1 297 100 AIM2 AND PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE OCCURRING WORLDWIDE, WITH MULTIPLE SYSTEMIC COMPLICATIONS, WHICH SERIOUSLY AFFECT THE QUALITY OF LIFE AND PHYSICAL AND MENTAL HEALTH OF PATIENTS. THE PATHOGENESIS OF PSORIASIS IS RELATED TO THE ENVIRONMENT, GENETICS, EPIGENETICS, AND DYSREGULATION OF IMMUNE CELLS SUCH AS T CELLS, DENDRITIC CELLS (DCS), AND NONIMMUNE CELLS SUCH AS KERATINOCYTES. ABSENT IN MELANOMA 2 (AIM2), A SUSCEPTIBILITY GENE LOCUS FOR PSORIASIS, HAS BEEN STRONGLY LINKED TO THE GENETIC AND EPIGENETIC ASPECTS OF PSORIASIS AND INCREASED IN EXPRESSION IN PSORIATIC KERATINOCYTES. AIM2 WAS FOUND TO BE ACTIVATED IN AN INFLAMMASOME-DEPENDENT WAY TO RELEASE IL-1BETA AND IL-18 TO MEDIATE INFLAMMATION, AND TO PARTICIPATE IN IMMUNE REGULATION IN PSORIASIS, OR IN AN INFLAMMASOME-INDEPENDENT WAY BY REGULATING THE FUNCTION OF REGULATORY T(TREG) CELLS OR PROGRAMMING CELL DEATH IN KERATINOCYTES AS WELL AS CONTROLLING THE PROLIFERATIVE STATE OF DIFFERENT CELLS. AIM2 MAY ALSO PLAY A ROLE IN THE RECURRENCE OF PSORIASIS BY TRAINED IMMUNITY. IN THIS REVIEW, WE WILL ELABORATE ON THE CHARACTERISTICS OF AIM2 AND HOW AIM2 MEDIATES THE DEVELOPMENT OF PSORIASIS. 2023 2 6210 29 THE INTERPLAY BETWEEN KERATINOCYTES AND IMMUNE CELLS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE RESULTING FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. TO DATE, SEVERAL IMMUNOPATHOGENIC MECHANISMS OF PSORIASIS HAVE BEEN ELUCIDATED, AND, IN THE CURRENT MODEL, THE CROSS TALK BETWEEN AUTOREACTIVE T CELLS AND RESIDENT KERATINOCYTES GENERATES INFLAMMATORY AND IMMUNE CIRCUITS RESPONSIBLE FOR THE INITIATION, PROGRESSION, AND PERSISTENCE OF THE DISEASE. SEVERAL AUTOANTIGENS DERIVED FROM KERATINOCYTES (I.E., LL37 CATHELECIDIN/NUCLEIC ACID COMPLEXES, NEWLY GENERATED LIPID ANTIGENS) HAVE BEEN IDENTIFIED, WHICH MAY TRIGGER INITIAL ACTIVATION OF T CELLS, PARTICULARLY IL-17-PRODUCING T CELLS, T HELPER (TH)1 AND TH22 CELLS. HENCE, LYMPHOKINES RELEASED IN SKIN LESIONS ARE PIVOTAL FOR KERATINOCYTE ACTIVATION AND PRODUCTION OF INFLAMMATORY MOLECULES, WHICH IN TURN LEAD TO AMPLIFICATION OF THE LOCAL IMMUNE RESPONSES. INTRINSIC GENETIC ALTERATIONS OF KERATINOCYTES IN THE ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS DEPENDENT ON T-CELL-DERIVED CYTOKINES ARE ALSO FUNDAMENTAL. THE CURRENT REVIEW EMPHASIZES THE ABERRANT INTERPLAY OF IMMUNE CELLS AND SKIN-RESIDENT KERATINOCYTES IN ESTABLISHING AND SUSTAINING INFLAMMATORY AND IMMUNE RESPONSES IN PSORIASIS. 2018 3 118 22 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY. 2012 4 1225 32 CRITICAL ROLE OF EPIGENETIC MODIFICATION IN THE PATHOGENESIS OF ATOPIC DERMATITIS. ATOPIC DERMATITIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERISED BY RECURRENT ECZEMA-LIKE LESIONS AND SEVERE PRURITUS, ALONG WITH DRYING AND DECRUSTATION OF SKIN. CURRENT RESEARCH RELATES THE PATHOGENESIS OF ATOPIC DERMATITIS MAINLY TO GENETIC SUSCEPTIBILITY, ABNORMAL SKIN BARRIER FUNCTION, IMMUNE DISORDERS, STAPHYLOCOCCUS AUREUS COLONISATION, MICROBIOLOGICAL DYSFUNCTION AND VITAMIN D INSUFFICIENCY. EPIGENETIC MODIFICATIONS ARE DISTINCT GENETIC PHENOTYPES RESULTING FROM ENVIRONMENT-DRIVEN CHANGES IN CHROMOSOME FUNCTIONS IN THE ABSENCE OF NUCLEAR DNA SEQUENCE VARIATION. CLASSIC EPIGENETIC EVENTS INCLUDE DNA