1 3139 108 GLOBAL ENDOMETRIAL DNA METHYLATION ANALYSIS REVEALS INSIGHTS INTO MQTL REGULATION AND ASSOCIATED ENDOMETRIOSIS DISEASE RISK AND ENDOMETRIAL FUNCTION. ENDOMETRIOSIS IS A LEADING CAUSE OF PAIN AND INFERTILITY AFFECTING MILLIONS OF WOMEN GLOBALLY. HEREIN, WE CHARACTERIZE VARIATION IN DNA METHYLATION (DNAM) AND ITS ASSOCIATION WITH MENSTRUAL CYCLE PHASE, ENDOMETRIOSIS, AND GENETIC VARIANTS THROUGH ANALYSIS OF GENOTYPE DATA AND METHYLATION IN ENDOMETRIAL SAMPLES FROM 984 DEEPLY-PHENOTYPED PARTICIPANTS. WE ESTIMATE THAT 15.4% OF THE VARIATION IN ENDOMETRIOSIS IS CAPTURED BY DNAM AND IDENTIFY SIGNIFICANT DIFFERENCES IN DNAM PROFILES ASSOCIATED WITH STAGE III/IV ENDOMETRIOSIS, ENDOMETRIOSIS SUB-PHENOTYPES AND MENSTRUAL CYCLE PHASE, INCLUDING OPENING OF THE WINDOW FOR EMBRYO IMPLANTATION. MENSTRUAL CYCLE PHASE WAS A MAJOR SOURCE OF DNAM VARIATION SUGGESTING CELLULAR AND HORMONALLY-DRIVEN CHANGES ACROSS THE CYCLE CAN REGULATE GENES AND PATHWAYS RESPONSIBLE FOR ENDOMETRIAL PHYSIOLOGY AND FUNCTION. DNAM QUANTITATIVE TRAIT LOCUS (MQTL) ANALYSIS IDENTIFIED 118,185 INDEPENDENT CIS-MQTLS INCLUDING 51 ASSOCIATED WITH RISK OF ENDOMETRIOSIS, HIGHLIGHTING CANDIDATE GENES CONTRIBUTING TO DISEASE RISK. OUR WORK PROVIDES FUNCTIONAL EVIDENCE FOR EPIGENETIC TARGETS CONTRIBUTING TO ENDOMETRIOSIS RISK AND PATHOGENESIS. DATA GENERATED SERVE AS A VALUABLE RESOURCE FOR UNDERSTANDING TISSUE-SPECIFIC EFFECTS OF METHYLATION ON ENDOMETRIAL BIOLOGY IN HEALTH AND DISEASE. 2023 2 146 40 ABERRANT ENDOMETRIAL DNA METHYLOME AND ASSOCIATED GENE EXPRESSION IN WOMEN WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT, PROGESTERONE-RESISTANT DISORDER LARGELY DERIVED FROM RETROGRADE TRANSPLANTATION OF MENSTRUAL TISSUE/CELLS INTO THE PELVIS, ELICITING AN INFLAMMATORY RESPONSE, PELVIC PAIN, AND INFERTILITY. EUTOPIC ENDOMETRIUM (WITHIN THE UTERUS), GIVING RISE TO PELVIC DISEASE, DISPLAYS CYCLE-DEPENDENT TRANSCRIPTOMIC, PROTEOMIC, AND SIGNALING ABNORMALITIES, AND ALTHOUGH ITS DNA METHYLATION PROFILES DYNAMICALLY CHANGE ACROSS THE CYCLE IN HEALTHY WOMEN, STUDIES IN ENDOMETRIOSIS ARE LIMITED. HEREIN, WE INVESTIGATED THE DNA METHYLOME AND ASSOCIATED GENE EXPRESSION IN THREE PHASES OF THE CYCLE IN EUTOPIC ENDOMETRIUM OF WOMEN WITH SEVERE ENDOMETRIOSIS VERSUS CONTROLS, MATCHED FOR ETHNICITY, MEDICATIONS, SMOKING, AND NO RECENT CONTRACEPTIVE STEROID USE. GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION WERE COASSESSED IN EACH SAMPLE. CYCLE PHASE WAS DETERMINED BY HISTOLOGY, SERUM HORMONE LEVELS, AND UNSUPERVISED PRINCIPAL COMPONENT AND HIERARCHICAL CLUSTER ANALYSES OF MICROARRAY DATA. ALTERED ENDOMETRIAL DNA METHYLATION IN ENDOMETRIOSIS WAS MOST PROMINENT IN THE MIDSECRETORY PHASE (PEAK PROGESTERONE), WITH DISRUPTION OF THE NORMAL PATTERN OF CYCLE-DEPENDENT DNA METHYLATION CHANGES, INCLUDING A BIAS TOWARD METHYLATION OF CPG ISLANDS, SUGGESTING WIDE-RANGE