1  3284 137 HIDRADENITIS SUPPURATIVA PRESENTS A METHYLOME DYSREGULATION CAPABLE TO EXPLAIN THE PRO-INFLAMMATORY MICROENVIRONMENT: ARE THESE DNA METHYLATIONS POTENTIAL THERAPEUTIC TARGETS? BACKGROUND: HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC, SYSTEMIC, INFLAMMATORY SKIN CONDITION WITH ELUSIVE PATHOGENESIS THAT AFFECTS THERAPEUTIC INTERVENTION DIRECTLY. OBJECTIVE: TO CHARACTERIZE EPIGENETIC VARIATIONS IN CYTOKINES GENES CONTRIBUTING TO HS. METHODS: EPIGENOME-WIDE DNA METHYLATION PROFILING WITH THE ILLUMINA EPIC ARRAY WAS PERFORMED ON BLOOD DNA SAMPLES FROM 24 HS PATIENTS AND 24 AGE- AND SEX-MATCHED CONTROLS TO EXPLORE DNA METHYLATION CHANGES IN CYTOKINE GENES. RESULTS: WE IDENTIFIED 170 CYTOKINE GENES INCLUDING 27 HYPERMETHYLATED CPG SITES AND 143 GENES WITH HYPOMETHYLATED SITES RESPECTIVELY. HYPERMETHYLATED GENES, INCLUDING LIF, HLA-DRB1, HLA-G, MTOR, FADD, TGFB3, MALAT1 AND CCL28; HYPOMETHYLATED GENES, INCLUDING NCSTN, SMAD3, IGF1R, IL1F9, NOD2, NOD1, YY1, DLL1 AND BCL2 MAY CONTRIBUTE TO THE PATHOGENESIS OF HS. THESE GENES WERE ENRICHED IN THE 117 DIFFERENT PATHWAYS (FDR P-VALUES </= 0.05), INCLUDING IL-4/IL-13 PATHWAYS AND WNT/BETA-CATENIN SIGNALLING. CONCLUSIONS: THE LACK OF WOUND HEALING, MICROBIOME DYSBIOSIS AND INCREASED TUMOUR SUSCEPTIBILITY ARE ALL SUSTAINED BY THESE DYSFUNCTIONAL METHYLOMES, HOPEFULLY, CAPABLE TO BE TARGETED IN THE NEXT FUTURE. SINCE METHYLOME DESCRIBES AND SUMMARIZES GENETIC AND ENVIRONMENTAL CONTRIBUTIONS, THESE DATA MAY REPRESENT A FURTHER STEP TOWARDS A FEASIBLE PRECISION MEDICINE ALSO FOR HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2   205  20 ACTIVATION OF HLA-G EXPRESSION BY 5-AZA-2 - DEOXYCYTIDINE IN MALIGNANT HEMATOPOETIC CELLS ISOLATED FROM LEUKEMIA PATIENTS. HUMAN LEUKOCYTE ANTIGEN - G (HLA-G) IS A NON-CLASSICAL HLA CLASS I ANTIGEN WITH RESTRICTED DISTRIBUTION IN NORMAL TISSUES. ECTOPIC HLA-G EXPRESSION OBSERVED AT SOME PATHOLOGICAL CIRCUMSTANCES AS MALIGNANT TRANSFORMATION MIGHT BE TRIGGERED BY EPIGENETIC MODIFICATIONS SUCH AS DNA DEMETHYLATION. RECENTLY IT WAS DEMONSTRATED THAT DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2 - DEOXYCYTIDINE (ADC) INDUCES/ENHANCES HLA-G TRANSCRIPTION IN MANY LEUKEMIA CELL LINES OF DIFFERENT ORIGIN. HERE WE INVESTIGATED THE EFFECT OF ADC ON HLA-G EXPRESSION IN MALIGNANT HEMATOPOETIC CELLS ISOLATED FROM PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) AND CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL). WE DETECTED HLA-G EXPRESSION IN UNTREATED CELLS FROM SOME PATIENTS. NEVERTHELESS TREATMENT WITH 5-AZA-2 - DEOXYCYTIDINE ENHANCED HLA-G TRANSCRIPTION AND CONCOMITANTLY HLA-G PROTEIN SYNTHESIS IN SOME LEUKEMIA CELLS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  5399  41 REDUCED TEN-ELEVEN TRANSLOCATION AND ISOCITRATE