METHYLATION, HISTONE PROTEIN MODIFICATIONS AND NON-CODING RNA REGULATION. INCREASING EVIDENCE HAS INDICATED THAT EPIGENETIC EVENTS ARE INVOLVED IN THE PATHOGENESIS OF ATOPIC DERMATITIS BY THEIR EFFECTS ON MULTIPLE SIGNALLING PATHWAYS WHICH IN TURN INFLUENCE THE ABOVE FACTORS. THIS REVIEW PRIMARILY ANALYSES THE FUNCTION OF EPIGENETIC REGULATION IN THE PATHOGENESIS OF ATOPIC DERMATITIS. IN ADDITION, IT TRIES TO MAKE RECOMMENDATIONS FOR PERSONALISED EPIGENETIC TREATMENT STRATEGIES FOR ATOPIC DERMATITIS IN THE FUTURE. 2023 5 2553 38 EPIGENETICS IN PSORIASIS: PERSPECTIVE OF DNA METHYLATION. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EXCESSIVE PROLIFERATION OF KERATINOCYTES (KCS). ONSET OF PSORIASIS IS RELATED TO GENETIC, IMMUNE AND ENVIRONMENTAL FACTORS. THE ENVIRONMENT CAN INTERACT WITH THE GENOME THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, AND THIS MODIFICATION IS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION TO A SKIN DISEASE, PSORIASIS IS ALSO CONSIDERED A SYSTEMIC DISEASE. WE REVIEWED THE CURRENT LITERATURE OF PSORIATIC DNA METHYLATION FOR STUDIES FROM SEVERAL ASPECTS ON THE DNA METHYLATION DISTRIBUTION PATTERNS IN DIFFERENT TISSUES/CELLS, SINGLE-NUCLEOTIDE POLYMORPHISMS, AND CANDIDATE DISEASE GENES AND IDENTIFIED TARGET GENES REGULATED BY DNA METHYLATION THAT HAVE BEEN DIRECTLY/INDIRECTLY VALIDATED. THIS REVIEW CONTRIBUTES TO A COMPREHENSIVE UNDERSTANDING OF THE IMPORTANT A ROLE THAT DNA METHYLATION PLAYS IN PSORIASIS FROM A HOLISTIC PERSPECTIVE AND WILL PROMOTE THE IMPLEMENTATION OF DNA METHYLATION IN DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR PSORIATIC PATIENTS. 2021 6 5998 27 THE ABERRANT EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABNORMAL KERATINOCYTE PROLIFERATION, VASCULAR HYPERPLASIA, AND INFILTRATION OF INFLAMMATORY CELLS INTO THE DERMIS AND EPIDERMIS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS DYSFUNCTION OF T LYMPHOCYTES, WHICH ARE AFFECTED BY THE COMPLEX INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS, INCLUDING TRAUMA, INFECTIONS, STRESS, DRUGS, SMOKING, AND ALCOHOL CONSUMPTION (NESTLE ET AL., 2009). THE ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF THIS DISEASE (ZHANG ET AL., 2012). 2018 7 6181 35 THE IMMUNE FUNCTIONS OF KERATINOCYTES IN SKIN WOUND HEALING. AS THE MOST DOMINANT CELL TYPE IN THE SKIN, KERATINOCYTES PLAY CRITICAL ROLES IN WOUND REPAIR NOT ONLY AS STRUCTURAL CELLS BUT ALSO EXERTING IMPORTANT IMMUNE FUNCTIONS. THIS REVIEW FOCUSES ON THE COMMUNICATIONS BETWEEN KERATINOCYTES AND IMMUNE CELLS IN WOUND HEALING, WHICH ARE MEDIATED BY VARIOUS CYTOKINES, CHEMOKINES, AND EXTRACELLULAR VESICLES. KERATINOCYTES CAN ALSO DIRECTLY INTERACT WITH T CELLS VIA ANTIGEN PRESENTATION. MOREOVER, KERATINOCYTES PRODUCE ANTIMICROBIAL PEPTIDES THAT CAN DIRECTLY KILL THE INVADING PATHOGENS AND CONTRIBUTE TO WOUND REPAIR IN MANY ASPECTS. WE ALSO REVIEWED THE EPIGENETIC MECHANISMS KNOWN TO REGULATE KERATINOCYTE IMMUNE FUNCTIONS, INCLUDING HISTONE MODIFICATIONS, NON-PROTEIN-CODING RNAS (E.G., MICRORNAS, AND LONG NONCODING RNAS), AND CHROMATIN DYNAMICS. LASTLY, WE SUMMARIZED THE CURRENT EVIDENCE ON THE DYSREGULATED IMMUNE FUNCTIONS OF KERATINOCYTES IN CHRONIC NONHEALING WOUNDS. BASED ON THEIR CRUCIAL IMMUNE FUNCTIONS IN SKIN WOUND HEALING, WE PROPOSE THAT KERATINOCYTES SIGNIFICANTLY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC WOUND INFLAMMATION. WE HOPE THIS REVIEW WILL TRIGGER AN INTEREST IN INVESTIGATING THE IMMUNE ROLES OF KERATINOCYTES IN CHRONIC WOUND PATHOLOGY, WHICH MAY OPEN UP NEW AVENUES FOR DEVELOPING INNOVATIVE WOUND TREATMENTS. 