1 2050 168 EPIGENETIC COMPONENTS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME UNCOVER POTENTIAL TRANSPOSABLE ELEMENT ACTIVATION. PURPOSE: STUDIES TO DETERMINE EPIGENETIC CHANGES ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) REMAIN SCARCE; HOWEVER, CURRENT EVIDENCE CLEARLY SHOWS THAT METHYLATION PATTERNS OF GENOMIC DNA AND NONCODING RNA PROFILES OF IMMUNE CELLS DIFFER BETWEEN PATIENTS AND HEALTHY SUBJECTS, SUGGESTING AN ACTIVE ROLE OF THESE EPIGENETIC MECHANISMS IN THE DISEASE. THE PRESENT STUDY COMPARES AND CONTRASTS THE AVAILABLE ME/CFS EPIGENETIC DATA IN AN EFFORT TO EVIDENCE OVERLAPPING PATHWAYS CAPABLE OF EXPLAINING AT LEAST SOME OF THE DYSFUNCTIONAL IMMUNE PARAMETERS LINKED TO THIS DISEASE. METHODS: A SYSTEMATIC SEARCH OF THE LITERATURE EVALUATING THE ME/CFS EPIGENOME LANDSCAPE WAS PERFORMED FOLLOWING THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES CRITERIA. DIFFERENTIAL DNA METHYLATION AND NONCODING RNA DIFFERENTIAL EXPRESSION PATTERNS ASSOCIATED WITH ME/CFS WERE USED TO SCREEN FOR THE PRESENCE OF TRANSPOSABLE ELEMENTS USING THE DFAM BROWSER, A SEARCH PROGRAM NURTURED WITH THE REPBASE REPETITIVE SEQUENCE DATABASE AND THE REPEATMASKER ANNOTATION TOOL. FINDINGS: UNEXPECTEDLY, PARTICULAR ASSOCIATIONS OF TRANSPOSABLE ELEMENTS AND ME/CFS EPIGENETIC HALLMARKS WERE UNCOVERED. A MODEL FOR THE DISEASE EMERGED INVOLVING TRANSCRIPTIONAL INDUCTION OF ENDOGENOUS DORMANT TRANSPOSONS AND STRUCTURED CELLULAR RNA INTERACTIONS, TRIGGERING THE ACTIVATION OF THE INNATE IMMUNE SYSTEM WITHOUT A CONCOMITANT ACTIVE INFECTION. IMPLICATIONS: REPETITIVE SEQUENCE FILTERS (IE, REPEATMASKER) SHOULD BE AVOIDED WHEN ANALYZING TRANSCRIPTOMIC DATA TO ASSESS THE POTENTIAL PARTICIPATION OF REPETITIVE SEQUENCES ("JUNK REPETITIVE DNA"), REPRESENTING >45% OF THE HUMAN GENOME, IN THE ONSET AND EVOLUTION OF ME/CFS. IN ADDITION, TRANSPOSABLE ELEMENT SCREENINGS AIMED AT DESIGNING COST-EFFECTIVE, FOCUSED EMPIRICAL ASSAYS THAT CAN CONFIRM OR DISPROVE THE SUSPECTED INVOLVEMENT OF TRANSPOSON TRANSCRIPTIONAL ACTIVATION IN THIS DISEASE, FOLLOWING THE PILOT STRATEGY PRESENTED HERE, WILL REQUIRE DATABASES GATHERING LARGE ME/CFS EPIGENETIC DATASETS. 2019 2 3041 35 GENOME-EPIGENOME INTERACTIONS ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE OF UNKNOWN ETIOLOGY. MULTIPLE STUDIES POINT TO DISRUPTIONS IN IMMUNE FUNCTIONING IN ME/CFS PATIENTS AS WELL AS SPECIFIC GENETIC POLYMORPHISMS AND ALTERATIONS OF THE DNA METHYLOME IN LYMPHOCYTES. HOWEVER, POTENTIAL INTERACTIONS BETWEEN DNA METHYLATION AND GENETIC BACKGROUND IN RELATION TO ME/CFS HAVE NOT BEEN EXAMINED. IN THIS STUDY WE EXPLORED THIS ASSOCIATION BY CHARACTERIZING THE EPIGENETIC (~480 THOUSAND CPG LOCI) AND GENETIC (~4.3 MILLION SNPS) VARIATION BETWEEN COHORTS OF ME/CFS PATIENTS AND HEALTHY CONTROLS. WE FOUND SIGNIFICANT ASSOCIATIONS OF DNA METHYLATION STATES IN T-LYMPHOCYTES AT SEVERAL CPG LOCI AND REGIONS WITH ME/CFS PHENOTYPE. THESE METHYLATION ANOMALIES ARE IN CLOSE PROXIMITY TO GENES INVOLVED WITH IMMUNE FUNCTION AND CELLULAR METABOLISM. FINALLY, WE FOUND SIGNIFICANT CORRELATIONS OF GENOTYPES WITH METHYLATION MODIFICATIONS ASSOCIATED WITH ME/CFS. THE FINDINGS