ABNORMALITIES OF THE CHROMATIN REMODELING MACHINERY IN ENDOMETRIOSIS. DNA METHYLATION CHANGES WERE ASSOCIATED WITH ALTERED GENE EXPRESSION RELEVANT TO ENDOMETRIAL FUNCTION/DYSFUNCTION, INCLUDING CELL PROLIFERATION, INFLAMMATION/IMMUNE RESPONSE, ANGIOGENESIS, AND STEROID HORMONE RESPONSE. THE DATA PROVIDE INSIGHT INTO EPIGENETIC REPROGRAMMING AND STEROID HORMONE ACTIONS IN ENDOMETRIUM CONTRIBUTING TO THE PATHOGENESIS AND PATHOPHYSIOLOGY OF ENDOMETRIOSIS. 2016 3 3047 30 GENOME-WIDE ANALYSIS OF DNA METHYLATION IN ENDOMETRIOSIS USING ILLUMINA HUMAN METHYLATION 450 K BEADCHIPS. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGIC DISORDER CHARACTERIZED BY THE PRESENCE AND GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE OF THE UTERINE CAVITY. ALTHOUGH THE EXACT ETIOLOGY REMAINS UNCLEAR, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE THOUGHT TO CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. HERE, WE USED THE ILLUMINA HUMAN METHYLATION 450 K BEADCHIP ARRAY TO ANALYZE THE GENOME-WIDE DNA METHYLATION PROFILES OF SIX ENDOMETRIOTIC LESIONS AND SIX EUTOPIC ENDOMETRIA FROM PATIENTS WITH OVARIAN ENDOMETRIOSIS AND SIX ENDOMETRIA OF WOMEN WITHOUT ENDOMETRIOSIS. COMPARED WITH THE EUTOPIC ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS, 12,159 DIFFERENTIALLY METHYLATED CPG SITES AND 375 DIFFERENTIALLY METHYLATED PROMOTER REGIONS WERE IDENTIFIED IN ENDOMETRIOTIC LESIONS. GO ANALYSES SHOWED THAT THESE PUTATIVE DIFFERENTIALLY METHYLATED GENES WERE PRIMARILY ASSOCIATED WITH IMMUNE RESPONSE, INFLAMMATORY RESPONSE, RESPONSE TO STEROID HORMONE STIMULUS, CELL ADHESION, NEGATIVE REGULATION OF APOPTOSIS, AND ACTIVATION OF THE MAPK ACTIVITY. IN ADDITION, THE EXPRESSION LEVELS OF DNMT1, DNMT3A, DNMT3B, AND MBD2 IN ENDOMETRIOTIC LESIONS AND EUTOPIC ENDOMETRIA WERE SIGNIFICANTLY DECREASED COMPARED WITH CONTROL ENDOMETRIA. OUR FINDINGS SUGGEST THAT ABERRANT DNA METHYLATION STATUS IN ENDOMETRIOTIC LESIONS MAY PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS AND PROGRESSION OF ENDOMETRIOSIS. 2019 4 605 34 BEYOND ENDOMETRIOSIS GENOME-WIDE ASSOCIATION STUDY: FROM GENOMICS TO PHENOMICS TO THE PATIENT. ENDOMETRIOSIS IS A HERITABLE, COMPLEX CHRONIC INFLAMMATORY DISEASE, FOR WHICH MUCH OF THE CAUSAL PATHOGENIC MECHANISM REMAINS UNKNOWN. GENOME-WIDE ASSOCIATION STUDIES (GWAS) TO DATE HAVE IDENTIFIED 12 SINGLE NUCLEOTIDE POLYMORPHISMS AT 10 INDEPENDENT GENETIC LOCI ASSOCIATED WITH ENDOMETRIOSIS. MOST OF THESE WERE MORE STRONGLY ASSOCIATED WITH REVISED AMERICAN FERTILITY SOCIETY STAGE III/IV, RATHER THAN STAGE I/II. THE LOCI ARE ALMOST ALL LOCATED IN INTERGENIC REGIONS THAT ARE KNOWN TO PLAY A ROLE IN THE REGULATION OF EXPRESSION OF TARGET GENES YET TO BE IDENTIFIED. TO IDENTIFY THE TARGET GENES AND PATHWAYS PERTURBED BY THE IMPLICATED VARIANTS, STUDIES ARE REQUIRED INVOLVING FUNCTIONAL GENOMIC ANNOTATION OF THE SURROUNDING