1 5125 135 POST-TRANSLATIONAL MODIFICATIONS OF TRYPANOSOMA CRUZI CANONICAL AND VARIANT HISTONES. CHAGAS DISEASE, CAUSED BY TRYPANOSOMA CRUZI, STILL AFFECTS MILLIONS OF PEOPLE AROUND THE WORLD. NO VACCINES NOR TREATMENT FOR CHRONIC CHAGAS DISEASE ARE AVAILABLE, AND CHEMOTHERAPY FOR THE ACUTE PHASE IS HINDERED BY LIMITED EFFICACY AND SEVERE SIDE EFFECTS. THE PROCESSES BY WHICH THE PARASITE ACQUIRES INFECTIVITY AND SURVIVES IN DIFFERENT HOSTS INVOLVE TIGHT REGULATION OF GENE EXPRESSION, MAINLY POST-TRANSCRIPTIONALLY. NEVERTHELESS, CHROMATIN STRUCTURE/ORGANIZATION OF TRYPANOSOMATIDS IS SIMILAR TO OTHER EUKARYOTES, INCLUDING HISTONE VARIANTS AND POST-TRANSLATIONAL MODIFICATIONS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ALSO PLAY AN IMPORTANT ROLE IN THE BIOLOGY/PATHOGENESIS OF THESE PARASITES, MAKING EPIGENETIC TARGETS SUITABLE CANDIDATES TO DRUG DISCOVERY. HERE, WE PRESENT THE FIRST COMPREHENSIVE MAP OF POST-TRANSLATIONAL MODIFICATIONS OF T. CRUZI CANONICAL AND VARIANT HISTONES AND SHOW THAT ITS HISTONE CODE CAN BE AS SOPHISTICATED AS THAT OF OTHER EUKARYOTES. A TOTAL OF 13 DISTINCT MODIFICATION TYPES WERE IDENTIFIED, INCLUDING RATHER NOVEL AND UNUSUAL ONES SUCH AS ALTERNATIVE LYSINE ACYLATIONS, SERINE/THREONINE ACETYLATION, AND N-TERMINAL METHYLATION. SOME HISTONE MARKS CORRELATE TO THOSE DESCRIBED FOR OTHER ORGANISMS, SUGGESTING THAT SIMILAR REGULATORY MECHANISMS MAY BE IN PLACE. OTHERS, HOWEVER, ARE UNIQUE TO T. CRUZI OR TO TRYPANOSOMATIDS AS A GROUP AND MIGHT REPRESENT GOOD CANDIDATES FOR THE DEVELOPMENT OF ANTIPARASITIC DRUGS. 2017 2 6749 40 WHOLE-GENOME CARDIAC DNA METHYLATION FINGERPRINT AND GENE EXPRESSION ANALYSIS PROVIDE NEW INSIGHTS IN THE PATHOGENESIS OF CHRONIC CHAGAS DISEASE CARDIOMYOPATHY. BACKGROUND: CHAGAS DISEASE, CAUSED BY THE PROTOZOAN TRYPANOSOMA CRUZI, IS ENDEMIC IN LATIN AMERICA AND AFFECTS 10 MILLION PEOPLE WORLDWIDE. APPROXIMATELY 12000 DEATHS ATTRIBUTABLE TO CHAGAS DISEASE OCCUR ANNUALLY DUE TO CHRONIC CHAGAS DISEASE CARDIOMYOPATHY (CCC), AN INFLAMMATORY CARDIOMYOPATHY PRESENTING WITH HEART FAILURE AND ARRYTHMIA; 30% OF INFECTED SUBJECTS DEVELOP CCC YEARS AFTER INFECTION. GENETIC MECHANISMS PLAY A ROLE IN DIFFERENTIAL PROGRESSION TO CCC, BUT LITTLE IS KNOWN ABOUT THE ROLE OF EPIGENETIC MODIFICATIONS IN PATHOLOGICAL GENE EXPRESSION PATTERNS IN CCC PATIENTS' MYOCARDIUM. DNA METHYLATION IS THE MOST COMMON MODIFICATION IN THE MAMMALIAN GENOME. METHODS: WE INVESTIGATED THE IMPACT OF GENOME-WIDE CARDIAC DNA METHYLATION ON GLOBAL GENE EXPRESSION IN MYOCARDIAL SAMPLES FROM END-STAGE CCC PATIENTS, COMPARED TO CONTROL SAMPLES FROM ORGAN DONORS. RESULTS: IN TOTAL, 4720 GENES WERE DIFFERENTIALLY METHYLATED BETWEEN CCC PATIENTS AND CONTROLS, OF WHICH 399 WERE ALSO DIFFERENTIALLY EXPRESSED. SEVERAL OF THEM WERE RELATED TO HEART FUNCTION OR TO THE IMMUNE RESPONSE AND