DEHYDROGENASE EXPRESSION IN INFLAMMATORY HIDRADENITIS SUPPURATIVA LESIONS. BACKGROUND: AS ENVIRONMENTAL FACTORS APPEAR TO PREDISPOSE PATIENTS TO HIDRADENITIS SUPPURATIVA (HS), STUDYING EPIGENETIC MODIFICATIONS IS OF INTEREST TO FURTHER UNDERSTAND THE PATHOGENESIS OF HS. OBJECTIVES: TO STUDY THE EXPRESSION OF DNA HYDROXYMETHYLATION REGULATORS, NAMELY THE TEN-ELEVEN TRANSLOCATION (TET) AND ISOCITRATE DEHYDROGENASE (IDH) FAMILY, IN THE SKIN OF HS PATIENTS. MATERIALS & METHODS: TWENTY PATIENTS WITH HS AND 12 HEALTHY SUBJECTS WERE RECRUITED. WE ANALYSED THE EXPRESSION OF TET1, TET2, TET3, IDH1, IDH2, IDH3A, AND IDH3B IN LESIONAL AND PERILESIONAL HS TISSUE AS WELL AS TISSUE FROM HEALTHY CONTROLS BY QUANTITATIVE REAL-TIME REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION (RT-PCR). IN ADDITION, IMMUNOHISTOCHEMISTRY WAS PERFORMED FOR TET1, TET2, AND TET3. RESULTS: RT-PCR ANALYSIS SHOWED THAT MRNA OF ALL THE STUDIED GENES WAS SIGNIFICANTLY UNDER-EXPRESSED IN LESIONAL HS SKIN COMPARED TO HEALTHY SKIN. IDH1 AND IDH2 MRNA EXPRESSION WAS ALSO SIGNIFICANTLY LOWER IN PERILESIONAL HS SKIN COMPARED TO HEALTHY SKIN, AND TET3 MRNA EXPRESSION WAS SIGNIFICANTLY LOWER IN LESIONAL HS SKIN COMPARED TO PERILESIONAL HS SKIN. RT-PCR ANALYSIS FOR TET1, TET2, AND TET3 MRNA EXPRESSION WAS CONFIRMED BY IMMUNOHISTOCHEMICAL ANALYSIS. CORRELATION ANALYSIS REVEALED A SIGNIFICANT POSITIVE CORRELATION BETWEEN TET AND IDH GENE EXPRESSION IN PERILESIONAL AND LESIONAL HS SKIN. CONCLUSIONS: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OCCUR IN HS TISSUE AND THAT ABERRANT EXPRESSION OF THE DNA HYDROXYMETHYLATION REGULATORS MAY PLAY A ROLE IN THE PATHOGENESIS OF HS. AS EPIGENETIC MODIFICATIONS ARE REVERSIBLE, FURTHER RESEARCH INTO THE CAUSE OF THESE ABERRANT EXPRESSION PATTERNS IS WARRANTED IN ORDER TO DEVELOP POSSIBLE NOVEL THERAPEUTIC APPROACHES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  5760  32 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  3070  43 GENOME-WIDE DNA METHYLATION PROFILING IN CD8 T-CELLS AND GAMMA DELTA T-CELLS OF ASIAN INDIAN PATIENTS WITH TAKAYASU ARTERITIS. BACKGROUND: TAKAYASU'S ARTERITIS (TA) IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS AORTA AND ITS MAIN BRANCHES AT THEIR ORIGIN. GENETIC, PATHOLOGICAL AND FUNCTIONAL STUDIES HAVE SHOWN THAT CD8 AND GAMMA DELTA (GAMMA/DELTA) T-LYMPHOCYTES ARE INVOLVED IN INFLAMMATORY PROCESSES IN AFFECTED REGIONS OF ARTERIES CAUSING VASCULAR DAMAGE. THE MOLECULAR FUNCTION OF THESE LYMPHOCYTES REMAINS UNCLEAR AND CURRENTLY NO EPIGENETIC STUDIES ARE AVAILABLE IN TA. WE PRIMARILY PERFORMED GENOME WIDE METHYLATION ANALYSIS IN CD8 T CELLS AND GAMMADELTA T CELLS OF PATIENTS WITH TA AND COMPARED WITH HEALTHY CONTROLS. METHODS: WE RECRUITED 12 SUBJECTS IN EACH GROUP NAMELY TA PATIENT AND HEALTHY