2020 8 4452 28 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017 9 3068 31 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES DIFFERENTIAL METHYLATION IN UNINVOLVED PSORIATIC EPIDERMIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH BOTH LOCAL AND SYSTEMIC COMPONENTS. GENOME-WIDE APPROACHES HAVE IDENTIFIED MORE THAN 60 PSORIASIS-SUSCEPTIBILITY LOCI, BUT GENES ARE ESTIMATED TO EXPLAIN ONLY ONE-THIRD OF THE HERITABILITY IN PSORIASIS, SUGGESTING ADDITIONAL, YET UNIDENTIFIED, SOURCES OF HERITABILITY. EPIGENETIC MODIFICATIONS HAVE BEEN LINKED TO PSORIASIS AND ALTERED DNA METHYLATION PATTERNS IN PSORIATIC VERSUS HEALTHY SKIN HAVE BEEN REPORTED IN WHOLE-SKIN BIOPSIES. IN THIS STUDY, FOCUSING ON EPIGENETIC MODIFICATIONS IN THE PSORIATIC UNINVOLVED SKIN, WE COMPARED THE LESIONAL AND NON-LESIONAL EPIDERMIS FROM PSORIASIS PATIENTS WITH EPIDERMIS FROM HEALTHY CONTROLS. WE PERFORMED AN EXHAUSTIVE GENOME-WIDE DNA METHYLATION PROFILING USING REDUCED REPRESENTATION BISULFITE SEQUENCING, WHICH INTERROGATES THE METHYLATION STATUS OF APPROXIMATELY 3-4 MILLION CPG SITES. MORE THAN 2,000 STRONGLY DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED AND A STRIKING OVERREPRESENTATION OF THE WNT AND CADHERIN PATHWAYS AMONG THE DIFFERENTIALLY METHYLATED SITES WAS FOUND. IN PARTICULAR, WE OBSERVE A STRONG DIFFERENTIAL METHYLATION IN SEVERAL PSORIASIS CANDIDATE GENES. A SUBSTANTIAL NUMBER OF DIFFERENTIALLY METHYLATED SITES PRESENT IN THE UNINVOLVED VERSUS HEALTHY EPIDERMIS SUGGESTS THE PRESENCE OF A PRE-PSORIATIC STATE IN THE CLINICALLY HEALTHY SKIN TYPE. OUR EXPLORATORY STUDY REPRESENTS A STARTING POINT FOR IDENTIFYING BIOMARKERS FOR PSORIASIS-PRONE SKIN BEFORE DISEASE ONSET. 2018 10 2063 32 EPIGENETIC CONTROL OF IL-23 EXPRESSION IN KERATINOCYTES IS IMPORTANT FOR CHRONIC SKIN INFLAMMATION. THE CHRONIC SKIN INFLAMMATION PSORIASIS IS CRUCIALLY DEPENDENT ON THE IL-23/IL-17 CYTOKINE AXIS. ALTHOUGH IL-23 IS EXPRESSED BY PSORIATIC KERATINOCYTES AND IMMUNE CELLS, ONLY THE IMMUNE CELL-DERIVED IL-23 IS BELIEVED TO BE DISEASE RELEVANT. HERE WE USE A GENETIC MOUSE MODEL TO SHOW THAT KERATINOCYTE-PRODUCED IL-23 IS SUFFICIENT TO CAUSE A CHRONIC SKIN INFLAMMATION WITH AN IL-17 PROFILE. FURTHERMORE, WE REVEAL A CELL-AUTONOMOUS NUCLEAR FUNCTION FOR THE ACTIN POLYMERIZING MOLECULE N-WASP, WHICH CONTROLS IL-23 EXPRESSION IN KERATINOCYTES BY REGULATING THE DEGRADATION OF THE HISTONE METHYLTRANSFERASES G9A AND GLP, AND H3K9 DIMETHYLATION OF THE IL-23 PROMOTER. THIS MECHANISM MEDIATES THE INDUCTION OF IL-23 BY TNF, A KNOWN INDUCER OF IL-23 IN PSORIASIS. FINALLY, IN KERATINOCYTES OF PSORIATIC LESIONS A DECREASE IN H3K9 DIMETHYLATION CORRELATES WITH INCREASED IL-23 EXPRESSION, SUGGESTING RELEVANCE FOR DISEASE. TAKEN TOGETHER, OUR DATA DESCRIBE A MOLECULAR PATHWAY WHERE EPIGENETIC REGULATION OF KERATINOCYTES CAN CONTRIBUTE TO CHRONIC SKIN INFLAMMATION. 