HAD METHYLATION SITES IN THEIR PROMOTER REGION. REPORTER GENE AND IN SILICO TRANSCRIPTION FACTOR BINDING ANALYSES INDICATED PROMOTER METHYLATION MODIFIED EXPRESSION OF KEY GENES. AMONG THOSE, WE FOUND POTASSIUM CHANNEL GENES KCNA4 AND KCNIP4, INVOLVED IN ELECTRICAL CONDUCTION AND ARRYTHMIA, SMOC2, INVOLVED IN MATRIX REMODELING, AS WELL AS ENKEPHALIN AND RUNX3, POTENTIALLY INVOLVED IN THE INCREASED T-HELPER 1 CYTOKINE-MEDIATED INFLAMMATORY DAMAGE IN HEART. CONCLUSIONS: RESULTS SUPPORT THAT DNA METHYLATION PLAYS A ROLE IN THE REGULATION OF EXPRESSION OF PATHOGENICALLY RELEVANT GENES IN CCC MYOCARDIUM, AND IDENTIFY NOVEL POTENTIAL DISEASE PATHWAYS AND THERAPEUTIC TARGETS IN CCC. 2017 3 2375 37 EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR BINDING MOTIFS PROMOTES TH1 RESPONSE IN CHAGAS DISEASE CARDIOMYOPATHY. CHAGAS DISEASE, CAUSED BY THE PROTOZOAN TRYPANOSOMA CRUZI, IS AN ENDEMIC PARASITIC DISEASE OF LATIN AMERICA, AFFECTING 7 MILLION PEOPLE. ALTHOUGH MOST PATIENTS ARE ASYMPTOMATIC, 30% DEVELOP COMPLICATIONS, INCLUDING THE OFTEN-FATAL CHRONIC CHAGASIC CARDIOMYOPATHY (CCC). ALTHOUGH PREVIOUS STUDIES HAVE DEMONSTRATED SOME GENETIC DEREGULATIONS ASSOCIATED WITH CCCS, THE CAUSES OF THEIR DEREGULATIONS REMAIN POORLY DESCRIBED. BASED ON BULK RNA-SEQ AND WHOLE GENOME DNA METHYLATION DATA, WE INVESTIGATED THE GENETIC AND EPIGENETIC DEREGULATIONS PRESENT IN THE MODERATE AND SEVERE STAGES OF CCC. ANALYSIS OF HEART TISSUE GENE EXPRESSION PROFILE ALLOWED US TO IDENTIFY 1407 DIFFERENTIALLY EXPRESSED TRANSCRIPTS (DEGS) SPECIFIC FROM CCC PATIENTS. A TISSUE DNA METHYLATION ANALYSIS DONE ON THE SAME TISSUE HAS PERMITTED THE IDENTIFICATION OF 92 REGULATORY DIFFERENTIALLY METHYLATED REGIONS (DMR) LOCALIZED IN THE PROMOTER OF DEGS. AN IN-DEPTH STUDY OF THE TRANSCRIPTION FACTORS BINDING SITES (TFBS) IN THE DMRS CORROBORATED THE IMPORTANCE OF TFBS'S DNA METHYLATION FOR GENE EXPRESSION IN CCC MYOCARDIUM. TBX21, RUNX3 AND EBF1 ARE THE TRANSCRIPTION FACTORS WHOSE BINDING MOTIF APPEARS TO BE AFFECTED BY DNA METHYLATION IN THE LARGEST NUMBER OF GENES. BY COMBINING BOTH TRANSCRIPTOMIC AND METHYLOMIC ANALYSIS ON HEART TISSUE, AND METHYLOMIC ANALYSIS ON BLOOD, 4 BIOLOGICAL PROCESSES AFFECTED BY SEVERE CCC HAVE BEEN IDENTIFIED, INCLUDING IMMUNE RESPONSE, ION TRANSPORT, CARDIAC MUSCLE PROCESSES AND NERVOUS SYSTEM. AN ADDITIONAL STUDY ON BLOOD METHYLATION OF MODERATE CCC SAMPLES PUT FORWARD THE IMPORTANCE OF ION TRANSPORT AND NERVOUS SYSTEM IN THE DEVELOPMENT OF THE DISEASE. 