FROM THIS STUDY HIGHLIGHT THE ROLE OF EPIGENETIC AND GENETIC INTERACTIONS IN COMPLEX DISEASES, AND SUGGEST SEVERAL GENETIC AND EPIGENETIC ELEMENTS POTENTIALLY INVOLVED IN THE MECHANISMS OF DISEASE IN ME/CFS. 2018 3 1699 34 DYNAMIC EPIGENETIC CHANGES DURING A RELAPSE AND RECOVERY CYCLE IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE WITH VARIABLE SEVERITY. PATIENTS EXPERIENCE FREQUENT RELAPSES WHERE SYMPTOMS INCREASE IN SEVERITY, LEAVING THEM WITH A MARKED REDUCTION IN QUALITY OF LIFE. PREVIOUS WORK HAS INVESTIGATED MOLECULAR DIFFERENCES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS, BUT NOT THE DYNAMIC CHANGES SPECIFIC TO EACH INDIVIDUAL PATIENT. WE APPLIED PRECISION MEDICINE HERE TO MAP GENOMIC CHANGES IN TWO SELECTED ME/CFS PATIENTS THROUGH A PERIOD THAT CONTAINED A RELAPSE RECOVERY CYCLE. DNA WAS ISOLATED FROM TWO PATIENTS AND A HEALTHY AGE/GENDER MATCHED CONTROL AT REGULAR INTERVALS AND CAPTURED THE PATIENT RELAPSE IN EACH CASE. REDUCED REPRESENTATION DNA METHYLATION SEQUENCING PROFILES WERE OBTAINED SPANNING THE RELAPSE RECOVERY CYCLE. BOTH PATIENTS SHOWED A SIGNIFICANTLY LARGER METHYLOME VARIABILITY (10-20-FOLD) THROUGH THE PERIOD OF SAMPLING COMPARED WITH THE CONTROL. DURING THE RELAPSE, CHANGES IN THE METHYLOME PROFILES OF THE TWO PATIENTS WERE DETECTED IN REGULATORY-ACTIVE REGIONS OF THE GENOME THAT WERE ASSOCIATED, RESPECTIVELY, WITH 157 AND 127 DOWNSTREAM GENES, INDICATING DISTURBED METABOLIC, IMMUNE AND INFLAMMATORY FUNCTIONS. SEVERE HEALTH RELAPSES IN THE ME/CFS PATIENTS RESULTED IN FUNCTIONALLY IMPORTANT CHANGES IN THEIR DNA METHYLOMES THAT, WHILE DIFFERING BETWEEN THE TWO PATIENTS, LED TO VERY SIMILAR COMPROMISED PHYSIOLOGY. DNA METHYLATION AS A SIGNATURE OF DISEASE VARIABILITY IN ONGOING ME/CFS MAY HAVE PRACTICAL APPLICATIONS FOR STRATEGIES TO DECREASE RELAPSE FREQUENCY. 2022 4 2207 42 EPIGENETIC MODIFICATIONS AND GLUCOCORTICOID SENSITIVITY IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS). BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A DEBILITATING IDIOPATHIC DISEASE CHARACTERIZED BY UNEXPLAINED FATIGUE THAT FAILS TO RESOLVE WITH SUFFICIENT REST. DIAGNOSIS IS BASED ON A LIST OF SYMPTOMS AND EXCLUSION OF OTHER FATIGUE-RELATED HEALTH CONDITIONS. DESPITE A HETEROGENEOUS PATIENT POPULATION, IMMUNE AND HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION DIFFERENCES, SUCH AS ENHANCED NEGATIVE FEEDBACK TO GLUCOCORTICOIDS, ARE RECURRING FINDINGS IN ME/CFS STUDIES. EPIGENETIC MODIFICATIONS, SUCH AS CPG METHYLATION, ARE KNOWN TO REGULATE LONG-TERM PHENOTYPIC DIFFERENCES AND PREVIOUS WORK BY OUR GROUP FOUND DNA METHYLOME DIFFERENCES IN ME/CFS, HOWEVER THE RELATIONSHIP BETWEEN DNA METHYLOME MODIFICATIONS, CLINICAL AND FUNCTIONAL CHARACTERISTICS ASSOCIATED WITH ME/CFS HAS NOT BEEN EXAMINED. METHODS: WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF A LARGER COHORT OF FEMALE ME/CFS PATIENTS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. IN PARALLEL TO THE DNA METHYLOME ANALYSIS, WE INVESTIGATED IN VITRO GLUCOCORTICOID SENSITIVITY DIFFERENCES BY STIMULATING PBMCS WITH PHYTOHAEMAGGLUTININ AND SUPPRESSED GROWTH WITH DEXAMETHASONE. WE EXPLORED DNA