2018 11 541 37 ATOPIC DERMATITIS: THE FATE OF THE FAT. ATOPIC DERMATITIS (AD) IS A CHRONIC AND RELAPSING INFLAMMATORY SKIN DISEASE IN WHICH DRY AND ITCHY SKIN MAY DEVELOP INTO SKIN LESIONS. AD HAS A STRONG GENETIC COMPONENT, AS CHILDREN FROM PARENTS WITH AD HAVE A TWO-FOLD INCREASED CHANCE OF DEVELOPING THE DISEASE. GENETIC RISK LOCI AND EPIGENETIC MODIFICATIONS REPORTED IN AD MAINLY LOCATE TO GENES INVOLVED IN THE IMMUNE RESPONSE AND EPIDERMAL BARRIER FUNCTION. HOWEVER, AD PATHOGENESIS CANNOT BE FULLY EXPLAINED BY (EPI)GENETIC FACTORS SINCE ENVIRONMENTAL TRIGGERS SUCH AS STRESS, POLLUTION, MICROBIOTA, CLIMATE, AND ALLERGENS ALSO PLAY A CRUCIAL ROLE. ALTERATIONS OF THE EPIDERMAL BARRIER IN AD, OBSERVED AT ALL STAGES OF THE DISEASE AND WHICH PRECEDE THE DEVELOPMENT OF OVERT SKIN INFLAMMATION, MANIFEST AS: DRY SKIN; EPIDERMAL ULTRASTRUCTURAL ABNORMALITIES, NOTABLY ANOMALIES OF THE LAMELLAR BODY CARGO SYSTEM; AND ABNORMAL EPIDERMAL LIPID COMPOSITION, INCLUDING SHORTER FATTY ACID MOIETIES IN SEVERAL LIPID CLASSES, SUCH AS CERAMIDES AND FREE FATTY ACIDS. THUS, A COMPELLING QUESTION IS WHETHER AD IS PRIMARILY A LIPID DISORDER EVOLVING INTO A CHRONIC INFLAMMATORY DISEASE DUE TO GENETIC SUSCEPTIBILITY LOCI IN IMMUNOGENIC GENES. IN THIS REVIEW, WE FOCUS ON LIPID ABNORMALITIES OBSERVED IN THE EPIDERMIS AND BLOOD OF AD PATIENTS AND EVALUATE THEIR PRIMARY ROLE IN ELICITING AN INFLAMMATORY RESPONSE. 2022 12 2635 39 EPIGENOME-WIDE DNA METHYLATION REGULATES CARDINAL PATHOLOGICAL FEATURES OF PSORIASIS. BACKGROUND: PSORIASIS IS A CHRONIC INFLAMMATORY AUTOIMMUNE SKIN DISORDER. SEVERAL STUDIES SUGGESTED PSORIASIS TO BE A COMPLEX MULTIFACTORIAL DISEASE, BUT THE EXACT TRIGGERING FACTOR IS YET TO BE DETERMINED. EVIDENCES SUGGEST THAT IN ADDITION TO GENETIC FACTORS, EPIGENETIC REPROGRAMMING IS ALSO INVOLVED IN PSORIASIS DEVELOPMENT. MAJOR HISTOPATHOLOGICAL FEATURES, LIKE INCREASED PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES, AND IMMUNE CELL INFILTRATIONS ARE CHARACTERISTIC MARKS OF PSORIATIC SKIN LESIONS. FOLLOWING THERAPY, HISTOPATHOLOGICAL FEATURES AS WELL AS ABERRANT DNA METHYLATION REVERSED TO NORMAL LEVELS. TO UNDERSTAND THE ROLE OF DNA METHYLATION IN REGULATING THESE CRUCIAL HISTOPATHOLOGIC FEATURES, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION PROFILE OF PSORIASIS PATIENTS WITH DIFFERENT HISTOPATHOLOGICAL FEATURES. RESULTS: GENOME-WIDE DNA METHYLATION PROFILING OF PSORIATIC AND ADJACENT NORMAL SKIN TISSUES IDENTIFIED SEVERAL NOVEL DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH PSORIASIS. DIFFERENTIALLY METHYLATED CPGS WERE SIGNIFICANTLY ENRICHED IN SEVERAL PSORIASIS SUSCEPTIBILITY (PSORS) REGIONS AND EPIGENETICALLY REGULATED THE EXPRESSION OF KEY PATHOGENIC GENES, EVEN WITH LOW-CPG PROMOTERS. TOP DIFFERENTIALLY METHYLATED GENES OVERLAPPED WITH PSORS REGIONS INCLUDING S100A9, SELENBP1, CARD14, KAZN AND PTPN22 SHOWED INVERSE CORRELATION BETWEEN METHYLATION AND GENE EXPRESSION. WE IDENTIFIED DIFFERENTIALLY METHYLATED GENES ASSOCIATED WITH CHARACTERISTIC HISTOPATHOLOGICAL FEATURES IN PSORIASIS. PSORIATIC SKIN WITH MUNRO'S MICROABSCESS, A DISTINCTIVE FEATURE IN PSORIASIS INCLUDING PARAKERATOSIS AND NEUTROPHIL ACCUMULATION AT THE STRATUM CORNEUM, WAS ENRICHED WITH DIFFERENTIALLY METHYLATED GENES INVOLVED IN NEUTROPHIL CHEMOTAXIS. RETE PEG ELONGATION AND FOCAL HYPERGRANULOSIS WERE ALSO ASSOCIATED WITH EPIGENETICALLY REGULATED GENES, SUPPORTING THE REVERSIBLE NATURE OF THESE CHARACTERISTIC FEATURES DURING REMISSION AND RELAPSE OF THE LESIONS. CONCLUSION: OUR STUDY, FOR THE FIRST TIME, INDICATED THE POSSIBLE INVOLVEMENT OF DNA METHYLATION IN REGULATING THE CARDINAL PATHOPHYSIOLOGICAL FEATURES IN PSORIASIS. COMMON GENES INVOLVED IN REGULATION OF THESE PATHOLOGIES MAY BE USED TO DEVELOP DRUGS FOR BETTER CLINICAL MANAGEMENT OF PSORIASIS. 