skin from atopic eczema patients [102] miR-203 is highly expressed in keratinocytes and plays a role in skin morphogenesis by suppressing the transcription factor p63 [104] Sonkoly et al [102] also reported specific expression of miR-203 in keratinocytes Their results suggest that miR-203 plays a role in the regulation of keratinocyte functions, especially in psoriatic skin One of the target genes of miR-203 is the suppressor of cytokine signaling-3 (SOCS-3), which is a negative regulator in the STAT3 pathway In the STAT3 pathway, SOCS-3 can be activated by inflammatory cytokines and it has important functions in cell growth, survival, and differentiation [105] A cell-based study showed that overexpression of miR-203 repressed skin inflammation by downregulating the cytokine levels of TNF-α and IL-24 in primary keratinocytes from psoriasis patients Sonkoly et al suggested that the inflammatory cytokines TNF-α and IL-24 are direct targets of miR-203 in keratinocytes in the pathway of epidermal remodeling and skin homeostasis in the pathogenesis of psoriasis (Figure 11.1) 11.6.2 miR-146a in Psoriasis In addition to miR-203, Sonkoly et al [102] also used the miRNA expression array technique to screen out three other miRNAs (miR-146a, miR-21, and miR-125b), which were differentially expressed in psoriatic skin For miR-146a, Taganov et al [106] showed that miR-146a inhibits the expression of TNF receptor-associated factor (TRAF-6) and IL-1 receptor-associated kinase (IRAK-1) These two proteins are the key adapter molecules downstream of Toll-like receptors and cytokine receptors Moreover, promoter analysis of the miR-146a gene also revealed that IMMUNOLOGIC SKIN DISEASES 239 11.6 NONCODING RNAs LPS, TNF-α, or IL-1β TLR4 mir-203 TLR4 IL-24 IL-20R1 mir-146a Keratinocyte IL-20R2 mir-203 MyD88 JAK MyD88 IRAK-1 IRAK-1 TRAF-6 TRAF-6 STAT3 P SOCS-3 P NF-κB No signaling Transcript STAT3 P P Immune-responsive genes SOCS-3 Keratinocyte differentiation Severity of psoriasis Psoriasis FIGURE 11.1 miR-146a and miR-203 act as key regulators in the pathogenesis of psoriasis NF-κB plays a critical role in the induction of miR-146a transcription after treatment with lipopolysaccharide (LPS), TNF-α, and IL-1β Similarly, Meisgen et al [107] reported the downregulation of IRAK-1 and TRAF-6 and suppression of NF-κB promoter-binding activity by miR-146a Furthermore, overexpression of miR-146a was reported to significantly suppress the production of IL-8, CCL20, and TNF-α; these factors in turn suppress the chemotactic attraction of neutrophils by keratinocytes Xia et al [108] found that overexpression of miR-146a could inhibit IRAK-1 expression and was positively correlated to the PASI score in psoriatic patients Thus, these results suggest that miR-146a may be a regulator in the innate immunity of keratinocytes, which prevents the production of inflammatory mediators under homeostatic conditions 11.6.3 miR-125b in Psoriasis The expression of miR-125b is also downregulated in psoriasis Unlike miR-146a, miR-125b targets TNF-α and directly inhibits its posttranscriptional modification Therefore, downregulation of miR-125b was considered to be correlated with excess production of TNF-α in skin inflammation [109] Xu et al [110] found that overexpression of miR-125b suppressed cell proliferation and induced the expression of IMMUNOLOGIC SKIN DISEASES 240 11 EPIGENETICS IN PSORIASIS several differentiation markers, such as keratin 10 (K10) and filaggrin, in primary human keratinocytes They also demonstrated that miR-125b modulates keratinocyte proliferation and differentiation through direct repression of fibroblast growth factor receptor (FGFR2) Therefore, miR-125b may be a potential therapeutic target for psoriasis that acts by modulating proliferation and differentiation in keratinocytes 11.6.4 miR-21 in Psoriasis Two studies have reported that miR-21 is significantly upregulated in psoriatic skin, as determined by miRNA expression array [102,111] miR-21 is a well-known oncogene, and some papers have reported that miR-21 plays an important role in cardiovascular diseases and inflammation [112,113] In addition, miR-21 is also considered as an antiapoptotic and antiproliferative molecule in a variety of cell types [114,115] Meisgen et al [107] found that downregulation of miR-21 increases the apoptosis rate of activated T cells and that upregulation of miR-21 may contribute to T-cell-derived inflammation in psoriatic skin Therefore, they suggested that upregulation of miR-21 in psoriatic skin was caused by infiltration of activated CD41 T cells In