2022 4 4573 20 MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT, A LONG NONCODING RNA, IS OVEREXPRESSED DURING DILATED CARDIOMYOPATHY DUE TO CHRONIC CHAGAS DISEASE. LONG NONCODING RNAS (LNCRNAS) MODULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. DYSREGULATION OF THE LNCRNA KNOWN AS MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT (MIAT) HAS BEEN ASSOCIATED WITH MYOCARDIAL INFARCTION. CHAGAS DISEASE CAUSES A SEVERE INFLAMMATORY DILATED CHRONIC CARDIOMYOPATHY (CCC). WE INVESTIGATED THE ROLE OF MIAT IN CCC. A WHOLE-TRANSCRIPTOME ANALYSIS OF HEART BIOPSY SPECIMENS AND FORMALIN-FIXED, PARAFFIN-EMBEDDED SAMPLES REVEALED THAT MIAT WAS OVEREXPRESSED IN PATIENTS WITH CCC, COMPARED WITH SUBJECTS WITH NONINFLAMMATORY DILATED CARDIOMYOPATHY AND CONTROLS. THESE RESULTS WERE CONFIRMED IN A MOUSE MODEL. RESULTS SUGGEST THAT MIAT IS A SPECIFIC BIOMARKER OF CCC. 2016 5 3501 36 IDENTIFICATION OF POTENTIAL BIOMARKERS FOR SYSTEMIC LUPUS ERYTHEMATOSUS BY INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA. INTRODUCTION: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS AND CHRONIC AUTOIMMUNE DISEASE. ABERRANT DNA METHYLATION OCCURS DURING VARIOUS PROCESSES OF SLE DEVELOPMENT REGULATING THE MRNA EXPRESSION OF INTERRELATED GENES. THIS STUDY AIMS TO SCREEN POTENTIAL DNA METHYLATION MARKERS FOR SLE. METHODS: GENE EXPRESSION AND METHYLATION DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN SLE PATIENTS AND HEALTHY CONTROLS WERE SCREENED USING THE LIMMA R PACKAGE, AND DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND REGIONS (DMRS) WERE IDENTIFIED USING DMPFINDER AND BUMPHUNTER (MINFI). ADDITIONALLY, THE DNA METHYLATION MARKERS TO DISTINGUISH SLE PATIENTS FROM HEALTHY CONTROLS WERE EXPLORED THROUGH RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES AND LOGISTIC REGRESSION ANALYSES. FINALLY, WE VALIDATED THE RESULTS OF THE BIOINFORMATIC ANALYSIS BY PYROSEQUENCING. RESULTS: IN TOTAL, 91 DEGS, 90,092 DMPS, 15 DMRS, AND 13 DMR-ASSOCIATED GENES WERE IDENTIFIED. THROUGH THE INTEGRATIVE ANALYSIS OF DEG- AND DMR-ASSOCIATED GENES, WE IDENTIFIED FIVE TYPE I INTERFERON (IFN)-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE. GO ENRICHMENT ANALYSIS SHOWED THAT THE FIVE SLE-ASSOCIATED EPIGENETIC-DRIVEN GENES WERE MAINLY ENRICHED IN THE TYPE I IFN SIGNALING PATHWAY INVOLVED IN IMMUNE RESPONSE AND DEFENSE RESPONSE TO VIRUS. MOREOVER, WE IDENTIFIED TWO SLE-SPECIFIC DNA METHYLATION MARKERS, THREE SLE WITHOUT LUPUS NEPHRITIS (SLE-LN(-))-SPECIFIC DNA METHYLATION MARKERS, AND TWO SLE WITH LUPUS NEPHRITIS (SLE-LN(+))-SPECIFIC DNA METHYLATION MARKERS BY STEPWISE LOGISTIC REGRESSION. CONCLUSIONS: OVERALL, OUR STUDY DEMONSTRATES POTENTIAL DNA METHYLATION MARKERS OF SLE, SLE-LN(-), AND SLE-LN(+), WHICH MAY HELP THE DIAGNOSIS, BOOST THE DEVELOPMENT OF NEW EPIGENETIC THERAPY, AND CONTRIBUTE TO INDIVIDUALIZED TREATMENT. KEY POINTS * THIS STUDY IDENTIFIED FIVE TYPE I IFN-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE, WHICH SUPPORT THE IMPORTANCE OF THE TYPE I IFN PATHWAY IN THE PATHOGENESIS OF SLE * WE IDENTIFIED NOVEL DNA METHYLATION BIOMARKERS IN SLE, SLE-LN-, AND SLE-LN+ BY A COMPREHENSIVE ANALYSIS OF BIOINFORMATICS METHODS AND EXECUTED EXPERIMENTAL VALIDATION, AND BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT THEY HAVE EXCELLENT POTENTIAL * THESE RESULTS MAY PROVIDE NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS OF SLE, AND IDENTIFY RELIABLE BIOMARKERS FOR SLE, SLE-LN-, AND SLE-LN+, WHICH MAY CONTRIBUTE TO DIAGNOSIS AND INDIVIDUALIZED TREATMENT. 