CHROMOSOMAL REGIONS, IN TERMS OF TRANSCRIPTION FACTOR BINDING, EPIGENETIC MODIFICATION (E.G., DNA METHYLATION AND HISTONE MODIFICATION) SITES, AS WELL AS THEIR CORRELATION WITH RNA TRANSCRIPTION. THESE STUDIES NEED TO BE CONDUCTED IN TISSUE TYPES RELEVANT TO ENDOMETRIOSIS-IN PARTICULAR, ENDOMETRIUM. IN ADDITION, TO ALLOW BIOLOGICALLY AND CLINICALLY RELEVANT INTERPRETATION OF MOLECULAR PROFILING DATA, THEY NEED TO BE COMBINED AND CORRELATED WITH DETAILED, SYSTEMATICALLY COLLECTED PHENOTYPIC INFORMATION (SURGICAL AND CLINICAL). THE WERF ENDOMETRIOSIS PHENOME AND BIOBANKING HARMONISATION PROJECT IS A GLOBAL STANDARDIZATION INITIATIVE THAT HAS PRODUCED CONSENSUS DATA AND SAMPLE COLLECTION PROTOCOLS FOR ENDOMETRIOSIS RESEARCH. THESE NOW PAVE THE WAY FOR COLLABORATIVE STUDIES INTEGRATING PHENOMIC WITH GENOMIC DATA, TO IDENTIFY INFORMATIVE SUBTYPES OF ENDOMETRIOSIS THAT WILL ENHANCE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE AND DISCOVERY OF NOVEL, TARGETED TREATMENTS. 2016 5 2820 24 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS. 2017 6 3061 36 GENOME-WIDE DNA METHYLATION ANALYSIS PREDICTS AN EPIGENETIC SWITCH FOR GATA FACTOR EXPRESSION IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A GYNECOLOGICAL DISEASE DEFINED BY THE EXTRAUTERINE GROWTH OF ENDOMETRIAL-LIKE CELLS THAT CAUSE CHRONIC PAIN AND INFERTILITY. THE DISEASE IS LIMITED TO PRIMATES THAT EXHIBIT SPONTANEOUS DECIDUALIZATION, AND DISEASED CELLS ARE CHARACTERIZED BY SIGNIFICANT DEFECTS IN THE STEROID-DEPENDENT GENETIC PATHWAYS THAT TYPIFY THIS PROCESS. ALTERED DNA METHYLATION MAY UNDERLIE THESE DEFECTS, BUT FEW REGIONS WITH DIFFERENTIAL METHYLATION HAVE BEEN IMPLICATED IN THE DISEASE. WE MAPPED GENOME-WIDE DIFFERENCES IN DNA METHYLATION BETWEEN HEALTHY HUMAN ENDOMETRIAL AND ENDOMETRIOTIC STROMAL CELLS AND CORRELATED THIS WITH GENE EXPRESSION USING AN INTERACTION ANALYSIS STRATEGY. WE IDENTIFIED 42,248 DIFFERENTIALLY METHYLATED CPGS IN ENDOMETRIOSIS COMPARED TO HEALTHY CELLS. THESE EXTENSIVE DIFFERENCES WERE NOT UNIDIRECTIONAL, BUT WERE FOCUSED INTRAGENICALLY AND AT SITES DISTAL TO CLASSIC CPG ISLANDS WHERE METHYLATION STATUS WAS TYPICALLY NEGATIVELY CORRELATED WITH GENE EXPRESSION. SIGNIFICANT DIFFERENCES IN METHYLATION WERE MAPPED TO 403 GENES, WHICH INCLUDED A DISPROPORTIONALLY LARGE NUMBER OF TRANSCRIPTION FACTORS. FURTHERMORE, MANY OF THESE GENES ARE IMPLICATED IN THE PATHOLOGY OF ENDOMETRIOSIS AND DECIDUALIZATION. OUR RESULTS TREMENDOUSLY IMPROVE THE SCOPE AND RESOLUTION OF DIFFERENTIAL METHYLATION AFFECTING THE HOX GENE CLUSTERS, NUCLEAR RECEPTOR GENES, AND INTRIGUINGLY THE GATA FAMILY OF TRANSCRIPTION FACTORS. FUNCTIONAL ANALYSIS OF THE GATA FAMILY REVEALED THAT GATA2 REGULATES KEY GENES NECESSARY FOR THE HORMONE-DRIVEN DIFFERENTIATION OF HEALTHY STROMAL CELLS, BUT IS HYPERMETHYLATED AND REPRESSED IN ENDOMETRIOTIC CELLS. GATA6, WHICH IS