CONTROLS. BLOOD SAMPLES WERE COLLECTED AFTER OBTAINING INFORMED WRITTEN CONSENT. CD8 T CELLS AND GAMMADELTA T CELLS WERE SEPARATED FROM WHOLE BLOOD. DNA EXTRACTED FROM THESE CELLS AND WERE SUBJECTED TO BISULFITE TREATMENT. FINALLY, BISULFITE TREATED DNA WAS LOADED IN INFINIUM METHYLATION EPIC ARRAY. BIOINFORMATICS ANALYSIS WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS WHICH WERE THEN MAPPED TO GENES. RESULTS: INTERLEUKIN (IL)-32 AND LYMPHOTOXIN-A WERE GENES SIGNIFICANTLY HYPOMETHYLATED IN CD8 T-CELLS. ANTI-INFLAMMATORY CYTOKINE GENES, IL-10, IL-1RN AND IL-27 WERE HYPOMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS AS COMPARED TO HEALTHY CONTROLS. GENE ENRICHMENT ANALYSIS USING GENE ONTOLOGY (GO) DATABASE AND KYOTO ENCYCLOPAEDIA OF GENES AND GENOMES (KEGG) IDENTIFIED THAT GENES INVOLVED IN T-CELL RECEPTOR SIGNALLING PATHWAYS WERE HYPOMETHYLATED IN CD8 T-CELLS AND HYPERMETHYLATED IN GAMMADELTA T CELLS OF TA PATIENTS. CONCLUSION: CD8 T-CELLS MIGHT PLAY A MAJOR ROLE IN IMMUNOPATHOGENESIS OF INFLAMMATION IN TA, WHEREAS GAMMADELTA T CELLS MAY PLAY A REGULATORY ROLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  3056  37 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  1571  43 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	
                                                                                                                                                                                                                                                                                    
8  3068  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9   552  36 AUTOINFLAMMATION IN SYNDROMIC HIDRADENITIS SUPPURATIVA: THE ROLE OF AIM2. BACKGROUND: AIM2 IS A KEY CYTOPLASMATIC PATHOGEN-SENSOR THAT DETECTS FOREIGN DNA FROM VIRUSES AND BACTERIA; IT CAN ALSO RECOGNIZE DAMAGED OR ANOMALOUS PRESENCE OF DNA, PROMOTING INFLAMMASOME ASSEMBLY AND ACTIVATION WITH THE SECRETION OF IL-1BETA, THUS SUSTAINING A CHRONIC INFLAMMATORY STATE, POTENTIALLY LEADING TO THE ONSET OF AUTOINFLAMMATORY SKIN DISEASES. GIVEN THE IMPLICATION OF THE IL-1BETA PATHWAY IN THE PATHOGENESIS OF SYNDROMIC HIDRADENITIS SUPPURATIVA (HS), AN AUTOINFLAMMATORY IMMUNE-MEDIATED SKIN CONDITION, THE POTENTIAL INVOLVEMENT OF AIM2 WAS INVESTIGATED. METHODS: SEQUENCING OF THE WHOLE CODING REGION OF THE AIM2 GENE, COMPRISING 5'- AND 3' UTR AND A REGION UPSTREAM OF THE FIRST EXON OF ~800 BP WAS PERFORMED IN TWELVE SYNDROMIC HS PATIENTS. RESULTS: SIX OUT OF TWELVE SYNDROMIC HS PATIENTS CARRIED A HETEROZYGOUS VARIANT C.