2023 6 1571 34 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 7 3056 32 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 8 408 29 ANALYSIS OF GENE EXPRESSION AND METHYLATION DATASETS IDENTIFIED ADAMTS9, FKBP5, AND PFKBF3 AS BIOMARKERS FOR OSTEOARTHRITIS. BACKGROUND: OSTEOARTHRITIS (OA) IS A KIND OF CHRONIC OSTEOARTHROPATHY AND DEGENERATIVE JOINT DISEASE. EPIGENETIC REGULATION IN THE GENE EXPRESSION DYNAMICS HAS BECOME INCREASINGLY IMPORTANT IN OA. WE PERFORMED A COMBINED ANALYSIS OF TWO TYPES OF MICROARRAY DATASETS (GENE EXPRESSION AND DNA METHYLATION) TO IDENTIFY METHYLATION-BASED KEY BIOMARKERS TO PROVIDE A BETTER UNDERSTANDING OF MOLECULAR BIOLOGICAL MECHANISMS OF OA. METHODS: WE OBTAINED TWO EXPRESSION PROFILING DATASETS (GSE55235, GSE55457) AND ONE DNA METHYLATION PROFILING DATA SET (GSE63695) FROM THE GENE EXPRESSION OMNIBUS. FIRST, DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN PATIENTS WITH OA AND CONTROLS WERE IDENTIFIED USING THE LIMMA PACKAGE IN R(V3.4.4). THEN, FUNCTION ENRICHMENT ANALYSIS OF DEGS WAS PERFORMED USING A DAVID DATABASE. FOR DNA METHYLATION DATASETS, CHAMP METHYLATION ANALYSIS PACKAGE WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION GENES (DMGS). FINALLY, A COMPREHENSIVE ANALYSIS OF DEGS AND DMGS WAS CONDUCTED TO IDENTIFY GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION SIMULTANEOUSLY. RESULTS: WE IDENTIFIED 112 DEGS AND 2,896 DMGS IN PATIENTS WITH OA COMPARED WITH CONTROLS. FUNCTIONAL ANALYSIS OF DEGS OBTAINED THAT INFLAMMATORY RESPONSES, IMMUNE RESPONSES, AND POSITIVE REGULATION OF APOPTOSIS, TUMOR NECROSIS FACTOR (TNF) SIGNALING PATHWAY, AND OSTEOCLAST DIFFERENTIATION MAY BE INVOLVED IN THE PATHOGENESIS OF OA. CROSS-ANALYSIS REVEALED 26 GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION IN OA. AMONG THEM, ADAMTS9, FKBP5, AND PFKBF3 WERE IDENTIFIED AS VALUABLE METHYLATION-BASED BIOMARKERS FOR OA. CONCLUSION: IN SUMMARY, OUR STUDY IDENTIFIED DIFFERENT MOLECULAR FEATURES BETWEEN PATIENTS WITH OA AND CONTROLS. THIS MAY PROVIDE NEW CLUES FOR CLARIFYING THE PATHOGENETIC MECHANISMS OF OA. 2019 9 3070 34 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 10 1129 31 COMPREHENSIVE ANALYSIS OF MRNA-LNCRNA CO-EXPRESSION PROFILES IN MOUSE BRAIN DURING INFECTION WITH TOXOPLASMA GONDII. TOXOPLASMA GONDII IS AN OBLIGATE INTRACELLULAR PROTOZOAN PARASITE WHICH SERIOUSLY THREATENS THE HEALTH OF DOMESTIC ANIMALS AND HUMANS. LONG NON-CODING RNAS (LNCRNAS) ARE