HYPOMETHYLATED AND ABUNDANT IN ENDOMETRIOTIC CELLS, POTENTLY BLOCKED HORMONE SENSITIVITY, REPRESSED GATA2, AND INDUCED MARKERS OF ENDOMETRIOSIS WHEN EXPRESSED IN HEALTHY ENDOMETRIAL CELLS. THE UNIQUE EPIGENETIC FINGERPRINT IN ENDOMETRIOSIS SUGGESTS DNA METHYLATION IS AN INTEGRAL COMPONENT OF THE DISEASE, AND IDENTIFIES A NOVEL ROLE FOR THE GATA FAMILY AS KEY REGULATORS OF UTERINE PHYSIOLOGY-ABERRANT DNA METHYLATION IN ENDOMETRIOTIC CELLS CORRELATES WITH A SHIFT IN GATA ISOFORM EXPRESSION THAT FACILITATES PROGESTERONE RESISTANCE AND DISEASE PROGRESSION. 2014 7 3003 41 GENETIC, EPIGENETIC AND STEM CELL ALTERATIONS IN ENDOMETRIOSIS: NEW INSIGHTS AND POTENTIAL THERAPEUTIC PERSPECTIVES. HUMAN ENDOMETRIUM IS A HIGHLY DYNAMIC TISSUE, UNDERGOING PERIODIC GROWTH AND REGRESSION AT EACH MENSTRUAL CYCLE. ENDOMETRIOSIS IS A FREQUENT CHRONIC PATHOLOGICAL STATUS CHARACTERIZED BY ENDOMETRIAL TISSUE WITH AN ECTOPIC LOCALIZATION, CAUSING PELVIC PAIN AND INFERTILITY AND A VARIABLE CLINICAL PRESENTATION. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION IN APPROXIMATELY 1.0% OF AFFECTED WOMEN, WITH THE INVOLVEMENT OF MULTIPLE PATHWAYS OF DEVELOPMENT. INCREASING EVIDENCE SUPPORTS A KEY CONTRIBUTION OF DIFFERENT STEM/PROGENITOR CELL POPULATIONS NOT ONLY IN THE CYCLIC REGENERATION OF EUTOPIC ENDOMETRIUM, BUT ALSO IN THE PATHOGENESIS OF AT LEAST SOME TYPES OF ENDOMETRIOSIS. EVIDENCE HAS ARISEN FROM EXPERIMENTS IN ANIMAL MODELS OF DISEASE THROUGH DIFFERENT KINDS OF ASSAYS (INCLUDING CLONOGENICITY, THE LABEL-RETAINING CELL APPROACH, THE ANALYSIS OF UNDIFFERENTIATION MARKERS), AS WELL AS FROM DESCRIPTIVE STUDIES ON ECTOPIC AND EUTOPIC TISSUE SAMPLES HARVESTED FROM AFFECTED WOMEN. CHANGES IN STEM CELL POPULATIONS IN ENDOMETRIOTIC LESIONS ARE ASSOCIATED WITH GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING IMBALANCE OF MIRNA EXPRESSION, HISTONE AND DNA MODIFICATIONS AND CHROMOSOMAL ABERRATIONS. THE PRESENT SHORT REVIEW MAINLY SUMMARIZES THE LATEST OBSERVATIONS CONTRIBUTING TO THE CURRENT KNOWLEDGE REGARDING THE PRESENCE AND THE POTENTIAL CONTRIBUTION OF STEM/PROGENITOR CELLS IN EUTOPIC ENDOMETRIUM AND THE AETIOLOGY OF ENDOMETRIOSIS, TOGETHER WITH A REPORT OF THE MOST RECENTLY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS IN ENDOMETRIOSIS. WE ALSO DESCRIBE THE POTENTIAL ADVANTAGES OF SINGLE CELL MOLECULAR PROFILING IN ENDOMETRIUM AND IN ENDOMETRIOTIC LESIONS. ALL THESE DATA CAN HAVE CLINICAL IMPLICATIONS AND PROVIDE A BASIS FOR NEW POTENTIAL THERAPEUTIC APPLICATIONS. 2014 8 1524 23 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT). 