2018 13 4883 33 OVERVIEW OF THE MOLECULAR DETERMINANTS CONTRIBUTING TO THE EXPRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS PHENOTYPES. PSORIASIS AND PSORIATIC ARTHRITIS ARE MULTIFACTORIAL CHRONIC DISORDERS WHOSE ETIOPATHOGENESIS ESSENTIALLY DERIVES FROM THE ALTERATION OF SEVERAL SIGNALLING PATHWAYS AND THE CO-OCCURRENCE OF GENETIC, EPIGENETIC AND NON-GENETIC SUSCEPTIBILITY FACTORS THAT ALTOGETHER AFFECT THE FUNCTIONAL AND STRUCTURAL PROPERTY OF THE SKIN. ALTHOUGH SHARED AND DIFFERENTIAL SUSCEPTIBILITY GENES AND MOLECULAR PATHWAYS ARE KNOWN TO CONTRIBUTE TO THE ONSET OF PATHOLOGICAL PHENOTYPES, FURTHER RESEARCH IS NEEDED TO DISSECT THE MOLECULAR CAUSES OF PSORIATIC DISEASE AND ITS PROGRESSION TOWARDS PSORIATIC ARTHRITIS. THIS REVIEW WILL THEREFORE BE ADDRESSED TO EXPLORE DIFFERENCES AND SIMILARITIES IN THE ETIOPATHOGENESIS AND PROGRESSION OF BOTH DISORDERS, WITH A PARTICULAR FOCUS ON GENES INVOLVED IN THE MAINTENANCE OF THE SKIN STRUCTURE AND INTEGRITY (KERATINS AND COLLAGENS), MODULATION OF PATTERNS OF RECOGNITION (THROUGH TOLL-LIKE RECEPTORS AND DECTIN-1) AND IMMUNO-INFLAMMATORY RESPONSE (BY NLRP3-DEPENDENT INFLAMMASOME) TO MICROBIAL PATHOGENS. IN ADDITION, SPECIAL EMPHASIS WILL BE GIVEN TO THE CONTRIBUTION OF EPIGENETIC ELEMENTS (METHYLATION PATTERN, NON-CODING RNAS, CHROMATIN MODIFIERS AND 3D GENOME ORGANIZATION) TO THE ETIOPATHOGENESIS AND PROGRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS. THE EVIDENCE DISCUSSED IN THIS REVIEW HIGHLIGHTS HOW THE KNOWLEDGE OF PATIENTS' CLINICAL AND (EPI)GENOMIC MAKE-UP COULD BE HELPFUL FOR IMPROVING THE AVAILABLE THERAPEUTIC STRATEGIES FOR PSORIASIS AND PSORIATIC ARTHRITIS TREATMENT. 2020 14 6274 25 THE P300/CBP INHIBITOR A485 NORMALIZES PSORIATIC FIBROBLAST GENE EXPRESSION IN VITRO AND REDUCES PSORIASIS-LIKE SKIN INFLAMMATION IN VIVO. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT OFTEN RECURS AT THE SAME LOCATIONS, INDICATING POTENTIAL EPIGENETIC CHANGES IN LESIONAL SKIN CELLS. IN THIS STUDY, WE DISCOVERED THAT FIBROBLASTS ISOLATED FROM PSORIATIC SKIN LESIONS RETAIN AN ABNORMAL PHENOTYPE EVEN AFTER SEVERAL PASSAGES IN CULTURE. TRANSCRIPTOMIC PROFILING REVEALED THE UPREGULATION OF SEVERAL GENES, INCLUDING THE EXTRA DOMAIN A SPLICE VARIANT OF FIBRONECTIN AND ITGA4 IN PSORIATIC FIBROBLASTS. A PHENOTYPIC LIBRARY SCREENING OF SMALL-MOLECULE EPIGENETIC MODIFIER DRUGS REVEALED THAT SELECTIVE CBP/P300 INHIBITORS WERE ABLE TO RESCUE THE PSORIATIC FIBROBLAST PHENOTYPE, REDUCING THE EXPRESSION LEVELS OF EXTRA DOMAIN A SPLICE VARIANT OF FIBRONECTIN AND ITGA4. IN THE IMIQUIMOD-INDUCED MOUSE MODEL OF PSORIASIS-LIKE SKIN INFLAMMATION, SYSTEMIC TREATMENT WITH A485, A POTENT CBP/P300 BLOCKER, SIGNIFICANTLY REDUCED SKIN INFLAMMATION, IMMUNE CELL RECRUITMENT, AND INFLAMMATORY CYTOKINE PRODUCTION. OUR FINDINGS INDICATE THAT EPIGENETIC REPROGRAMMING MIGHT REPRESENT A NEW APPROACH FOR THE TREATMENT AND/OR PREVENTION OF RELAPSES OF PSORIASIS. 