NON-PROTEIN-CODING TRANSCRIPTS GREATER THAN 200 NUCLEOTIDES, WHICH ARE WIDELY INVOLVED IN TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLES OF HOST LNCRNAS IN THE RESPONSE TO T. GONDII INFECTIONS. IN THIS STUDY, USING ILLUMINA SEQUENCING TECHNOLOGY, WE ANALYZED THE EXPRESSION PROFILES OF MRNAS AND LNCRNAS IN BALB/C MOUSE BRAIN FOLLOWING INFECTION BY T. GONDII PRU STRAIN (TYPE II GENOTYPE) CYSTS. THE IDENTIFIED DIFFERENTIALLY EXPRESSED (DE) RNAS WERE SUBJECTED TO BIOINFORMATICS ANALYSIS. A TOTAL OF 2,090 ANNOTATED LNCRNAS ALONG WITH 3,577 NOVEL LNCRNAS WERE IDENTIFIED. IN THE ACUTELY INFECTED MOUSE BRAIN, A TOTAL OF 330 MRNAS AND 19 LNCRNAS WERE DYS-REGULATED, WHEREAS 136 DE MRNAS AND 9 DE LNCRNAS WERE IDENTIFIED IN CHRONICALLY INFECTED MOUSE BRAIN. GO ANALYSIS REVEALED THAT THESE DE MRNAS IDENTIFIED AT ACUTE INFECTION STAGE WERE INVOLVED IN IMMUNE RESPONSE, WHEREAS DE MRNAS FOUND AT CHRONIC INFECTION STAGE WERE MOSTLY ENRICHED IN RESPONSE TO PROTOZOAN. KEGG ANALYSIS SHOWED THAT DE MRNAS WERE SIGNIFICANTLY ENRICHED IN DISEASE RELATED PATHWAYS. IN ADDITION, THE PUTATIVE MRNA-LNCRNA CO-EXPRESSION NETWORK WAS CONSTRUCTED, AND SEVERAL HUB REGULATORY RNAS WERE IDENTIFIED BASED ON THE TRANSCRIPTOME DATA. THIS STUDY FIRSTLY CHARACTERIZED THE CO-EXPRESSION PROFILE OF MRNAS AND LNCRNAS IN MOUSE BRAIN INFECTED WITH T. GONDII AND PROVIDED A FRAMEWORK FOR FURTHER STUDIES OF THE ROLES OF LNCRNAS IN HOST NEUROPATHOLOGY DURING TOXOPLASMOSIS PROGRESSION. 2023 11 336 28 ALTERATIONS IN DNA METHYLATION STATUS ASSOCIATED WITH GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) AFFECTS ABOUT 25% OF PERSIAN GULF VETERANS WITH A CLUSTER OF CHRONIC SYMPTOMS, INCLUDING IMMUNE DYSFUNCTION AND NEUROLOGICAL ISSUES. RECENT STUDIES IMPLICATE GENE EXPRESSION CHANGES IN IMMUNE FUNCTION TO BE ASSOCIATED WITH GWI. SINCE DNA METHYLATION CAN REGULATE SUCH CHANGES IN GENE EXPRESSION, AND DISRUPTION OF DNA METHYLATION PATTERN IS IMPLICATED IN VARIOUS IMMUNE AND NEUROLOGICAL DISEASES, WE AIMED TO STUDY THE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM GWI PATIENTS. GLOBAL DNA METHYLATION LEVELS WERE SIMILAR IN GWI PATIENTS AND CONTROLS. HOWEVER, THE GENOME-WIDE MICROARRAY TECHNOLOGY DETECTED 10,767 DIFFERENTIALLY METHYLATED CPG SITES ACROSS GENE REGULATORY ELEMENTS AND WITHIN CODING REGIONS. APPROXIMATELY 88% OF THEM WERE HYPERMETHYLATED IN GWI PATIENTS. THE SEPARATE ANALYSIS FOUND 776 DIFFERENTIALLY METHYLATED GENE PROMOTERS (DMP), WHICH WERE PREDOMINANTLY HYPERMETHYLATED. PYROSEQUENCING VALIDATION CONFIRMED MICROARRAY RESULTS. FUNCTIONAL ANALYSIS REVEALED THAT MAJORITY OF THE DMPS BELONGED TO GENES RESPONSIBLE FOR METABOLISM AND IMMUNE SYSTEM. THIS IS THE FIRST PILOT HUMAN STUDY CHARACTERIZING GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH GWI. IT SUGGESTS A SIGNIFICANT CONTRIBUTION OF EPIGENETIC DYSFUNCTION IN GWI. MOREOVER, IT SUPPORTS THE DYSREGULATION OF IMMUNE FUNCTION IN GWI. LASTLY, IT SUGGESTS STUDIES WITH THE LARGER COHORT TO VALIDATE OUR FINDINGS. 