2020 9 6468 27 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL. 2015 10 2653 29 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES. 2008 11 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 12 3743 45 INSIGHTS FROM GENOMIC STUDIES ON THE ROLE OF SEX STEROIDS IN THE AETIOLOGY OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC NEURO-INFLAMMATORY DISORDER THE DEFINING FEATURE OF WHICH IS THE GROWTH OF TISSUE (LESIONS) THAT RESEMBLES THE ENDOMETRIUM OUTSIDE THE UTERUS. ESTIMATES OF PREVALENCE QUOTE RATES OF ~10% OF WOMEN OF REPRODUCTIVE AGE, EQUATING TO AT LEAST 190 MILLION WOMEN WORLD-WIDE. GENETIC, HORMONAL AND IMMUNOLOGICAL FACTORS HAVE ALL BEEN PROPOSED AS CONTRIBUTING TO RISK FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LESIONS. TWIN STUDIES REPORT THE HERITABLE COMPONENT OF ENDOMETRIOSIS AS ~50%. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT APPEAR OVER-REPRESENTED IN PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY THOSE WITH MORE EXTENSIVE DISEASE (STAGE III/IV). IN DIFFERENT SAMPLE POPULATIONS, THERE HAS BEEN REPLICATION OF SNPS NEAR GENES INVOLVED IN OESTROGEN AND OTHER STEROID REGULATED PATHWAYS INCLUDING ESR1 (OESTROGEN RECEPTOR ALPHA), GREB1, HOXA10, WNT4 AND MAPK KINASE SIGNALLING. COMPARISONS WITH GWAS CONDUCTED ON OTHER PATIENT COHORTS HAVE FOUND LINKS WITH REPRODUCTIVE TRAITS (AGE AT MENARCHE) AND DISORDERS (FIBROIDS, ENDOMETRIAL AND OVARIAN CANCER) AND COMMON CO-MORBIDITIES (MIGRAINE, DEPRESSION, ASTHMA). IN SUMMARY, GENETIC ANALYSES HAVE PROVIDED NEW INSIGHTS INTO THE HORMONE-REGULATED PATHWAYS THAT MAY CONTRIBUTE TO INCREASED RISK OF DEVELOPING ENDOMETRIOSIS SOME OF WHICH MAY ACT IN EARLY LIFE. NEW STUDIES ARE NEEDED TO CLARIFY THE RELATIONSHIP BETWEEN THE MANY SNPS IDENTIFIED, THE GENES THAT THEY REGULATE AND THEIR CONTRIBUTION(S) TO DEVELOPMENT OF DIFFERENT FORMS OF ENDOMETRIOSIS. WE HOPE THAT MORE ADVANCED METHODS ALLOWING INTEGRATION BETWEEN GWAS, EPIGENETIC AND TISSUE EXPRESSION DATA WILL IMPROVE RISK ANALYSIS AND REDUCE DIAGNOSITIC DELAY. LAY SUMMARY: ENDOMETRIOSIS IS A DEBILITATING REPRODUCTIVE DISORDER AFFECTING ~10% OF REPRODUCTIVE-AGE WOMEN, AND THOSE ASSIGNED FEMALE AT BIRTH, WHICH CAUSES A RANGE OF SYMPTOMS INCLUDING CHRONIC PAIN AND INFERTILITY. THE REASON WHY SOME, BUT NOT ALL THESE INDIVIDUALS, DEVELOP THE LESIONS THAT CHARACTERISE THE DISEASE ARE POORLY UNDERSTOOD, BUT RECENTLY ATTENTION HAS FOCUSED ON GENETIC RISK FACTORS TO EXPLAIN WHY THE INCIDENCE IS HIGHER IN SOME FAMILIES. STUDIES ON LARGE COHORTS OF PATIENTS WITH COMPARISON OF THEIR DNA TO WOMEN WITHOUT ENDOMETRIOSIS OR WITH OTHER DISORDERS HAVE DOCUMENTED CHANGES IN GENES ASSOCIATED WITH STEROID HORMONE PRODUCTION OR ACTION. THE RESULTS PROVIDE FURTHER EVIDENCE THAT ENDOMETRIOSIS SHARES GENETIC RISK FACTORS WITH OTHER DISORDERS OF THE REPRODUCTIVE SYSTEM AND A PLATFORM FOR NEW IDEAS RELATED TO RISK, BIOMARKERS AND THERAPIES. 