-208 A >/= C (RS41264459), LOCATED ON THE PROMOTER REGION OF THE AIM2 GENE, WITH A MINOR ALLELE FREQUENCY OF 0.25, WHICH IS MUCH HIGHER THAN THAT REPORTED IN 1000 G AND GNOMAD (0.075 AND 0.094, RESPECTIVELY). THE SAME VARIANT WAS FOUND AT A LOWER ALLELIC FREQUENCY IN SPORADIC HS AND ISOLATED PYODERMA GANGRENOSUM (PG) (0.125 AND 0.065, RESPECTIVELY). CONCLUSION: OUR DATA SUGGEST THAT THIS VARIANT MIGHT PLAY A ROLE IN SUSCEPTIBILITY TO DEVELOP SYNDROMIC FORMS OF HS BUT NOT TO PROGRESS TO SPORADIC HS AND PG. FURTHERMORE, EPIGENETIC AND/OR SOMATIC VARIATIONS COULD AFFECT AIM2 EXPRESSION LEADING TO DIFFERENT, CONTEXT-DEPENDENT RESPONSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  1161  37 CONTINUOUS DEVELOPMENTAL AND EARLY LIFE TRICHLOROETHYLENE EXPOSURE PROMOTED DNA METHYLATION ALTERATIONS IN POLYCOMB PROTEIN BINDING SITES IN EFFECTOR/MEMORY CD4(+) T CELLS. TRICHLOROETHYLENE (TCE) IS AN INDUSTRIAL SOLVENT AND DRINKING WATER POLLUTANT ASSOCIATED WITH CD4(+) T CELL-MEDIATED AUTOIMMUNITY. IN OUR MOUSE MODEL, DISCONTINUATION OF TCE EXPOSURE DURING ADULTHOOD AFTER DEVELOPMENTAL EXPOSURE DID NOT PREVENT IMMUNOTOXICITY. TO DETERMINE WHETHER PERSISTENT EFFECTS WERE LINKED TO EPIGENETIC CHANGES WE CONDUCTED WHOLE GENOME REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO EVALUATE METHYLATION OF CPG SITES IN AUTOSOMAL CHROMOSOMES IN ACTIVATED EFFECTOR/MEMORY CD4(+) T CELLS. FEMALE MRL+/+ MICE WERE EXPOSED TO VEHICLE CONTROL OR TCE IN THE DRINKING WATER FROM GESTATION UNTIL ~37 WEEKS OF AGE [POSTNATAL DAY (PND) 259]. IN A SUBSET OF MICE, TCE EXPOSURE WAS DISCONTINUED AT ~22 WEEKS OF AGE (PND 154). AT PND 259, RRBS ASSESSMENT REVEALED MORE GLOBAL METHYLATION CHANGES IN THE CONTINUOUS EXPOSURE GROUP VS. THE DISCONTINUOUS EXPOSURE GROUP. A MAJORITY OF THE DIFFERENTIALLY METHYLATED CPG REGIONS (DMRS) ACROSS PROMOTERS, ISLANDS, AND REGULATORY ELEMENTS WERE HYPERMETHYLATED (~90%). HOWEVER, CONTINUOUS DEVELOPMENTAL TCE EXPOSURE ALTERED THE METHYLATION OF 274 CPG SITES IN PROMOTERS AND CPG ISLANDS. IN CONTRAST, ONLY 4 CPG ISLAND REGIONS WERE DIFFERENTIALLY METHYLATED (HYPERMETHYLATED) IN THE DISCONTINUOUS GROUP. INTERESTINGLY, 2 OF THESE 4 SITES WERE ALSO HYPERMETHYLATED IN THE CONTINUOUS EXPOSURE GROUP, AND BOTH OF THESE ISLAND REGIONS ARE ASSOCIATED WITH LYSINE 27 ON HISTONE H3 (H3K27) INVOLVED IN POLYCOMB COMPLEX-DEPENDENT TRANSCRIPTIONAL REPRESSION VIA H3K27 TRI-METHYLATION. CPG SITES WERE OVERLAPPED WITH THE OPEN REGULATORY ANNOTATION DATABASE. UNLIKE THE DISCONTINUOUS GROUP, CONTINUOUS TCE TREATMENT RESULTED IN 129 DMRS INCLUDING 12 UNIQUE TRANSCRIPTION FACTORS AND REGULATORY ELEMENTS; 80% OF WHICH WERE ENRICHED FOR ONE OR MORE POLYCOMB GROUP (PCG) PROTEIN BINDING REGIONS (I.E., SUZ12, EZH2, JARID2, AND MTF2). PATHWAY ANALYSIS OF THE DMRS INDICATED THAT TCE PRIMARILY ALTERED THE METHYLATION OF GENES ASSOCIATED WITH REGULATION OF CELLULAR METABOLISM AND CELL SIGNALING. THE RESULTS DEMONSTRATED THAT CONTINUOUS DEVELOPMENTAL EXPOSURE TO TCE DIFFERENTIALLY METHYLATED BINDING SITES OF PCG PROTEINS IN