2019 12 4775 38 NUCLEIC ACID-SENSING AND INTERFERON-INDUCIBLE PATHWAYS SHOW DIFFERENTIAL METHYLATION IN MZ TWINS DISCORDANT FOR LUPUS AND OVEREXPRESSION IN INDEPENDENT LUPUS SAMPLES: IMPLICATIONS FOR PATHOGENIC MECHANISM AND DRUG TARGETING. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, AUTOIMMUNE INFLAMMATORY DISEASE WITH GENOMIC AND NON-GENOMIC CONTRIBUTIONS TO RISK. WE HYPOTHESIZE THAT EPIGENETIC FACTORS ARE A SIGNIFICANT CONTRIBUTOR TO SLE RISK AND MAY BE INFORMATIVE FOR IDENTIFYING PATHOGENIC MECHANISMS AND THERAPEUTIC TARGETS. TO TEST THIS HYPOTHESIS WHILE CONTROLLING FOR GENETIC BACKGROUND, WE PERFORMED AN EPIGENOME-WIDE ANALYSIS OF DNA METHYLATION IN GENOMIC DNA FROM WHOLE BLOOD IN THREE PAIRS OF FEMALE MONOZYGOTIC (MZ) TWINS OF EUROPEAN ANCESTRY, DISCORDANT FOR SLE. RESULTS WERE REPLICATED ON THE SAME ARRAY IN FOUR CELL TYPES FROM A SET OF FOUR DANISH FEMALE MZ TWIN PAIRS DISCORDANT FOR SLE. GENES IMPLICATED BY THE EPIGENETIC ANALYSES WERE THEN EVALUATED IN 10 INDEPENDENT SLE GENE EXPRESSION DATASETS FROM THE GENE EXPRESSION OMNIBUS (GEO). THERE WERE 59 DIFFERENTIALLY METHYLATED LOCI BETWEEN UNAFFECTED AND AFFECTED MZ TWINS IN WHOLE BLOOD, INCLUDING 11 NOVEL LOCI. ALL BUT TWO OF THESE LOCI WERE HYPOMETHYLATED IN THE SLE TWINS RELATIVE TO THE UNAFFECTED TWINS. THE GENES HARBORING THESE HYPOMETHYLATED LOCI EXHIBITED INCREASED EXPRESSION IN MULTIPLE INDEPENDENT DATASETS OF SLE PATIENTS. THIS PATTERN WAS LARGELY CONSISTENT REGARDLESS OF DISEASE ACTIVITY, CELL TYPE, OR RENAL TISSUE TYPE. THE GENES PROXIMAL TO CPGS EXHIBITING DIFFERENTIAL METHYLATION (DM) IN THE SLE-DISCORDANT MZ TWINS AND EXHIBITING DIFFERENTIAL EXPRESSION (DE) IN INDEPENDENT SLE GEO COHORTS (DM-DE GENES) CLUSTERED INTO TWO PATHWAYS: THE NUCLEIC ACID-SENSING PATHWAY AND THE TYPE I INTERFERON PATHWAY. THE DM-DE GENES WERE ALSO INFORMATICALLY QUERIED FOR POTENTIAL GENE-DRUG INTERACTIONS, YIELDING A LIST OF 41 DRUGS INCLUDING A KNOWN SLE THERAPY. THE DM-DE GENES DELINEATE TWO IMPORTANT BIOLOGIC PATHWAYS THAT ARE NOT ONLY REFLECTIVE OF THE HETEROGENEITY OF SLE BUT MAY ALSO CORRELATE WITH DISTINCT IFN RESPONSES THAT DEPEND ON THE SOURCE, TYPE, AND LOCATION OF NUCLEIC ACID MOLECULES AND THE ACTIVATED RECEPTORS IN INDIVIDUAL PATIENTS. CELL- AND TISSUE-SPECIFIC ANALYSES WILL BE CRITICAL TO THE UNDERSTANDING OF GENETIC FACTORS DYSREGULATING THE NUCLEIC ACID-SENSING AND IFN PATHWAYS AND WHETHER THESE FACTORS COULD BE APPROPRIATE TARGETS FOR THERAPEUTIC INTERVENTION. 