2023 15 3285 30 HIDRADENITIS SUPPURATIVA: A PERSPECTIVE ON GENETIC FACTORS INVOLVED IN THE DISEASE. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE OF THE PILOSEBACEOUS UNIT, CLINICALLY CONSISTING OF PAINFUL NODULES, ABSCESSES, AND SINUS TRACTS MOSTLY IN, BUT NOT LIMITED TO, INTERTRIGINOUS SKIN AREAS. HS CAN BE DEFINED AS A COMPLEX SKIN DISEASE WITH MULTIFACTORIAL ETIOLOGIES, INCLUDING-AMONG OTHERS-GENETIC, IMMUNOLOGIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. BASED ON GENETIC HETEROGENEITY AND COMPLEXITY, THREE DIFFERENT FORMS CAN BE RECOGNIZED AND CONSIDERED SEPARATELY AS SPORADIC, FAMILIAL, AND SYNDROMIC. TO DATE, SEVERAL GENETIC VARIANTS ASSOCIATED TO DISEASE SUSCEPTIBILITY, DISEASE-ONSET, AND/OR TREATMENT RESPONSE HAVE BEEN REPORTED; SOME OF THESE RESIDE IN GENES ENCODING THE GAMMA-SECRETASE SUBUNITS WHEREAS OTHERS INVOLVE AUTOINFLAMMATORY AND/OR KERATINIZATION GENES. THE AIM OF THIS PERSPECTIVE WORK IS TO PROVIDE AN OVERVIEW OF THE CONTRIBUTION OF SEVERAL GENETIC STUDIES ENCOMPASSING FAMILY LINKAGE ANALYSES, TARGET CANDIDATE GENE STUDIES, AND -OMIC STUDIES IN THIS FIELD. IN OUR VIEWPOINT, WE DISCUSS THE ROLE OF GENETICS IN HIDRADENITIS SUPPURATIVA CONSIDERING FINDINGS BASED ON SANGER SEQUENCING AS WELL AS THE MORE RECENT NEXT GENERATION SEQUENCING (I.E., EXOME SEQUENCING OR RNA SEQUENCING) WITH THE AIM OF BETTER UNDERSTANDING THE ETIO-PATHOGENESIS OF THE DISEASE AS WELL AS IDENTIFYING NOVEL THERAPEUTIC STRATEGIES. 2022 16 258 30 ADVANCES IN PATHOGENESIS AND NANOPARTICLES (NPS)-MEDIATED TREATMENT OF PSORIASIS. PSORIASIS IS A CHRONIC PAPULOSQUAMOUS SKIN DISEASE WITH AN AUTOIMMUNE PATHOGENIC TRAITS AND STRONG GENETIC PREDISPOSITION. IN THE PAST FEW DECADES, WITH THE RAPID DEVELOPMENT OF MOLECULAR BIOLOGY AND CELL BIOLOGY, THE INHERENT PATHOGENESIS OF PSORIASIS HAS BEEN GRADUALLY ELUCIDATED, IN WHICH CYTOKINE INFLAMMATORY LOOPS, CELL SIGNALING PATHWAYS, AND EPIGENETIC FACTORS SUCH AS MIRNAS HAVE BEEN DEMONSTRATED TO PLAY IMPORTANT ROLES IN REGULATING THE DEVELOPMENT AND PROGRESSION OF PSORIASIS. MORE IMPORTANTLY, UNDERSTANDING THE PATHOGENESIS OF PSORIASIS HAS PROMOTED THE DEVELOPMENT OF EFFECTIVE TREATMENT FOR PSORIASIS. IN THIS REVIEW, WE SYSTEMICALLY SUMMARIZED THE MOLECULAR MECHANISMS REGULATING THE DEVELOPMENT AND PROGRESSION PSORIASIS, INTRODUCED VARIOUS THERAPEUTICS USED FOR CLINICAL PSORIASIS THERAPY, AND HIGHLIGHTED THE RECENT ADVANCES IN NANOPARTICLES (NPS)-MEDIATED DRUG DELIVERY FOR PSORIASIS TREATMENT. 2022 17 2082 32 EPIGENETIC DOWNREGULATION OF SFRP4 CONTRIBUTES TO EPIDERMAL HYPERPLASIA IN PSORIASIS. PSORIASIS IS A CHRONIC RECURRENT INFLAMMATORY SKIN DISORDER CHARACTERIZED BY THE DYSREGULATED CROSS-TALK BETWEEN EPIDERMAL KERATINOCYTES AND IMMUNE CELLS, LEADING TO KERATINOCYTE HYPERPROLIFERATION. SEVERAL STUDIES DEMONSTRATED THAT WNT PATHWAY GENES WERE DIFFERENTIALLY EXPRESSED IN PSORIATIC PLAQUES AND LIKELY WERE INVOLVED IN THE PATHOPHYSIOLOGY OF DISEASE. