1 3503 85 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 2 2920 38 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 3 6013 41 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 4 2909 30 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA. 2020 5 1508 31 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 6 605 33 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 7 4228 25 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 8 1269 33 CYTOSINE METHYLATION CHANGES IN ENHANCER REGIONS OF CORE PRO-FIBROTIC GENES CHARACTERIZE KIDNEY FIBROSIS DEVELOPMENT. BACKGROUND: ONE IN ELEVEN PEOPLE IS AFFECTED BY CHRONIC KIDNEY DISEASE, A CONDITION CHARACTERIZED BY KIDNEY FIBROSIS AND PROGRESSIVE LOSS OF KIDNEY FUNCTION. EPIDEMIOLOGICAL STUDIES INDICATE THAT ADVERSE INTRAUTERINE AND POSTNATAL ENVIRONMENTS HAVE A LONG-LASTING ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT. EPIGENETIC INFORMATION REPRESENTS A PLAUSIBLE CARRIER FOR MEDIATING THIS PROGRAMMING EFFECT. HERE WE DEMONSTRATE THAT GENOME-WIDE CYTOSINE METHYLATION PATTERNS OF HEALTHY AND CHRONIC KIDNEY DISEASE TUBULE SAMPLES OBTAINED FROM PATIENTS SHOW SIGNIFICANT DIFFERENCES. RESULTS: WE IDENTIFY DIFFERENTIALLY METHYLATED REGIONS AND VALIDATE THESE IN A LARGE REPLICATION DATASET. THE DIFFERENTIALLY METHYLATED REGIONS ARE RARELY OBSERVED ON PROMOTERS, BUT MOSTLY OVERLAP WITH PUTATIVE ENHANCER REGIONS, AND THEY ARE ENRICHED IN CONSENSUS BINDING SEQUENCES FOR IMPORTANT RENAL TRANSCRIPTION FACTORS. THIS INDICATES THEIR IMPORTANCE IN GENE EXPRESSION REGULATION. A CORE SET OF GENES THAT ARE KNOWN TO BE RELATED TO KIDNEY FIBROSIS, INCLUDING GENES ENCODING COLLAGENS, SHOW CYTOSINE METHYLATION CHANGES CORRELATING WITH DOWNSTREAM TRANSCRIPT LEVELS. CONCLUSIONS: OUR REPORT RAISES THE POSSIBILITY THAT EPIGENETIC DYSREGULATION PLAYS A ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT VIA INFLUENCING CORE PRO-FIBROTIC PATHWAYS AND CAN AID THE DEVELOPMENT OF NOVEL BIOMARKERS AND FUTURE THERAPEUTICS. 2013 9 1307 26 DEFINING A METHYLATION SIGNATURE ASSOCIATED WITH OPERATIONAL TOLERANCE IN KIDNEY TRANSPLANT RECIPIENTS. OPERATIONAL TOLERANCE AFTER KIDNEY TRANSPLANTATION IS DEFINED AS STABLE GRAFT ACCEPTANCE WITHOUT THE NEED FOR IMMUNOSUPPRESSION THERAPY. HOWEVER, IT IS NOT CLEAR WHICH CELLULAR AND MOLECULAR PATHWAYS ARE DRIVING TOLERANCE IN THESE PATIENTS. WE PERFORMED GENOME-WIDE ANALYSIS OF DNA METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM KIDNEY TRANSPLANT RECIPIENTS WITH CHRONIC REJECTION AND OPERATIONAL TOLERANCE FROM THE GENETIC ANALYSIS OF MOLECULAR BIOMARKERS OF IMMUNOLOGICAL TOLERANCE (GAMBIT) STUDY. OUR RESULTS SHOWED THAT BOTH CLINICAL STAGES DIVERGE IN 2737 GENES, INDICATING THAT EACH ONE HAS A SPECIFIC METHYLATION SIGNATURE ASSOCIATED WITH TRANSPLANT OUTCOME. WE ALSO OBSERVED THAT TOLERANCE IS ASSOCIATED WITH DEMETHYLATION IN GENES INVOLVED IN IMMUNE FUNCTION, INCLUDING B AND T CELL ACTIVATION AND TH17 DIFFERENTIATION, WHILE IN CHRONIC REJECTION IT IS ASSOCIATED WITH INTRACELLULAR SIGNALING AND UBIQUITINATION PATHWAYS. USING CO-EXPRESSION NETWORK ANALYSIS, WE SELECTED 12 GENOMIC REGIONS THAT ARE SPECIFICALLY HYPOMETHYLATED OR HYPERMETHYLATED IN TOLERANT PATIENTS. ANALYSIS OF THESE GENES IN TRANSPLANTED PATIENTS WITH LOW DOSE OF STEROIDS SHOWED THAT THESE HAVE A SIMILAR METHYLATION SIGNATURE TO THAT OF TOLERANT RECIPIENTS. OVERALL, THESE RESULTS DEMONSTRATE THAT METHYLATION ANALYSIS CAN MIRROR THE IMMUNE STATUS ASSOCIATED WITH TRANSPLANT OUTCOME AND PROVIDES A STARTING POINT FOR UNDERSTANDING THE EPIGENETIC MECHANISMS ASSOCIATED WITH TOLERANCE. 