METHYLATION DIFFERENCES USING BISULFITE PYROSEQUENCING AND STATISTICAL PERMUTATION. LINEAR REGRESSION WAS IMPLEMENTED TO DISCOVER EPIGENOMIC REGIONS ASSOCIATED WITH SELF-REPORTED QUALITY OF LIFE AND NETWORK ANALYSIS OF GENE ONTOLOGY TERMS TO BIOLOGICALLY CONTEXTUALIZE RESULTS. RESULTS: WE DETECTED 12,608 DIFFERENTIALLY METHYLATED SITES BETWEEN ME/CFS PATIENTS AND HEALTHY CONTROLS PREDOMINANTLY LOCALIZED TO CELLULAR METABOLISM GENES, SOME OF WHICH WERE ALSO RELATED TO SELF-REPORTED QUALITY OF LIFE HEALTH SCORES. AMONG ME/CFS PATIENTS, GLUCOCORTICOID SENSITIVITY WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION AT 13 LOCI. CONCLUSIONS: OUR RESULTS INDICATE DNA METHYLATION MODIFICATIONS IN CELLULAR METABOLISM IN ME/CFS DESPITE A HETEROGENEOUS PATIENT POPULATION, IMPLICATING THESE PROCESSES IN IMMUNE AND HPA AXIS DYSFUNCTION IN ME/CFS. MODIFICATIONS TO EPIGENETIC LOCI ASSOCIATED WITH DIFFERENCES IN GLUCOCORTICOID SENSITIVITY MAY BE IMPORTANT AS BIOMARKERS FOR FUTURE CLINICAL TESTING. OVERALL, THESE FINDINGS ALIGN WITH RECENT ME/CFS WORK THAT POINT TOWARDS IMPAIRMENT IN CELLULAR ENERGY PRODUCTION IN THIS PATIENT POPULATION. 2017 5 6159 37 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 6 1556 45 DNA METHYLATION MODIFICATIONS ASSOCIATED WITH CHRONIC FATIGUE SYNDROME. CHRONIC FATIGUE SYNDROME (CFS), ALSO KNOWN AS MYALGIC ENCEPHALOMYELITIS, IS A COMPLEX MULTIFACTORIAL DISEASE THAT IS CHARACTERIZED BY THE PERSISTENT PRESENCE OF FATIGUE AND OTHER PARTICULAR SYMPTOMS FOR A MINIMUM OF 6 MONTHS. SYMPTOMS FAIL TO DISSIPATE AFTER SUFFICIENT REST AND HAVE MAJOR EFFECTS ON THE DAILY FUNCTIONING OF CFS SUFFERERS. CFS IS A MULTI-SYSTEM DISEASE WITH A HETEROGENEOUS PATIENT POPULATION SHOWING A WIDE VARIETY OF FUNCTIONAL DISABILITIES AND ITS BIOLOGICAL BASIS REMAINS POORLY UNDERSTOOD. STABLE ALTERATIONS IN GENE FUNCTION IN THE IMMUNE SYSTEM HAVE BEEN REPORTED IN SEVERAL STUDIES OF CFS. EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN LONG-TERM EFFECTS ON GENE FUNCTION, HOWEVER, TO OUR KNOWLEDGE, GENOME-WIDE EPIGENETIC MODIFICATIONS ASSOCIATED WITH CFS HAVE NOT BEEN EXPLORED. WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS ISOLATED FROM CFS PATIENTS AND HEALTHY CONTROLS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY, CONTROLLING FOR INVARIANT PROBES AND PROBES OVERLAPPING POLYMORPHIC SEQUENCES. GENE ONTOLOGY (GO) AND NETWORK ANALYSIS OF DIFFERENTIALLY METHYLATED GENES WAS PERFORMED TO DETERMINE POTENTIAL BIOLOGICAL PATHWAYS SHOWING CHANGES IN DNA METHYLATION IN CFS. WE FOUND AN INCREASED ABUNDANCE OF DIFFERENTIALLY METHYLATED GENES RELATED TO THE IMMUNE RESPONSE, CELLULAR METABOLISM, AND KINASE ACTIVITY. GENES ASSOCIATED WITH IMMUNE CELL REGULATION, THE LARGEST COORDINATED ENRICHMENT OF DIFFERENTIALLY METHYLATED PATHWAYS, SHOWED HYPOMETHYLATION WITHIN PROMOTERS AND OTHER GENE REGULATORY ELEMENTS IN CFS. THESE DATA ARE CONSISTENT WITH EVIDENCE OF MULTISYSTEM DYSREGULATION IN CFS AND IMPLICATE THE INVOLVEMENT OF DNA MODIFICATIONS IN CFS PATHOLOGY. 