2022 13 1519 22 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS. 2021 14 5754 20 SOCIAL PSYCHOGENIC STRESS PROMOTES THE DEVELOPMENT OF ENDOMETRIOSIS IN MOUSE. EXPOSURE TO CHRONIC STRESS BEFORE AND WELL AFTER THE INDUCTION OF ENDOMETRIOSIS IS REPORTED TO INCREASE LESION SIZES IN RATS, BUT IT IS UNCLEAR WHETHER STRESS, EXPOSED SHORTLY AFTER THE INDUCTION OF ENDOMETRIOSIS, WOULD ALSO PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS, NOR IS IT CLEAR WHAT THE UNDERLYING POSSIBLE MOLECULAR MECHANISM IS. THIS STUDY WAS UNDERTAKEN TO TEST THE HYPOTHESIS THAT CHRONIC STRESS CAN PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS. A PROSPECTIVE RANDOMIZED MOUSE EXPERIMENT WAS CONDUCTED THAT SUBJECTED MICE WITH INDUCED ENDOMETRIOSIS TO PREDATOR STRESS. IN ADDITION, A CROSS-SECTIONAL IMMUNOHISTOCHEMISTRY STUDY WAS PERFORMED IN ECTOPIC AND EUTOPIC ENDOMETRIAL TISSUE SAMPLES FROM AGE- AND ROUGHLY MENSTRUAL PHASE-MATCHED WOMEN WITH OVARIAN ENDOMETRIOMAS. IT WAS FOUND THAT THE CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS IN MOUSE INDEPENDENT OF ENDOMETRIOSIS. IT WAS ALSO FOUND THAT CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS OF MICE WITH ENDOMETRIOSIS, AND SEEMINGLY ACTIVATED THE ADRENERGIC SIGNALLING IN ECTOPIC ENDOMETRIUM, RESULTING IN INCREASED ANGIOGENESIS AND ACCELERATED GROWTH OF ENDOMETRIOTIC LESIONS. THUS, CHRONIC PSYCHOGENIC STRESS PROMOTES ENDOMETRIOSIS DEVELOPMENT, RAISING THE POSSIBILITY THAT THE USE OF ANTI-DEPRESSANTS IN CASES OF PROLONGED AND INTENSE STRESS MIGHT FORESTALL THE NEGATIVE IMPACT OF STRESS ON THE DEVELOPMENT OF ENDOMETRIOSIS. 2017 15 468 33 ARGININE METHYLTRANSFERASES MEDIATE AN EPIGENETIC OVARIAN RESPONSE TO ENDOMETRIOSIS. ENDOMETRIOSIS IS ASSOCIATED WITH INFERTILITY AND DEBILITATING CHRONIC PAIN. ABNORMAL EPIGENETIC MODIFICATIONS IN THE HUMAN ENDOMETRIUM HAVE RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF THIS CONDITION. HOWEVER, WHETHER AN ALTERED EPIGENETIC LANDSCAPE CONTRIBUTES TO PATHOLOGICAL CHANGES IN THE OVARY IS UNKNOWN. USING AN ESTABLISHED BABOON ENDOMETRIOSIS MODEL, EARLY-, AND LATE-STAGE EPIGENETIC CHANGES IN THE OVARY WERE INVESTIGATED. TRANSCRIPT PROFILING OF KEY CHROMATIN-MODIFYING ENZYMES USING PATHWAY-FOCUSED PCR ARRAYS ON OVARIAN TISSUE FROM HEALTHY CONTROL ANIMALS AND AT 3 AND 15 MONTHS OF ENDOMETRIOSIS REVEALED DRAMATIC CHANGES IN GENE EXPRESSION IN A DISEASE DURATION-DEPENDENT MANNER. INGENUITY PATHWAY ANALYSIS INDICATED THAT TRANSCRIPTS FOR CHROMATIN-REMODELING ENZYMES ASSOCIATED WITH REPRODUCTIVE SYSTEM DISEASE AND CANCER DEVELOPMENT WERE ABNORMALLY REGULATED, MOST PROMINENTLY THE ARGININE METHYLTRANSFERASES CARM1, PRMT2, AND PRMT8. DOWNREGULATION OF CARM1 PROTEIN EXPRESSION WAS ALSO DETECTED IN THE OVARY, FULLY-GROWN OOCYTES AND EUTOPIC ENDOMETRIUM FOLLOWING 15 MONTHS OF ENDOMETRIOSIS. SODIUM BISULFITE SEQUENCING REVEALED DNA HYPERMETHYLATION WITHIN THE PRMT8 PROMOTER, SUGGESTING THAT DEREGULATED CPG METHYLATION MAY PLAY A ROLE IN TRANSCRIPTIONAL REPRESSION OF THIS GENE. THESE RESULTS DEMONSTRATE THAT ENDOMETRIOSIS IS ASSOCIATED WITH CHANGES OF EPIGENETIC PROFILES IN THE PRIMATE OVARY AND SUGGEST THAT