2021 13 5236 34 PROFILING NON-CODING RNA LEVELS WITH CLINICAL CLASSIFIERS IN PEDIATRIC CROHN'S DISEASE. BACKGROUND: CROHN'S DISEASE (CD) IS A HERITABLE CHRONIC INFLAMMATORY DISORDER. NON-CODING RNAS (NCRNAS) PLAY AN IMPORTANT ROLE IN EPIGENETIC REGULATION BY AFFECTING GENE EXPRESSION, BUT CAN ALSO DIRECTLY AFFECT PROTEIN FUNCTION, THUS HAVING A SUBSTANTIAL IMPACT ON BIOLOGICAL PROCESSES. WE INVESTIGATED WHETHER NON-CODING RNAS (NCRNA) AT DIAGNOSIS ARE DYSREGULATED DURING CD AT DIFFERENT CD LOCATIONS AND FUTURE DISEASE BEHAVIORS TO DETERMINE IF NCRNA SIGNATURES CAN SERVE AS AN INDEX TO OUTCOMES. METHODS: USING SUBJECTS BELONGING TO THE RISK COHORT, WE ANALYZED NCRNA FROM THE ILEAL BIOPSIES OF 345 CD AND 71 NON-IBD CONTROLS, AND NCRNA FROM RECTAL BIOPSIES OF 329 CD AND 61 NON-IBD CONTROLS. SEQUENCE ALIGNMENT WAS DONE (STAR PACKAGE) USING HUMAN GENOME VERSION 38 (HG38) AS REFERENCE PANEL. THE DIFFERENTIAL EXPRESSION (DE) ANALYSIS WAS PERFORMED WITH EDGER PACKAGE AND DE NCRNAS WERE IDENTIFIED WITH A THRESHOLD OF FOLD CHANGE (FC) > 2 AND FDR < 0.05 AFTER MULTIPLE TEST CORRECTIONS. RESULTS: IN TOTAL, WE IDENTIFIED 130 CD SPECIFIC DE NCRNAS (89 IN ILEUM AND 41 IN RECTUM) WHEN COMPARED TO NON-IBD CONTROLS. SIMILARLY, 35 DE NCRNAS WERE IDENTIFIED BETWEEN B1 AND B2 IN ILEUM, WHEREAS NO DIFFERENCES AMONG CD DISEASE BEHAVIORS WERE NOTICED IN RECTUM. WE ALSO FOUND INFLAMMATION SPECIFIC NCRNAS BETWEEN INFLAMED AND NON-INFLAMED GROUPS IN ILEAL BIOPSIES. OVERALL, WE OBSERVED THAT EXPRESSION OF MIR1244-2, MIR1244-3, MIR1244-4, AND RN7SL2 WERE INCREASED DURING CD, REGARDLESS OF DISEASE BEHAVIOR, LOCATION, OR INFLAMMATORY STATUS. LASTLY, WE TESTED NCRNA EXPRESSION AT BASELINE AS POTENTIAL TOOL TO PREDICT THE DISEASE STATUS, DISEASE BEHAVIORS AND DISEASE INFLAMMATION AT 3-YEAR FOLLOW UP. CONCLUSIONS: WE HAVE IDENTIFIED NCRNAS THAT ARE SPECIFIC TO DISEASE LOCATION, DISEASE BEHAVIOR, AND DISEASE INFLAMMATION IN CD. BOTH ILEAL AND RECTAL SPECIFIC NCRNA ARE CHANGING OVER THE COURSE OF CD, SPECIFICALLY DURING THE DISEASE PROGRESSION IN THE INTESTINAL MUCOSA. COLLECTIVELY, OUR FINDINGS SHOW CHANGES IN NCRNA DURING CD AND MAY HAVE A CLINICAL UTILITY IN EARLY IDENTIFICATION AND CHARACTERIZATION OF DISEASE PROGRESSION. 2021 14 972 26 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE. 2022 15 3046 26 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR. 2020 16 118 26 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 17 3918 28 LINKING ABERRANT CHROMATIN FEATURES IN CHRONIC LYMPHOCYTIC LEUKEMIA TO TRANSCRIPTION FACTOR NETWORKS. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A DIVERSE SET OF GENETIC MUTATIONS IS EMBEDDED IN A DEREGULATED EPIGENETIC LANDSCAPE THAT DRIVES CANCEROGENESIS. TO ELUCIDATE THE ROLE OF ABERRANT CHROMATIN FEATURES, WE MAPPED DNA METHYLATION, SEVEN HISTONE MODIFICATIONS, NUCLEOSOME POSITIONS, CHROMATIN ACCESSIBILITY, BINDING OF EBF1 AND CTCF, AS WELL AS THE TRANSCRIPTOME OF B CELLS FROM CLL PATIENTS AND HEALTHY DONORS. A GLOBALLY INCREASED HISTONE DEACETYLASE