2014 7 6405 46 THE SARS-COV-2 RECEPTOR ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME: ANALYSIS OF HIGH-THROUGHPUT EPIGENETIC AND GENE EXPRESSION STUDIES. PATIENTS AFFECTED BY MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) SHOW SPECIFIC EPIGENETIC AND GENE EXPRESSION SIGNATURES OF THE DISEASE. HOWEVER, IT IS UNKNOWN WHETHER THESE SIGNATURES INCLUDE ABNORMAL LEVELS OF THE HUMAN ANGIOTENSIN-CONVERTING ENZYMES, ACE AND ACE2, THE LATTER BEING THE MAIN RECEPTOR DESCRIBED FOR THE HOST-CELL INVASION BY SARS-COV-2. TO INVESTIGATE THAT, WE FIRST RE-ANALYZED AVAILABLE CASE-CONTROL EPIGENOME-WIDE ASSOCIATION STUDIES BASED ON DNA METHYLATION DATA, AND CASE-CONTROL GENE EXPRESSION STUDIES BASED ON MICROARRAY DATA. FROM THESE PUBLISHED STUDIES, WE FOUND AN ASSOCIATION BETWEEN ME/CFS AND 4 POTENTIALLY HYPOMETHYLATED PROBES LOCATED IN THE ACE LOCUS. WE ALSO FOUND ANOTHER DISEASE ASSOCIATION WITH ONE HYPOMETHYLATED PROBE LOCATED IN THE TRANSCRIPTION START SITE OF ACE2. THE SAME DISEASE ASSOCIATIONS WERE OBTAINED FOR WOMEN BUT NOT FOR MEN AFTER PERFORMING SEX-SPECIFIC ANALYSES. IN CONTRAST, A META-ANALYSIS OF GENE EXPRESSION LEVELS COULD NOT PROVIDE EVIDENCE FOR A DIFFERENTIALLY EXPRESSION OF ACE AND ACE2 IN AFFECTED PATIENTS WHEN COMPARED TO HEALTHY CONTROLS. IN LINE WITH THIS NEGATIVE FINDING, THE ANALYSIS OF A NEW DATA SET ON THE GENE EXPRESSION OF ACE AND ACE2 IN PERIPHERAL BLOOD MONONUCLEAR CELLS DID NOT FIND ANY DIFFERENCES BETWEEN A FEMALE COHORT OF 37 PATIENTS AND 34 AGE-MATCHED HEALTHY CONTROLS. FUTURE STUDIES SHOULD BE CONDUCTED TO EXTEND THIS INVESTIGATION TO OTHER POTENTIAL RECEPTORS USED BY SARS-COV-2. THESE STUDIES WILL HELP RESEARCHERS AND CLINICIANS TO IMPROVE THE UNDERSTANDING OF THE HEALTH RISK IMPOSED BY THIS VIRUS WHEN INFECTING PATIENTS AFFECTED BY THIS DEBILITATING DISEASE. 2021 8 2920 41 GENE-SET ANALYSIS IS SEVERELY BIASED WHEN APPLIED TO GENOME-WIDE METHYLATION DATA. MOTIVATION: DNA METHYLATION IS AN EPIGENETIC MARK THAT CAN STABLY REPRESS GENE EXPRESSION. BECAUSE OF ITS BIOLOGICAL AND CLINICAL SIGNIFICANCE, SEVERAL METHODS HAVE BEEN DEVELOPED TO COMPARE GENOME-WIDE PATTERNS OF METHYLATION BETWEEN GROUPS OF SAMPLES. THE APPLICATION OF GENE SET ANALYSIS TO IDENTIFY RELEVANT GROUPS OF GENES THAT ARE ENRICHED FOR DIFFERENTIALLY METHYLATED GENES IS OFTEN A MAJOR COMPONENT OF THE ANALYSIS OF THESE DATA. THIS CAN BE USED, FOR EXAMPLE, TO IDENTIFY PROCESSES OR PATHWAYS THAT ARE PERTURBED IN DISEASE DEVELOPMENT. WE SHOW THAT GENE-SET ANALYSIS, AS IT IS TYPICALLY APPLIED TO GENOME-WIDE METHYLATION ASSAYS, IS SEVERELY BIASED AS A RESULT OF DIFFERENCES IN THE NUMBERS OF CPG SITES ASSOCIATED WITH DIFFERENT CLASSES OF GENES AND GENE PROMOTERS. RESULTS: WE DEMONSTRATE THIS BIAS USING PUBLISHED DATA FROM A STUDY OF DIFFERENTIAL CPG ISLAND METHYLATION IN LUNG CANCER AND A DATASET WE GENERATED TO STUDY METHYLATION CHANGES IN PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS. WE SHOW THAT SEVERAL OF THE GENE SETS THAT SEEM ENRICHED WOULD ALSO BE IDENTIFIED WITH RANDOMIZED DATA. WE SUGGEST TWO EXISTING APPROACHES THAT CAN BE ADAPTED TO CORRECT THE BIAS. ACCOUNTING FOR THE BIAS IN THE LUNG CANCER AND ULCERATIVE COLITIS DATASETS PROVIDES NOVEL BIOLOGICAL INSIGHTS INTO THE ROLE OF METHYLATION IN CANCER DEVELOPMENT AND CHRONIC INFLAMMATION, RESPECTIVELY. OUR RESULTS HAVE SIGNIFICANT IMPLICATIONS FOR MANY PREVIOUS GENOME-WIDE METHYLATION STUDIES THAT HAVE DRAWN CONCLUSIONS ON THE BASIS OF SUCH STRONGLY BIASED ANALYSIS. CONTACT: CATHAL.SEOIGHE@NUIGALWAY.IE SUPPLEMENTARY INFORMATION: SUPPLEMENTARY DATA ARE AVAILABLE AT BIOINFORMATICS ONLINE. 