EFFECTOR/MEMORY CD4(+) CELLS. THERE WERE MINIMAL YET POTENTIALLY BIOLOGICALLY SIGNIFICANT EFFECTS THAT OCCURRED WHEN EXPOSURE WAS DISCONTINUED. THESE RESULTS POINT TOWARD A NOVEL MECHANISM BY WHICH CHRONIC DEVELOPMENTAL TCE EXPOSURE MAY ALTER TERMINALLY DIFFERENTIATED CD4(+) T CELL FUNCTION IN ADULTHOOD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  6540  34 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  2473  20 EPIGENETIC TREATMENTS OF ADULT RATS PROMOTE RECOVERY FROM VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION. IN MAMMALS THE DEVELOPMENT OF THE VISUAL SYSTEM MAY BE ALTERED DURING A SENSITIVE PERIOD BY MODIFYING THE VISUAL INPUT TO ONE OR BOTH EYES. THESE PLASTIC PROCESSES ARE REDUCED AFTER THE END OF THE SENSITIVE PERIOD. IT HAS BEEN PROPOSED THAT REDUCED LEVELS OF PLASTICITY ARE AT THE BASIS OF THE LACK OF RECOVERY FROM EARLY VISUAL DEPRIVATION OBSERVED IN ADULT ANIMALS. A DEVELOPMENTAL DOWNREGULATION OF EXPERIENCE-DEPENDENT REGULATION OF HISTONE ACETYLATION HAS RECENTLY BEEN FOUND TO BE INVOLVED IN CLOSING THE SENSITIVE PERIOD. THEREFORE, WE TESTED WHETHER PHARMACOLOGICAL EPIGENETIC TREATMENTS INCREASING HISTONE ACETYLATION COULD BE USED TO REVERSE VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION INITIATED DURING THE SENSITIVE PERIOD. WE FOUND THAT CHRONIC INTRAPERITONEAL ADMINISTRATION OF VALPROIC ACID OR SODIUM BUTYRATE (TWO DIFFERENT HISTONE DEACETYLASES INHIBITORS) TO LONG-TERM MONOCULARLY DEPRIVED ADULT RATS COUPLED WITH REVERSE LID-SUTURING CAUSED A COMPLETE RECOVERY OF VISUAL ACUITY, TESTED ELECTROPHYSIOLOGICALLY AND BEHAVIORALLY. THUS, MANIPULATIONS OF THE EPIGENETIC MACHINERY CAN BE USED TO PROMOTE FUNCTIONAL RECOVERY FROM EARLY ALTERATIONS OF SENSORY INPUT IN THE ADULT CORTEX.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  3075  37 GENOME-WIDE EPIGENETIC STUDY OF CHRONIC RHINOSINUSITIS TISSUES REVEALS DYSREGULATED INFLAMMATORY, IMMUNOLOGIC AND REMODELING PATHWAYS. BACKGROUND: EPIGENETICS STUDIES MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS, AND ALTERNATIVE POLYADENYLATION THAT CAN MODIFY GENE ACTIVITY WITHOUT CHANGING THE UNDERLYING DNA NUCLEOTIDE BASE-PAIR STRUCTURE. BECAUSE THESE CHANGES ARE REVERSIBLE, THEY HAVE POTENTIAL IN DEVELOPING NOVEL THERAPEUTICS. CURRENTLY, SEVEN PHARMACEUTICAL AGENTS TARGETING EPIGENETIC CHANGES ARE FDA APPROVED AND COMMERCIALLY AVAILABLE FOR TREATMENT OF CERTAIN CANCERS. HOWEVER, STUDIES INVESTIGATING EPIGENETICS IN CHRONIC RHINOSINUSITIS (CRS) HAVE NOT BEEN UNDERTAKEN PREVIOUSLY IN THE UNITED STATES. OBJECTIVES: THE GOAL OF THIS STUDY WAS TO INVESTIGATE SINONASAL DNA METHYLATION PATTERNS IN CRS VERSUS CONTROLS, TO DISCERN ENVIRONMENTALLY-INDUCED EPIGENETIC CHANGES IMPACTING CRS SUBJECTS. METHODS AND RESULTS: ETHMOIDAL SAMPLES FROM CRS AND INFERIOR