ACTIVITY WAS DETECTED AND HALF OF THE GENOME COMPRISED TRANSCRIPTIONALLY DOWNREGULATED PARTIALLY DNA METHYLATED DOMAINS DEMARCATED BY CTCF CLL SAMPLES DISPLAYED A H3K4ME3 REDISTRIBUTION AND NUCLEOSOME GAIN AT PROMOTERS AS WELL AS CHANGES OF ENHANCER ACTIVITY AND ENHANCER LINKAGE TO TARGET GENES. A DNA BINDING MOTIF ANALYSIS IDENTIFIED TRANSCRIPTION FACTORS THAT GAINED OR LOST BINDING IN CLL AT SITES WITH ABERRANT CHROMATIN FEATURES. THESE FINDINGS WERE INTEGRATED INTO A GENE REGULATORY ENHANCER CONTAINING NETWORK ENRICHED FOR B-CELL RECEPTOR SIGNALING PATHWAY COMPONENTS. OUR STUDY PREDICTS NOVEL MOLECULAR LINKS TO TARGETS OF CLL THERAPIES AND PROVIDES A VALUABLE RESOURCE FOR FURTHER STUDIES ON THE EPIGENETIC CONTRIBUTION TO THE DISEASE. 2019 18 812 26 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 19 3068 24 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 20 4059 32 MASSIVE ANALYSIS OF CDNA ENDS (MACE) AND MIRNA EXPRESSION PROFILING IDENTIFIES PROATHEROGENIC PATHWAYS IN CHRONIC KIDNEY DISEASE. EPIGENETIC DYSREGULATION CONTRIBUTES TO THE HIGH CARDIOVASCULAR DISEASE BURDEN IN CHRONIC KIDNEY DISEASE (CKD) PATIENTS. ALTHOUGH MICRORNAS (MIRNAS) ARE CENTRAL EPIGENETIC REGULATORS, WHICH SUBSTANTIALLY AFFECT THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE (CVD), NO DATA ON MIRNA DYSREGULATION IN CKD-ASSOCIATED CVD ARE AVAILABLE UNTIL NOW. WE NOW PERFORMED HIGH-THROUGHPUT MIRNA SEQUENCING OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM TEN CLINICALLY STABLE HEMODIALYSIS (HD) PATIENTS AND TEN HEALTHY CONTROLS, WHICH ALLOWED US TO IDENTIFY 182 DIFFERENTIALLY EXPRESSED MIRNAS (E.G., MIR-21, MIR-26B, MIR-146B, MIR-155). TO TEST BIOLOGICAL RELEVANCE, WE AIMED TO CONNECT MIRNA DYSREGULATION TO DIFFERENTIAL GENE EXPRESSION. GENOME-WIDE GENE EXPRESSION PROFILING BY MACE (MASSIVE ANALYSIS OF CDNA ENDS) IDENTIFIED 80 GENES TO BE DIFFERENTIALLY EXPRESSED BETWEEN HD PATIENTS AND CONTROLS, WHICH COULD BE LINKED TO CARDIOVASCULAR DISEASE (E.G., KLF6, DUSP6, KLF4), TO INFECTION / IMMUNE DISEASE (E.G., ZFP36, SOCS3, JUND), AND TO DISTINCT PROATHEROGENIC PATHWAYS SUCH AS THE TOLL-LIKE RECEPTOR SIGNALING PATHWAY (E.G., IL1B, MYD88, TICAM2), THE MAPK SIGNALING PATHWAY (E.G., DUSP1, FOS, HSPA1A), AND THE CHEMOKINE SIGNALING PATHWAY (E.G., RHOA, PAK1, CXCL5). FORMAL INTERACTION NETWORK ANALYSIS PROVED BIOLOGICAL RELEVANCE OF MIRNA DYSREGULATION, AS 68 DIFFERENTIALLY EXPRESSED MIRNAS COULD BE CONNECTED TO 47 RECIPROCALLY EXPRESSED TARGET GENES. OUR STUDY IS THE FIRST COMPREHENSIVE MIRNA ANALYSIS IN CKD THAT LINKS DYSREGULATED MIRNA EXPRESSION WITH DIFFERENTIAL EXPRESSION OF GENES CONNECTED TO INFLAMMATION AND CVD. AFTER RECENT ANIMAL DATA SUGGESTED THAT TARGETING MIRNAS IS BENEFICIAL IN EXPERIMENTAL CVD, OUR DATA MAY NOW SPUR FURTHER RESEARCH IN THE FIELD OF CKD-ASSOCIATED HUMAN CVD. 2014