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING WNT SIGNALING REGULATION IN EPIDERMAL HYPERPLASIA IN PSORIASIS REMAIN LARGELY UNKNOWN. WE REPORT THAT THE EXPRESSION OF SECRETED FRIZZLED-RELATED PROTEIN (SFRP) 4, A NEGATIVE REGULATOR OF THE WNT SIGNALING PATHWAY, WAS DIMINISHED IN LESIONAL SKIN OF MOUSE MODELS AND PATIENTS WITH PSORIASIS. SFRP4 DIRECTLY INHIBITED EXCESSIVE KERATINOCYTE PROLIFERATION EVOKED BY PROINFLAMMATORY CYTOKINES IN VITRO. PHARMACOLOGICAL INHIBITION OF WNT SIGNALING OR INTRADERMAL INJECTION OF SFRP4 DECREASED THE SEVERITY OF THE PSORIASIFORM SKIN PHENOTYPE IN VIVO, INCLUDING DECREASED ACANTHOSIS AND REDUCED LEUKOCYTE INFILTRATION. MECHANISTICALLY, WE IDENTIFIED THAT ABERRANT PROMOTER METHYLATION RESULTED IN EPIGENETIC DOWNREGULATION OF SFRP4 IN INFLAMED SKIN OF PATIENTS WITH PSORIASIS AND IN THE IL-23-INDUCED MOUSE MODEL. OUR FINDINGS SUGGEST THAT THIS EPIGENETIC EVENT IS CRITICALLY INVOLVED IN THE PATHOGENESIS OF PSORIASIS, AND THE DOWNREGULATION OF SFRP4 BY CPG ISLAND METHYLATION IS ONE POSSIBLE MECHANISM CONTRIBUTING TO THE HYPERPLASIA OF EPIDERMIS IN THE DISEASE. 2015 18 1570 29 DNA METHYLATION PATTERNS IN CD4(+) T-CELLS SEPARATE PSORIASIS PATIENTS FROM HEALTHY CONTROLS, AND SKIN PSORIASIS FROM PSORIATIC ARTHRITIS. BACKGROUND: PSORIASIS IS AN AUTOIMMUNE/INFLAMMATORY DISORDER PRIMARILY AFFECTING THE SKIN. CHRONIC JOINT INFLAMMATION TRIGGERS THE DIAGNOSIS OF PSORIATIC ARTHRITIS (PSA) IN APPROXIMATELY ONE-THIRD OF PSORIASIS PATIENTS. ALTHOUGH JOINT DISEASE TYPICALLY FOLLOWS THE ONSET OF SKIN PSORIASIS, IN AROUND 15% OF CASES IT IS THE INITIAL PRESENTATION, WHICH CAN RESULT IN DIAGNOSTIC DELAYS. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING PSORIASIS AND PSA ARE NOT YET FULLY UNDERSTOOD, BUT THERE IS EVIDENCE POINTING TOWARDS EPIGENETIC DYSREGULATION INVOLVING CD4(+) AND CD8(+) T-CELLS. OBJECTIVES: THE AIM OF THIS STUDY WAS TO INVESTIGATE DISEASE-ASSOCIATED DNA METHYLATION PATTERNS IN CD4(+) T-CELLS FROM PSORIASIS AND PSA PATIENTS THAT MAY REPRESENT POTENTIAL DIAGNOSTIC AND/OR PROGNOSTIC BIOMARKERS. METHODS: PBMCS WERE COLLECTED FROM 12 PATIENTS WITH CHRONIC PLAQUE PSORIASIS AND 8 PSA PATIENTS, AND 8 HEALTHY CONTROLS. CD4(+) T-CELLS WERE SEPARATED THROUGH FACS SORTING, AND DNA METHYLATION PROFILING WAS PERFORMED (ILLUMINA EPIC850K ARRAYS). BIOINFORMATIC ANALYSES, INCLUDING GENE ONTOLOGY (GO) AND KEGG PATHWAY ANALYSIS, WERE PERFORMED USING R. TO IDENTIFY GENES UNDER THE CONTROL OF INTERFERON (IFN), THE INTERFEROME DATABASE WAS CONSULTED, AND DNA METHYLATION SCORES WERE CALCULATED. RESULTS: NUMBERS AND PROPORTIONS OF CD4(+) T-CELL SUBSETS (NAIVE, CENTRAL MEMORY, EFFECTOR MEMORY, CD45RA RE-EXPRESSING EFFECTOR MEMORY CELLS) DID NOT VARY BETWEEN CONTROLS, SKIN PSORIASIS AND PSA PATIENTS. 883 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AFFECTING 548 GENES WERE IDENTIFIED BETWEEN CONTROLS AND "ALL" PSORIASIS PATIENTS. PRINCIPAL COMPONENT AND PARTIAL LEAST-SQUARES DISCRIMINANT ANALYSIS SEPARATED CONTROLS FROM SKIN PSORIASIS AND PSA PATIENTS. GO ANALYSIS CONSIDERING PROMOTER DMPS DELIVERED HYPERMETHYLATION OF GENES INVOLVED IN "REGULATION OF WOUND HEALING, SPREADING OF EPIDERMAL CELLS", "NEGATIVE REGULATION OF CELL-SUBSTRATE JUNCTION ORGANIZATION" AND "NEGATIVE REGULATION OF FOCAL ADHESION ASSEMBLY". COMPARING CONTROLS AND "ALL" PSORIASIS, A MAJORITY OF DMPS MAPPED TO IFN-RELATED GENES (69.2%). NOTABLY, DNA METHYLATION PROFILES ALSO DISTINGUISHED SKIN PSORIASIS FROM PSA PATIENTS (2,949 DMPS/1,084 GENES) THROUGH GENES AFFECTING "CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ACTIVITY" AND "CAMP-DEPENDENT PROTEIN KINASE REGULATOR ACTIVITY". TREATMENT WITH CYTOKINE INHIBITORS (IL-17/TNF) CORRECTED DNA METHYLATION PATTERNS OF IL-17/TNF-ASSOCIATED GENES, AND METHYLATION SCORES CORRELATED WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: DNA METHYLATION PROFILES IN CD4(+) T-CELLS DISCRIMINATE BETWEEN SKIN PSORIASIS AND PSA. DNA METHYLATION SIGNATURES MAY BE APPLIED FOR QUANTIFICATION OF DISEASE ACTIVITY AND PATIENT STRATIFICATION TOWARDS INDIVIDUALIZED TREATMENT. 