TURBINATE MUCOSAL TISSUE SAMPLES FROM CONTROLS WITHOUT CRS WERE STUDIED. DNA METHYLATION WAS STUDIED BY REDUCED REPRESENTATION BISULFITE SEQUENCING. RADMETH(R) BIOSTATISTICAL PACKAGE WAS USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) BETWEEN CRS AND CONTROLS. INGENUITY PATHWAY ANALYSIS OF DMRS WAS PERFORMED TO IDENTIFY TOP UPSTREAM REGULATORS AND CANONICAL PATHWAYS. NINETY-THREE SAMPLES FROM 64 CRS SUBJECTS (36 CRSWNP; 28 CRSSNP) AND 29 CONTROLS WERE STUDIED. CRS AND CONTROL SAMPLES DIFFERED IN 13 662 CPGS SITES AND 1381 DMRS. TOP UPSTREAM REGULATORS IDENTIFIED INCLUDED: 1. CRS VERSUS CONTROLS: TGFB1, TNF, TP53, DGCR8, AND BETA-ESTRADIOL. 2. CRSWNP VERSUS CONTROLS: TGFB1, CTNNB1, LIPOPOLYSACCHARIDE, ID2, AND TCF7L2. 3. CRSSNP VERSUS CONTROLS: MYOD1, ACETONE, ID2, ST8SIA4, AND LEPR. CONCLUSIONS: DIFFERENTIAL PATTERNS OF METHYLATION WERE IDENTIFIED BETWEEN CONTROLS AND CRS, CRSWNP, AND CRSSNP. EPIGENETIC, ENVIRONMENTALLY-INDUCED CHANGES RELATED TO NOVEL, INFLAMMATORY, IMMUNOLOGIC, AND REMODELING PATHWAYS APPEAR TO AFFECT EPITHELIAL INTEGRITY, CELL PROLIFERATION, HOMEOSTASIS, VASCULAR PERMEABILITY, AND OTHER YET UNCHARACTERIZED PATHWAYS AND GENES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14   118  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15  1061  38 CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS IS CHARACTERIZED BY AN UPREGULATION OF PERIPHERAL T-REGULATORY CELL POLARIZED TOWARDS T-BET AND TIGIT. BACKGROUND: NON-INFECTIOUS UVEITIS CAN CAUSE CHRONIC RELAPSING AND REMITTING OCULAR INFLAMMATION, WHICH MAY REQUIRE HIGH DOSE SYSTEMIC IMMUNOSUPPRESSION TO PREVENT SEVERE SIGHT LOSS. IT HAS BEEN CLASSICALLY DESCRIBED AS AN AUTOIMMUNE DISEASE, MEDIATED BY PRO-INFLAMMATORY TH1 AND TH17 T-CELL SUBSETS. STUDIES SUGGEST THAT NATURAL IMMUNOSUPPRESSIVE CD4(+)CD25(+)FOXP3(+) T-REGULATORY CELLS (TREGS) ARE INVOLVED IN RESOLUTION OF INFLAMMATION AND MAY BE INVOLVED IN THE MAINTENANCE OF CLINICAL REMISSION. OBJECTIVE: TO INVESTIGATE WHETHER THERE IS A PERIPHERAL BLOOD IMMUNOREGULATORY PHENOTYPE ASSOCIATED WITH CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS BY COMPARING PERIPHERAL BLOOD LEVELS OF TREG, TH1, AND TH17, AND ASSOCIATED DNA METHYLATION AND CYTOKINE LEVELS IN PATIENTS WITH ACTIVE UVEITIC DISEASE, CONTROL SUBJECTS AND PATIENTS (WITH PREVIOUSLY ACTIVE DISEASE) IN CLINICAL REMISSION INDUCED BY IMMUNOSUPPRESSIVE DRUGS. METHODS: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM PERIPHERAL BLOOD SAMPLES FROM PROSPECTIVELY RECRUITED SUBJECTS WERE ANALYZED BY FLOW CYTOMETRY FOR CD3, CD4, FOXP3, TIGIT, T-BET, AND RELATED ORPHAN RECEPTOR GAMMAT. EPIGENETIC DNA METHYLATION LEVELS OF FOXP3 TREG-SPECIFIC DEMETHYLATED REGION (TSDR), FOXP3 PROMOTER, TBX21, RORC2, AND TIGIT LOCI WERE DETERMINED IN CRYOPRESERVED PBMC