2013 9 6013 40 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 10 3496 49 IDENTIFICATION OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME-ASSOCIATED DNA METHYLATION PATTERNS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX CONDITION INVOLVING MULTIPLE ORGAN SYSTEMS AND CHARACTERIZED BY PERSISTENT/RELAPSING DEBILITATING FATIGUE, IMMUNE DYSFUNCTION, NEUROLOGICAL PROBLEMS, AND OTHER SYMPTOMS NOT CURABLE FOR AT LEAST 6 MONTHS. DISRUPTION OF DNA METHYLATION PATTERNS HAS BEEN TIED TO VARIOUS IMMUNE AND NEUROLOGICAL DISEASES; HOWEVER, ITS STATUS IN ME/CFS REMAINS UNCERTAIN. OUR STUDY AIMED AT IDENTIFYING CHANGES IN THE DNA METHYLATION PATTERNS THAT ASSOCIATE WITH ME/CFS. METHODS: WE EXTRACTED GENOMIC DNA FROM PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 13 ME/CFS STUDY SUBJECTS AND 12 HEALTHY CONTROLS AND MEASURED GLOBAL DNA METHYLATION BY ELISA-LIKE METHOD AND SITE-SPECIFIC METHYLATION STATUS USING ILLUMINA METHYLATIONEPIC MICROARRAYS. PYROSEQUENCING VALIDATION INCLUDED 33 ME/CFS CASES AND 31 CONTROLS FROM TWO GEOGRAPHICALLY DISTANT COHORTS. RESULTS: GLOBAL DNA METHYLATION LEVELS OF ME/CFS CASES WERE SIMILAR TO THOSE OF CONTROLS. HOWEVER, MICROARRAY-BASED APPROACH ALLOWED DETECTION OF 17,296 DIFFERENTIALLY METHYLATED CPG SITES IN 6,368 GENES ACROSS REGULATORY ELEMENTS AND WITHIN CODING REGIONS OF GENES. ANALYSIS OF DNA METHYLATION IN PROMOTER REGIONS REVEALED 307 DIFFERENTIALLY METHYLATED PROMOTERS. INGENUITY PATHWAY ANALYSIS INDICATED THAT GENES ASSOCIATED WITH DIFFERENTIALLY METHYLATED PROMOTERS PARTICIPATED IN AT LEAST 15 DIFFERENT PATHWAYS MOSTLY RELATED TO CELL SIGNALING WITH A STRONG IMMUNE COMPONENT. CONCLUSIONS: THIS IS THE FIRST STUDY THAT HAS EXPLORED GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH ME/CFS USING THE ADVANCED ILLUMINA METHYLATIONEPIC MICROARRAYS COVERING ABOUT 850,000 CPG SITES IN TWO GEOGRAPHICALLY DISTANT COHORTS OF ME/CFS CASES AND MATCHED CONTROLS. OUR RESULTS ARE ALIGNED WITH PREVIOUS STUDIES THAT INDICATE A DYSREGULATION OF THE IMMUNE SYSTEM IN ME/CFS. THEY ALSO SUGGEST A POTENTIAL ROLE OF EPIGENETIC DE-REGULATION IN THE PATHOBIOLOGY OF ME/CFS. WE PROPOSE SCREENING OF LARGER COHORTS OF ME/CFS CASES TO DETERMINE THE EXTERNAL VALIDITY OF THESE EPIGENETIC CHANGES IN ORDER TO IMPLEMENT THEM AS POSSIBLE DIAGNOSTIC MARKERS IN CLINICAL SETTING. 2018 11 6790 29 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS. 2005 12 822 31 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 13 6458 32 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021 14 5303 29 PROTEOME DATA OF SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A COMPLEX CHRONIC DISEASE. THE MOLECULAR DETERMINANTS AND NEUROPATHOLOGY OF SCHIZOPHRENIA ARE MULTIFACETED; AN IMPORTANT ROLE IN THE PATHOGENESIS IS PLAYED BY THE DYSREGULATION OF MOLECULAR AND EPIGENETIC