ARGININE METHYLTRANSFERASES PLAY A PROMINENT ROLE IN MEDIATING THE OVARIAN RESPONSE TO ENDOMETRIOSIS. OWING TO THE CRITICAL ROLE OF CARM1 IN NUCLEAR RECEPTOR-MEDIATED TRANSCRIPTION AND MAINTENANCE OF PLURIPOTENCY IN THE CLEAVAGE STAGE EMBRYO, OUR RESULTS SUGGEST THAT EPIGENETIC ALTERATIONS IN THE OVARY MAY HAVE FUNCTIONAL CONSEQUENCES FOR OOCYTE QUALITY AND THE ETIOLOGY OF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS. 2015 16 2086 30 EPIGENETIC DYSREGULATION IN ENDOMETRIOSIS: IMPLICATIONS FOR PATHOPHYSIOLOGY AND THERAPEUTICS. ENDOMETRIOSIS IS A PREVALENT GYNECOLOGICAL CONDITION ASSOCIATED WITH PELVIC PAIN AND INFERTILITY. DESPITE MORE THAN A CENTURY OF RESEARCH, THE ETIOLOGY OF ENDOMETRIOSIS STILL ELUDES SCIENTIFIC CONSENSUS. THIS LACK OF CLARITY HAS RESULTED IN SUBOPTIMAL PREVENTION, DIAGNOSIS, AND TREATMENT OPTIONS. EVIDENCE OF GENETIC CONTRIBUTORS TO ENDOMETRIOSIS IS INTERESTING BUT LIMITED; HOWEVER, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS IN IDENTIFYING EPIGENETIC ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS THROUGH CLINICAL STUDIES, IN VITRO CELL CULTURE EXPERIMENTS, AND IN VIVO ANIMAL MODELS. THE PREDOMINANT FINDINGS INCLUDE ENDOMETRIOSIS-RELATED DIFFERENTIAL EXPRESSION OF DNA METHYLTRANSFERASES AND DEMETHYLASES, HISTONE DEACETYLASES, METHYLTRANSFERASES, AND DEMETHYLASES, AND REGULATORS OF CHROMATIN ARCHITECTURE. THERE IS ALSO AN EMERGING ROLE FOR MIRNAS IN THE CONTROL OF EPIGENETIC REGULATORS IN THE ENDOMETRIUM AND ENDOMETRIOSIS. CHANGES IN THESE EPIGENETIC REGULATORS RESULT IN DIFFERENTIAL CHROMATIN ORGANIZATION AND DNA METHYLATION WITH CONSEQUENCES FOR GENE EXPRESSION INDEPENDENT OF A GENETIC SEQUENCE. EPIGENETICALLY ALTERED EXPRESSION OF GENES RELATED TO STEROID HORMONE PRODUCTION AND SIGNALING, IMMUNE REGULATION, AND ENDOMETRIAL CELL IDENTITY AND FUNCTION HAVE ALL BEEN IDENTIFIED AND APPEAR TO PLAY INTO THE PATHOPHYSIOLOGICAL MECHANISMS OF ENDOMETRIOSIS AS WELL AS RESULTING INFERTILITY. THIS REVIEW SUMMARIZES AND CRITICALLY DISCUSSES EARLY SEMINAL FINDINGS, THE EVER-GROWING RECENT EVIDENCE OF EPIGENETIC CONTRIBUTIONS TO THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS, AND IMPLICATIONS FOR PROPOSED EPIGENETICALLY TARGETED THERAPEUTICS. 2023 17 276 26 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021 18 2602 29 EPIGENETICS, ENDOMETRIOSIS AND SEX STEROID RECEPTORS: AN UPDATE ON THE EPIGENETIC REGULATORY MECHANISMS OF ESTROGEN AND PROGESTERONE RECEPTORS IN PATIENTS WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS A BENIGN GYNECOLOGICAL DISEASE AFFECTING APPROXIMATELY 10% OF REPRODUCTIVE-AGED WOMEN AND IS DEFINED AS THE PRESENCE OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. ENDOMETRIOSIS CAN CAUSE A VARIETY OF HEALTH PROBLEMS, FROM PELVIC DISCOMFORT TO CATAMENIAL PNEUMOTHORAX, BUT IT'S MAINLY LINKED WITH SEVERE AND CHRONIC PELVIC PAIN, DYSMENORRHEA, AND