USING A NEXT-GENERATION SEQUENCING APPROACH. RELATED CYTOKINES WERE MEASURED IN BLOOD SERA. FUNCTIONAL SUPPRESSIVE CAPACITY OF TREG WAS ASSESSED USING T-CELL PROLIFERATION ASSAYS. RESULTS: FIFTY PATIENTS WITH UVEITIS (INTERMEDIATE, POSTERIOR, AND PANUVEITIS) AND 10 CONTROL SUBJECTS WERE RECRUITED. THE FREQUENCY OF CD4(+)CD25(+)FOXP3(+) TREG, TIGIT(+) TREG, AND T-BET(+) TREG AND THE RATIO OF TREG TO TH1 WERE SIGNIFICANTLY HIGHER IN REMISSION PATIENTS COMPARED WITH PATIENTS WITH ACTIVE UVEITIC DISEASE; AND TIGIT(+) TREGS WERE A SIGNIFICANT PREDICTOR OF CLINICAL REMISSION. TREG FROM PATIENTS IN CLINICAL REMISSION DEMONSTRATED A HIGH LEVEL OF IN VITRO SUPPRESSIVE FUNCTION COMPARED WITH TREG FROM CONTROL SUBJECTS AND FROM PATIENTS WITH UNTREATED ACTIVE DISEASE. PBMC FROM PATIENTS IN CLINICAL REMISSION HAD SIGNIFICANTLY LOWER METHYLATION LEVELS AT THE FOXP3 TSDR, FOXP3 PROMOTER, AND TIGIT LOCI AND HIGHER LEVELS AT RORC LOCI THAN THOSE WITH ACTIVE DISEASE. CLINICAL REMISSION WAS ALSO ASSOCIATED WITH SIGNIFICANTLY HIGHER SERUM LEVELS OF TRANSFORMING GROWTH FACTOR BETA AND IL-10, WHICH POSITIVELY CORRELATED WITH TREG LEVELS, AND LOWER SERUM LEVELS OF IFNGAMMA, IL-17A, AND IL-22 COMPARED WITH PATIENTS WITH ACTIVE DISEASE. CONCLUSION: CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS HAS AN IMMUNOREGULATORY PHENOTYPE CHARACTERIZED BY UPREGULATION OF PERIPHERAL TREG, POLARIZED TOWARD T-BET AND TIGIT. THESE FINDINGS MAY ASSIST WITH INDIVIDUALIZED THERAPY OF UVEITIS, BY INFORMING WHETHER DRUG THERAPY HAS INDUCED PHENOTYPICALLY STABLE TREG ASSOCIATED WITH LONG-TERM CLINICAL REMISSION.	2018	

16  3456  32 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  3645  27 INCREASED PRESENCE AND DIFFERENTIAL MOLECULAR IMPRINTING OF TRANSIT AMPLIFYING CELLS IN PSORIASIS. PSORIASIS IS A VERY COMMON CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL THICKENING AND SCALING RESULTING FROM KERATINOCYTE HYPERPROLIFERATION AND IMPAIRED DIFFERENTIATION. PATHOMECHANISTIC STUDIES IN PSORIASIS ARE OFTEN LIMITED BY USING WHOLE SKIN TISSUE BIOPSIES, NEGLECTING THEIR STRATIFICATION AND CELLULAR DIVERSITY. THIS STUDY AIMED AT CHARACTERIZING EPIDERMAL ALTERATIONS IN PSORIASIS AT THE LEVEL OF KERATINOCYTE POPULATIONS. EPIDERMAL CELL POPULATIONS WERE PURIFIED FROM SKIN BIOPSIES OF PSORIASIS PATIENTS AND HEALTHY DONORS USING A NOVEL CELL TYPE-SPECIFIC APPROACH. MOLECULAR CHARACTERIZATION OF THE TRANSIT-AMPLIFYING CELLS (TAC), THE KEY PLAYERS OF EPIDERMAL RENEWAL, WAS PERFORMED USING IMMUNOCYTOFLUORESCENCE-TECHNIQUE AND INTEGRATED MULTISCALE-OMICS ANALYSES. ALREADY TAC FROM NON-LESIONAL PSORIATIC SKIN SHOWED ALTERED METHYLATION AND DIFFERENTIAL EXPRESSION IN 1.7% AND 1.0% OF ALL PROTEIN-CODING GENES, RESPECTIVELY. IN PSORIATIC LESIONS, TAC WERE STRONGLY EXPANDED SHOWING FURTHER