MECHANISMS. HOWEVER, THE MOLECULAR MECHANISMS OF THE DEVELOPMENT OF THE DISEASE HAVE NOT YET BEEN STUDIED. AN IMPORTANT TASK IS THE ACCUMULATION AND SYSTEMATIZATION OF "OMICS"-KNOWLEDGE OF THE MOLECULAR PROFILES (TRANSCRIPTOME, PROTEOME, METABOLOME) OF BLOOD SPECIFIC TO PATHOLOGY. THEREBY THE DEVELOPMENT AND IMPROVEMENT OF MASS SPECTROMETRIC METHODS FOR THE DETECTION OF BIOLOGICAL MOLECULES HAS BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL RESEARCH. IN THE FIELD OF APPLIED PROBLEMS IN BIOMEDICAL RESEARCH, THE MOST PREVALENT ISSUE INVOLVES THE IDENTIFICATION OF SEROLOGICAL PROTEIN MARKERS ASSOCIATED WITH THE DEVELOPMENT OF SCHIZOPHRENIA, WHICH ACCOUNT FOR THE DISEASES THAT CAUSE THE A LIFE-SHORTENING ILLNESS, DISABILITY, DECREASED OF FUNCTIONING AND QUALITY OF LIFE AND WELLBEING OR HEALTH STATUS. OMICS APPROACHES ARE DESIGNED TO DETECT GENES (GENOMICS), MRNA (TRANSCRIPTOMICS), PROTEINS (PROTEOMICS) AND METABOLITES (METABOLOMICS) IN A SPECIFIC BIOLOGICAL SAMPLE. WE REPORT THE PROTEOMIC DATASETS ON THE SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA (SERIES "SCZ") AND HEALTHY VOLUNTEERS (SERIES "CNT"). DATA WERE ACQUIRED USING SHOTGUN ULTRA-HIGH RESOLUTION MASS SPECTROMETRY. 2020 15 1998 43 EPIGENETIC AND MIRNA EXPRESSION CHANGES IN PEOPLE WITH PAIN: A SYSTEMATIC REVIEW. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS MAY HOLD GREAT POTENTIAL IN THE FIELD OF PAIN. WE SYSTEMATICALLY REVIEWED THE LITERATURE EXPLORING EPIGENETIC MECHANISMS IN PEOPLE WITH PAIN. FOUR DATABASES HAVE BEEN INTERROGATED: MEDLINE, THE COCHRANE CENTRAL REGISTER OF CONTROLLED TRIAL, SCOPUS, AND WEB OF SCIENCE, FOLLOWING PRISMA GUIDELINES IN CONDUCTING STUDY SELECTION AND ASSESSMENT. THIRTY-SEVEN STUDIES WERE INCLUDED. STUDIES EXPLORED EPIGENETICS IN CONDITIONS SUCH AS FIBROMYALGIA, CRPS, NEUROPATHIES, OR OSTEOARTHRITIS. RESEARCH FOCUSSED ON GENOME-WIDE AND GENE-SPECIFIC DNA METHYLATION, AND MIRNA EXPRESSION. BIOINFORMATICS ANALYSES EXPLORING MIRNA-ASSOCIATED MOLECULAR PATHWAYS WERE ALSO PERFORMED. SEVERAL GENES ALREADY KNOWN FOR THEIR ROLE IN PAIN (BDNF, HDAC4, PRKG1, IL-17, TNFRSF13B, ETC.), AND SEVERAL MIRNAS LINKED TO INFLAMMATORY REGULATION, NOCICEPTIVE SIGNALLING AND PROTEIN KINASES FUNCTIONS HAVE BEEN FOUND TO DIFFER SIGNIFICANTLY BETWEEN PEOPLE WITH CHRONIC PAIN AND HEALTHY CONTROLS. ALTHOUGH THE STUDIES INCLUDED WERE CROSS-SECTIONAL IN NATURE, AND NO CONCLUSION ON CAUSAL LINKS BETWEEN EPIGENETIC CHANGES AND PAIN COULD BE DRAWN, WE SUMMARISED THE LARGE AMOUNT OF DATA AVAILABLE IN LITERATURE ON THE TOPIC, HIGHLIGHTING RESULTS THAT HAVE BEEN REPLICATED BY INDEPENDENT INVESTIGATIONS. THE FIELD OF PAIN EPIGENETICS APPEARS VERY EXCITING AND HAS ALL THE POTENTIAL TO LEAD TO REMARKABLE SCIENTIFIC ADVANCES. HOWEVER, HIGH-QUALITY, WELL-POWERED, LONGITUDINAL STUDIES ARE WARRANTED. PERSPECTIVE: THOUGH MORE HIGH-QUALITY RESEARCH IS NEEDED, AVAILABLE RESEARCH EXPLORING EPIGENETIC MECHANISMS OR MIRNAS IN PEOPLE WITH PAIN SHOWS THAT GENES REGULATING SYNAPTIC PLASTICITY AND EXCITABILITY, PROTEIN KINASES, AND ELEMENTS OF THE IMMUNE SYSTEM MIGHT HOLD GREAT POTENTIAL IN UNDERSTANDING THE PATHOPHYSIOLOGY OF DIFFERENT CONDITIONS. 