2023 19 6624 36 UNDERSTANDING PSORIASIS: ROLE OF MIRNAS. PSORIASIS IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY SKIN DISEASE, WITH A MULTIFACTORIAL ETIOLOGY AND IMPORTANT IMMUNOLOGIC, GENETIC AND ENVIRONMENTAL COMPONENTS. PSORIASIS VULGARIS REPRESENTS ITS MOST COMMON FORM, WITH A VARIABLE PREVALENCE ACROSS THE GLOBE. ALTHOUGH ITS PATHOGENESIS REMAINS TO BE FULLY ELUCIDATED, A LACK OF BALANCE IN THE EPIGENETIC NETWORK HAS BEEN SHOWN TO TRIGGER CERTAIN ELEMENTS OF THIS DISEASE, POSSIBLY ALTERING ITS OUTCOME. MICRORNAS ARE SMALL NON-CODING RNA MOLECULES INVOLVED IN RNA-SILENCING AND THE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, WHICH ALSO APPEAR TO MEDIATE THE IMMUNE DYSFUNCTION IN PSORIASIS. ALTHOUGH MICRORNA RESEARCH IS A NEW FIELD IN DERMATOLOGY AND PSORIASIS, THERE IS RAPIDLY ACCUMULATING EVIDENCE FOR ITS MAJOR CONTRIBUTION IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PSORIASIS AND OTHER DERMATOLOGICAL DISORDERS. FURTHERMORE, CIRCULATING MIRNAS IDENTIFIED IN PATIENTS' BLOOD SAMPLES HAVE BEEN IDENTIFIED AS PROMISING BIOMARKERS OF DIAGNOSIS, PROGNOSIS OR TREATMENT RESPONSE. EXTENDED INVESTIGATIONS IN THIS FIELD ARE REQUIRED, AS UNTIL NOW, THE EXACT INVOLVEMENT OF MIRNAS IN PSORIASIS HAVE REMAINED TO BE ENTIRELY ELUCIDATED. THIS SHORT REVIEW HIGHLIGHTS A NUMBER OF THE ROLES OF MIRNAS FOUND IN DIFFERENT STAGES OF PSORIASIS. 2018 20 4961 38 PATHOGENESIS OF PSORIASIS IN THE "OMIC" ERA. PART II. GENETIC, GENOMIC AND EPIGENETIC CHANGES IN PSORIASIS. PSORIASIS IS A MULTIFACTORIAL DISEASE IN WHICH GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS REGULATING GENE EXPRESSION PLAY A KEY ROLE. IN THE "GENOMIC ERA", GENOME-WIDE ASSOCIATION STUDIES TOGETHER WITH TARGET GENOTYPING PLATFORMS PERFORMED IN DIFFERENT ETHNIC POPULATIONS HAVE FOUND MORE THAN 50 GENETIC SUSCEPTIBLE MARKERS ASSOCIATED WITH THE RISK OF PSORIASIS WHICH HAVE BEEN IDENTIFIED SO FAR. UP TILL NOW, THE STRONGEST ASSOCIATION WITH THE RISK OF THE DISEASE HAS BEEN PROVED FOR HLA-C*06 GENE. THE MAJORITY OF OTHER PSORIASIS RISK SNPS ARE SITUATED NEAR THE GENES ENCODING MOLECULES INVOLVED IN ADAPTIVE AND INNATE IMMUNITY, AND SKIN BARRIER FUNCTION. MANY CONTEMPORARY STUDIES INDICATE THAT THE EPIGENETIC CHANGES: HISTONE MODIFICATION, PROMOTER METHYLATIONS, LONG NON-CODING AND MICRO-RNA HYPEREXPRESSION ARE CONSIDERED AS FACTORS CONTRIBUTING TO PSORIASIS PATHOGENESIS AS THEY REGULATE ABNORMAL KERATINOCYTE DIFFERENTIATION AND PROLIFERATION, ABERRANT KERATINOCYTES - INFLAMMATORY CELLS COMMUNICATION, NEOANGIOGENESIS AND CHRONIC INFLAMMATION. THE CIRCULATING MIRNAS DETECTED IN THE BLOOD MAY BECOME SPECIFIC MARKERS IN THE DIAGNOSIS, PROGNOSIS AND RESPONSE TO THE TREATMENT OF THE DISEASE. THE INHIBITION OF EXPRESSION IN SELECTED MIRNAS MAY BE A NEW PROMISING THERAPY OPTION FOR PATIENTS WITH PSORIASIS. 2020