INCREASED DIFFERENTIALLY METHYLATED (10-FOLD) AND EXPRESSED (22-FOLD) GENES NUMBERS. IMPORTANTLY, 17.2% OF DIFFERENTIALLY EXPRESSED GENES WERE ASSOCIATED WITH RESPECTIVE GENE METHYLATIONS. COMPARED WITH NON-LESIONAL TAC, PATHWAY ANALYSES REVEALED METABOLIC ALTERATIONS AS ONE FEATURE PREDOMINANTLY CHANGED IN TAC DERIVED FROM ACTIVE PSORIATIC LESIONS. OVERALL, OUR STUDY SHOWED STAGE-SPECIFIC MOLECULAR ALTERATIONS, ALLOWS NEW INSIGHTS INTO THE PATHOGENESIS, AND IMPLIES THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LESION DEVELOPMENT IN PSORIASIS. KEY MESSAGES: TRANSIT AMPLIFYING CELL (TAC) NUMBERS ARE HIGHLY INCREASED IN PSORIATIC LESIONS PSORIATIC TAC SHOW PROFOUND MOLECULAR ALTERATIONS & STAGE-SPECIFIC IDENTITY TAC FROM UNAFFECTED AREAS ALREADY SHOW FIRST SIGNS OF MOLECULAR ALTERATIONS LESIONAL TAC SHOW A PREFERENCE IN METABOLIC-RELATED ALTERATIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18  1570  47 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  6382  31 THE ROLE OF PARTICULATE MATTERS ON METHYLATION OF IFN-GAMMA AND IL-4 PROMOTER GENES IN PEDIATRIC ALLERGIC RHINITIS. ALLERGIC RHINITIS (AR) IS A CHRONIC INFLAMMATORY DISORDER DRIVEN BY T CELL ACTIVATION. HOW PARTICULATE MATTER CONTRIBUTES TO EPIGENETIC CHANGES THAT IN TURN INFLUENCE CYTOKINE GENE EXPRESSION IN CD4(+)T CELLS REMAINS UNCLEAR. IN THIS STUDY, 105 CHILDREN DIAGNOSED WITH AR AND 90 HEALTHY CONTROLS WERE RECRUITED TO EXPLORE THE POSSIBLE MECHANISM OF PARTICULATE MATTER (PM) ON THE EPIGENETIC REGULATION OF CD4(+)T IFN-GAMMA AND IL-4 PROMOTER GENES. DAILY AVERAGE PM(10) AND PM(2.5) WERE OBTAINED FROM FIVE STATE-CONTROLLED MONITORING STATIONS, AND ACTIVITY-BASED DYNAMIC EXPOSURE AND PERSONAL EXPOSURE DATA WERE COLLECTED. DNA METHYLATION PATTERNS OF IFN-GAMMA AND IL-4 PROMOTER REGIONS WERE ANALYZED USING BISULFITE SEQUENCING. MRNA LEVELS WERE DETECTED BY REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION. WE FOUND THAT THE METHYLATION RATE IN IFN-GAMMA WAS HIGHER IN AR CD4(+)T CELLS THAN IN THE CONTROLS. IFN-GAMMA MRNA EXPRESSION WAS SIGNIFICANTLY DECREASED IN CD4(+)T CELLS, AND NEGATIVELY CORRELATED WITH THE MEAN METHYLATION LEVEL OF IFN-GAMMA. HOWEVER, NO CORRELATION BETWEEN IL-4 METHYLATION AND IL-4 MRNA EXPRESSION WAS FOUND. AFTER ADJUSTING FOR AGE, GENDER, EXCLUSIVE BREASTFEEDING WITHIN 4 MONTHS AFTER BIRTH AND PARENTAL HISTORY OF ALLERGIC DISEASE, OUT DATA SHOWED THAT PM(2.5) EXPOSURE LEVEL WAS POSITIVELY CORRELATED WITH METHYLATION LEVEL IN IFN-GAMMA PROMOTER REGION AND DECREASED CYTOKINE EXPRESSION. WE CONCLUDE THAT THE EFFECT OF PM(2.5) ON PEDIATRIC AR MAY BE MEDIATED THROUGH EPIGENETIC MODIFICATION OF IFN-GAMMA PROMOTER REGION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20   812  41 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020