addition, upregulation of miR-21 may contribute to skin inflammation by suppressing CD41 T-cell apoptosis Therefore, regulation of miR-21 in T cells is considered to modify activated T cells in the microenvironment of psoriatic lesions 11.6.5 Other miRNAs in Psoriasis In recent microarray-based studies, some miRNAs were identified as being associated with the pathogenesis of psoriasis, but the detailed mechanism of their association remains unclear Zibert et al [116] investigated the interaction of miRNA and mRNA expression in lesional/nonlesional skin in psoriasis patients They found 42 upregulated and downregulated miRNAs expressed in lesional skin as compared with normal skin Furthermore, they also validated that overexpression of miR-221 and miR-222 leads to degradation of TIMP3, resulting in decreased TIMP3 protein levels in a cell line model Another study indicated that 38 circulating miRNAs were suppressed by the TNF-inhibitor etanercept in psoriasis patients, by using the TaqMan miRNA lowdensity array (TLDA) After validation by quantitative polymerase chain reaction (PCR), the serum levels of miR-106b, miR-26b, miR-142-3p, miR223, and miR-126 were found to be significantly downregulated by etanercept in responders (PASI score 50%) [117] Lerman et al [118] found IMMUNOLOGIC SKIN DISEASES 241 11.7 CONCLUSION Environmental factors UV radiation Epigenetic markers Skin pathology p16INK4amethylation HDAC-SIRT gene expression Keratinocyte proliferation Smoking habits miR-125b Keratinocyte differentiation Psoriasis miR-203 Infectious agents ? Stress Physical trauma Cardiovascular disease Metabolic syndrome Skin inflammation miR-21 T-cell apoptosis miR-146a Regulation of innate immunity in keratinocytes FIGURE 11.2 The overview of published epigenetic markers between exposure to environmental factors and the pathogenesis of psoriasis The question mark indicates lack of evidence to prove the association between risk factors of psoriasis and epigenetic markers 14 differentially expressed miRNAs in psoriatic skin and determined that IGF-1R and miR-99a are reciprocally expressed in the epidermis They also found that overexpression of miR-99a in primary keratinocytes leads to downregulation of the endogenous IGF-1R protein level and inhibition of keratinocyte proliferation, and that it leads to the upregulation of keratin 10 Ichihara et al [119] determined the role of miR-424 in psoriatic skin and serum samples They found that downregulation of miR-424 could lead to overexpression of MEK1 and cyclin E1 in keratinocytes and reduction of serum miR-424 concentration in psoriasis patients miR-31, a miRNA overexpressed in psoriasis keratinocytes, may contribute to skin inflammation by enhancing leukocyte migration into the skin [120] 11.7 CONCLUSION In this review, we have summarized the epigenetic modifications of some genes that are involved in the pathogenesis of psoriasis and discussed epigenetic aberrations acting as triggers in psoriasis We have also reviewed some candidate epigenetic markers involved in the pathogenesis of psoriasis based on the reports of the published studies summarized in this review (see Figure 11.2) However, the detailed mechanisms involved between epigenetic modifications and the pathogenesis of psoriasis need to be further examined to elucidate the mystery behind this relatively common disease In addition, some previous studies have reported that epigenetic changes are also influenced by environmental factors such as UV radiation and smoking habits Therefore, future studies need to determine exposure to environmental factors as a risk factor in the regulation of epigenetic changes that contribute to the pathogenesis of psoriasis IMMUNOLOGIC SKIN DISEASES 242 11 EPIGENETICS IN PSORIASIS List of Abbreviations CHARM ChIP DNMT FGFR2 GO HAT HDAC HPP-CFC HSC IRAK-1 K10 LPS MBD MeDIP miRNA MSC PASI SAM SIRT1 SOCS-3 TRAF-6 UV comprehensive analysis of relative DNA methylation chromatin immunoprecipitation DNA methyltransferase fibroblast growth factor receptor gene ontology histone acetyltransferase histone deacetylase high-proliferative potential colony-forming cell hematopoietic stem cell IL-1 receptor-associated kinase keratin 10 lipopolysaccharide methyl-DNA binding domain methylated DNA immunoprecipitation microRNA mesenchymal stem cell psoriasis area and severity index S-adenosyl methionine silent mating type information regulation homologue suppressor of cytokine signaling-3 TNF receptor-associated factor ultraviolet References [1] Chandran V, Raychaudhuri SP 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