DEEP DYSPAREUNIA, AS WELL AS REPRODUCTIVE ISSUES. THE PATHOGENESIS OF ENDOMETRIOSIS INVOLVES AN ENDOCRINE DYSFUNCTION, WITH ESTROGEN DEPENDENCY AND PROGESTERONE RESISTANCE, AND INFLAMMATORY MECHANISM ACTIVATION, TOGETHER WITH IMPAIRED CELL PROLIFERATION AND NEUROANGIOGENESIS. THE PRESENT CHAPTER AIMS TO DISCUSS THE MAIN EPIGENETIC MECHANISMS RELATED TO ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS. THERE ARE NUMEROUS EPIGENETIC MECHANISMS PARTICIPATING IN ENDOMETRIOSIS, REGULATING THE EXPRESSION OF THE GENES ENCODING THESE RECEPTORS BOTH INDIRECTLY, THROUGH THE REGULATION OF TRANSCRIPTION FACTORS, AND DIRECTLY, THROUGH DNA METHYLATION, HISTONE MODIFICATIONS, MICRO RNAS AND LONG NONCODING RNAS. THIS REPRESENTS AN OPEN FIELD OF INVESTIGATION, WHICH MAY LEAD TO IMPORTANT CLINICAL IMPLICATIONS SUCH AS THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF ENDOMETRIOSIS AND THE IDENTIFICATION OF SPECIFIC AND EARLY BIOMARKERS FOR THE DISEASE. 2023 19 1587 31 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS. 2016 20 6678 32 USING GENETIC BURDEN SCORES FOR GENE-BY-METHYLATION INTERACTION ANALYSIS ON METABOLIC SYNDROME IN AFRICAN AMERICANS. WITH THE RAPID ADVANCEMENT OF OMICS-BASED RESEARCH, PARTICULARLY BIG DATA SUCH AS GENOME- AND EPIGENOME-WIDE ASSOCIATION STUDIES THAT INCLUDE EXTENSIVE ENVIRONMENTAL AND CLINICAL VARIABLES, DATA ANALYTICS HAVE BECOME INCREASINGLY COMPLEX. RESEARCHERS FACE SIGNIFICANT CHALLENGES REGARDING HOW TO ANALYZE MULTIFACTORIAL DATA AND MAKE USE OF THE FINDINGS FOR CLINICAL TRANSLATION. THE PURPOSE OF THIS ARTICLE IS TO PROVIDE A SCIENTIFIC EXEMPLAR FOR USE OF GENETIC BURDEN SCORES AS A DATA ANALYSIS METHOD FOR STUDIES WITH BOTH GENOTYPE AND DNA METHYLATION DATA IN WHICH THE GOAL IS TO EVALUATE ASSOCIATIONS WITH CHRONIC CONDITIONS SUCH AS METABOLIC SYNDROME (METS). THIS STUDY INCLUDED 739 AFRICAN AMERICAN MEN AND WOMEN FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY STUDY WHO MET DIAGNOSTIC CRITERIA FOR METS AND HAD AVAILABLE GENETIC AND EPIGENETIC DATA. GENETIC BURDEN SCORES FOR EVALUATED GENES WERE NOT SIGNIFICANT AFTER MULTIPLE TESTING CORRECTIONS, BUT DNA METHYLATION AT 2 CPG SITES (DIHYDROOROTATE DEHYDROGENASE CG22381196 PFDR = .014; CTNNA3 CG00132141 PFDR = .043) WAS SIGNIFICANTLY ASSOCIATED WITH METS AFTER CONTROLLING FOR MULTIPLE COMPARISONS. INTERACTIONS BETWEEN THE MARGINALLY SIGNIFICANT CPG SITES AND BURDEN SCORES, HOWEVER, WERE NOT SIGNIFICANT. MORE WORK IS REQUIRED IN THIS AREA TO IDENTIFY INTERMEDIATE BIOLOGICAL PATHWAYS INFLUENCED BY ENVIRONMENTAL, GENETIC, AND EPIGENETIC VARIATION THAT MAY EXPLAIN THE HIGH PREVALENCE OF METS AMONG AFRICAN AMERICANS. THIS STUDY DOES SERVE, HOWEVER, AS AN EXAMPLE OF THE USE OF THE GENETIC BURDEN SCORE AS AN ALTERNATIVE DATA ANALYSIS APPROACH FOR COMPLEX STUDIES INVOLVING THE ANALYSIS OF GENETIC AND EPIGENETIC DATA SIMULTANEOUSLY. 2019