2020 16 4531 37 MULTILAYER-OMICS ANALYSES OF HUMAN CANCERS: EXPLORATION OF BIOMARKERS AND DRUG TARGETS BASED ON THE ACTIVITIES OF THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM. EPIGENETIC ALTERATIONS CONSISTING MAINLY OF DNA METHYLATION ALTERATIONS AND HISTONE MODIFICATION ALTERATIONS ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS FREQUENTLY ASSOCIATED WITH TUMOR AGGRESSIVENESS AND POOR PATIENT OUTCOME. RECENTLY, EPIGENOME ALTERATIONS HAVE BEEN ATTRACTING A GREAT DEAL OF ATTENTION FROM RESEARCHERS WHO ARE FOCUSING ON NOT ONLY CANCERS BUT ALSO NEURONAL, IMMUNE AND METABOLIC DISORDERS. IN ORDER TO ACCURATELY IDENTIFY DISEASE-SPECIFIC EPIGENOME PROFILES THAT COULD BE POTENTIALLY APPLICABLE FOR DISEASE PREVENTION, DIAGNOSIS AND THERAPY, STRICT COMPARISON WITH STANDARD EPIGENOME PROFILES OF NORMAL TISSUES IS INDISPENSABLE. HOWEVER, EPIGENOME MECHANISMS SHOW HETEROGENEITY AMONG TISSUES AND CELL LINEAGES. THEREFORE, IT IS NOT EASY TO OBTAIN A COMPREHENSIVE PICTURE OF STANDARD EPIGENOME PROFILES OF NORMAL TISSUES. IN 2010, THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM (IHEC) WAS ESTABLISHED TO COORDINATE THE PRODUCTION OF REFERENCE MAPS OF HUMAN EPIGENOMES FOR KEY CELLULAR STATES. IN ORDER TO GAIN SUBSTANTIAL COVERAGE OF THE HUMAN EPIGENOME, THE IHEC HAS SET AN AMBITIOUS GOAL TO DECIPHER AT LEAST 1000 EPIGENOMES WITHIN THE NEXT 7-10 YEARS. WE CONSIDER THAT PATHWAY ANALYSIS USING GENES SHOWING MULTILAYER-OMICS ABNORMALITIES, INCLUDING GENOME, EPIGENOME, TRANSCRIPTOME, PROTEOME AND METABOLOME ABNORMALITIES, MAY BE USEFUL FOR ELUCIDATING THE MOLECULAR BACKGROUND OF PATHOGENESIS AND FOR EXPLORING POSSIBLE THERAPEUTIC TARGETS FOR EACH DISEASE. 2014 17 1026 47 CIRCULATING MIRNAS EXPRESSION IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX MULTIFACTORIAL DISEASE THAT CAUSES INCREASING MORBIDITY WORLDWIDE, AND MANY INDIVIDUALS WITH ME/CFS SYMPTOMS REMAIN UNDIAGNOSED DUE TO THE LACK OF DIAGNOSTIC BIOMARKERS. ITS ETIOLOGY IS STILL UNKNOWN, BUT INCREASING EVIDENCE SUPPORTS A ROLE OF HERPESVIRUSES (INCLUDING HHV-6A AND HHV-6B) AS POTENTIAL TRIGGERS. INTERESTINGLY, THE INFECTION BY THESE VIRUSES HAS BEEN REPORTED TO IMPACT THE EXPRESSION OF MICRORNAS (MIRNAS), SHORT NON-CODING RNA SEQUENCES WHICH HAVE BEEN SUGGESTED TO BE EPIGENETIC FACTORS MODULATING ME/CFS PATHOGENIC MECHANISMS. NOTABLY, THE PRESENCE OF CIRCULATING MIRNAS IN PLASMA HAS RAISED THE POSSIBILITY TO USE THEM AS VALUABLE BIOMARKERS FOR DISTINGUISHING ME/CFS PATIENTS FROM HEALTHY CONTROLS. THUS, THIS STUDY AIMED AT DETERMINING THE ROLE OF EIGHT MIRNAS, WHICH WERE SELECTED FOR THEIR PREVIOUS ASSOCIATION WITH ME/CFS, AS POTENTIAL CIRCULATING BIOMARKERS OF THE DISEASE. THEIR PRESENCE WAS QUANTITATIVELY EVALUATED IN PLASMA FROM 40 ME/CFS PATIENTS AND 20 HEALTHY CONTROLS BY SPECIFIC TAQMAN ASSAYS, AND THE RESULTS SHOWED THAT SIX OUT OF THE EIGHT OF THE SELECTED MIRNAS WERE DIFFERENTLY EXPRESSED IN PATIENTS COMPARED TO CONTROLS; MORE SPECIFICALLY, FIVE MIRNAS WERE SIGNIFICANTLY UPREGULATED (MIR-127-3P, MIR-142-5P, MIR-143-3P, MIR-150-5P, AND MIR-448), AND ONE WAS DOWNMODULATED (MIR-140-5P). MIRNA LEVELS DIRECTLY CORRELATED WITH DISEASE SEVERITY, WHEREAS NO SIGNIFICANT CORRELATIONS WERE OBSERVED WITH THE PLASMA LEVELS OF SEVEN PRO-INFLAMMATORY CYTOKINES OR WITH THE PRESENCE/LOAD OF HHV-6A/6B GENOME, AS JUDGED BY SPECIFIC PCR AMPLIFICATION. THE RESULTS MAY OPEN THE WAY FOR FURTHER VALIDATION OF MIRNAS AS NEW POTENTIAL BIOMARKERS IN ME/CFS AND INCREASE THE KNOWLEDGE OF THE COMPLEX PATHWAYS INVOLVED IN THE ME/CFS DEVELOPMENT. 2023 18 287 26 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 19 3503 25 IDENTIFICATION OF POTENTIAL DIFFERENTIALLY METHYLATED GENE-RELATED BIOMARKERS IN ENDOMETRIOSIS. AIM: TO IDENTIFY EPIGENETIC ALTERATIONS OF DIFFERENTIALLY EXPRESSED GENES AND SCREEN OUT TARGETED THERAPEUTIC DRUGS IN ENDOMETRIOSIS. METHODS: BASED ON THE GENE EXPRESSION OMNIBUS DATABASE AND A SERIES OF BIOLOGICAL INFORMATION ANALYSIS TOOLS, SUPPLEMENTED BY VALIDATION OF CLINICAL SAMPLES, ABERRANT DNA METHYLATION-DRIVEN GENES AND THEIR FUNCTIONS WERE EXPLORED, AS WELL AS POSSIBLE TARGETED DRUGS. RESULTS: THIS STUDY SCREENED OUT A RANGE OF DNA METHYLATION-DRIVEN GENES THAT WERE ASSOCIATED WITH POWERFUL PROPERTIES AND CORRESPONDING PATHWAYS. AMONG THEM, BDNF AND CCL2 WERE KEY GENES IN THE DEVELOPMENT OF ENDOMETRIOSIS. FOUR CHEMICAL AGENTS HAVE BEEN FLAGGED AS POTENTIAL TREATMENTS FOR ENDOMETRIOSIS. CONCLUSION: THESE CANDIDATE GENES AND SMALL-MOLECULE AGENTS MAY BE FURTHER EXPLORED AS POTENTIAL TARGETS AND DRUGS FOR ENDOMETRIOSIS DIAGNOSIS AND THERAPY, RESPECTIVELY. 2022 20 2093 36 EPIGENETIC EFFECTS FOLLOWING ACUTE AND CHRONIC EXERCISE IN CARDIOVASCULAR DISEASE: A SYSTEMATIC REVIEW. INTRODUCTION: ACUTE EXERCISE AND EXERCISE TRAINING MAY CONFER EPIGENETIC MODIFICATIONS IN HEALTHY SUBJECTS. EPIGENETIC EFFECTS AFTER EXERCISE HAVE BEEN SHOWED IN PATIENTS WITH CARDIOVASCULAR DISEASE. THE AIM OF THIS SYSTEMATIC REVIEW WAS TO SUMMARIZE THE EVIDENCE FROM AVAILABLE CLINICAL TRIALS THAT STUDY EPIGENETIC ADAPTATIONS AFTER EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. METHODS: THE SEARCH STRATEGY WAS PERFORMED IN PUBMED AND CENTRAL DATABASES ON ARTICLES PUBLISHED UNTIL SEPTEMBER 2020. STUDIES WITH TITLES AND ABSTRACTS RELEVANT TO EXERCISE EPIGENETIC MODIFICATION APPLIED TO CARDIOVASCULAR PATIENTS WERE FULLY EXAMINED. INCLUSION AND EXCLUSION CRITERIA WERE UTILIZED FOR STUDIES SCREENING. QUALITY ASSESSMENT WITH PEDRO SCALE AND EVALUATION BY TWO INDEPENDENT REVIEWERS WAS PERFORMED. RESULTS: OF THE 1714 ARTICLES RETRIEVED, 88 ARTICLES WERE ASSESSED FOR ELIGIBILITY CRITERIA AND 8 ARTICLES MATCHED OUR SEARCH CRITERIA AND FINALLY INCLUDED IN THE SYSTEMATIC ANALYSIS. THE ACUTE EXERCISE EPIGENETIC (MIRNAS) EFFECTS WERE ASSESSED IN THREE STUDIES AND THE CHRONIC EXERCISE TRAINING EFFECTS (MIRNAS AND DNA METHYLATION) IN SIX STUDIES. THE RESULTS HAVE SHOWN THAT THERE IS POSSIBLY AN ACUTE SIGNIFICANT EXERCISE EFFECT ON EPIGENETIC TARGETS WHICH IS MORE EVIDENT AFTER CHRONIC EXERCISE TRAINING. CONCLUSIONS: BY THE PRESENT SYSTEMATIC REVIEW, WE PROVIDE PRELIMINARY EVIDENCE OF BENEFICIAL EPIGENETIC ADAPTATIONS FOLLOWING ACUTE AND CHRONIC EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. MORE CONTROLLED STUDIES ARE NEEDED TO CONFIRM SUCH EVIDENCE. 2021