2021 10 4531 34 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 11 606 35 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE. 2004 12 6790 27 [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 13 6616 33 UNCOVERING THE DNA METHYLOME IN CHRONIC LYMPHOCYTIC LEUKEMIA. OVER THE PAST TWO DECADES, ABERRANT DNA METHYLATION HAS EMERGED AS A KEY PLAYER IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND KNOWLEDGE REGARDING ITS BIOLOGICAL AND CLINICAL CONSEQUENCES IN THIS DISEASE HAS EVOLVED RAPIDLY. SINCE THE INITIAL STUDIES RELATING DNA HYPOMETHYLATION TO GENOMIC INSTABILITY IN CLL, A PLETHORA OF REPORTS HAVE FOLLOWED SHOWING THE IMPACT OF DNA HYPERMETHYLATION IN SILENCING VITAL SINGLE GENE PROMOTERS AND THE REVERSIBLE NATURE OF DNA METHYLATION THROUGH INHIBITOR DRUGS. WITH THE RECOGNITION THAT DNA HYPERMETHYLATION EVENTS COULD POTENTIALLY ACT AS NOVEL PROGNOSTIC AND TREATMENT TARGETS IN CLL, THE SEARCH FOR ABERRANTLY METHYLATED GENES, GENE FAMILIES AND PATHWAYS HAS ENSUED. SUBSEQUENTLY, THE ADVENT OF MICROARRAY AND NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS SUPPORTED THE HUNT FOR SUCH TARGETS, ALLOWING EXPLORATION OF THE METHYLATION LANDSCAPE IN CLL AT AN UNPRECEDENTED SCALE. IN LIGHT OF THESE ANALYSES, WE NOW UNDERSTAND THAT DIFFERENT CLL PROGNOSTIC SUBGROUPS ARE CHARACTERIZED BY DIFFERENTIAL METHYLATION PROFILES; WE RECOGNIZE DNA METHYLATION OF A NUMBER OF SIGNALING PATHWAYS GENES TO BE ALTERED IN CLL, AND ACKNOWLEDGE THE ROLE OF DNA METHYLATION OUTSIDE OF TRADITIONAL CPG ISLAND PROMOTERS AS FUNDAMENTAL PLAYERS IN THE REGULATION OF GENE EXPRESSION. TODAY, THE SIGNIFICANCE AND TIMING OF ALTERED DNA METHYLATION WITHIN THE COMPLEX EPIGENETIC NETWORK OF CONCOMITANT EPIGENETIC MESSENGERS SUCH AS HISTONES AND MIRNAS IS AN INTENSIVE AREA OF RESEARCH. IN CLL, IT APPEARS THAT DNA METHYLATION IS A RATHER STABLE EPIGENETIC MARK OCCURRING RATHER EARLY IN THE DISEASE PATHOGENESIS. HOWEVER, OTHER CONSEQUENCES, SUCH AS HOW AND WHY ABERRANT METHYLATION MARKS OCCUR, ARE LESS EXPLORED. IN THIS REVIEW, WE WILL NOT ONLY PROVIDE A COMPREHENSIVE SUMMARY OF THE CURRENT LITERATURE WITHIN THE EPIGENETICS FIELD OF CLL, BUT ALSO HIGHLIGHT SOME OF THE NOVEL FINDINGS RELATING TO WHEN, WHERE, WHY AND HOW ALTERED DNA METHYLATION MATERIALIZES IN CLL. 2013 14 2483 21 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 15 1518 29 DNA METHYLATION AS AN EPIGENETIC MECHANISM IN THE DEVELOPMENT OF MULTIPLE SCLEROSIS. THE EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION ARE A GROUP OF THE KEY CELLULAR AND MOLECULAR PATHWAYS THAT LEAD TO INHERITED ALTERATIONS IN GENES' ACTIVITY WITHOUT CHANGING THEIR CODING SEQUENCE. DNA METHYLATION AT THE C5 POSITION OF CYTOSINE IN CPG DINUCLEOTIDES IS AMONGST THE CENTRAL EPIGENETIC MECHANISMS. CURRENTLY, THE NUMBER OF STUDIES THAT ARE DEVOTED TO THE IDENTIFICATION OF METHYLATION PATTERNS SPECIFIC TO MULTIPLE SCLEROSIS (MS), A SEVERE CHRONIC AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS ON A RAPID RISE. HOWEVER, THE ISSUE OF THE CONTRIBUTION OF DNA METHYLATION TO THE DEVELOPMENT OF THE DIFFERENT CLINICAL PHENOTYPES OF THIS HIGHLY HETEROGENEOUS DISEASE HAS ONLY BEGUN TO ATTRACT THE ATTENTION OF RESEARCHERS. THIS REVIEW SUMMARIZES THE DATA ON THE MOLECULAR MECHANISMS UNDERLYING DNA METHYLATION AND THE MS RISK FACTORS THAT CAN AFFECT THE DNA METHYLATION PROFILE AND, THEREBY, MODULATE THE EXPRESSION OF THE GENES INVOLVED IN THE DISEASE'S PATHOGENESIS. THE FOCUS OF OUR ATTENTION IS CENTERED ON THE ANALYSIS OF THE PUBLISHED DATA ON THE DIFFERENTIAL METHYLATION OF DNA FROM VARIOUS BIOLOGICAL SAMPLES OF MS PATIENTS OBTAINED USING BOTH THE CANDIDATE GENE APPROACH AND HIGH-THROUGHPUT METHODS. 2021 16 2074 32 EPIGENETIC DEREGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: CLINICAL AND BIOLOGICAL IMPACT. DEREGULATED TRANSCRIPTIONAL CONTROL CAUSED BY ABERRANT DNA METHYLATION AND/OR HISTONE MODIFICATIONS IS A HALLMARK OF CANCER CELLS. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST COMMON ADULT LEUKEMIA, THE EPIGENETIC 'LANDSCAPE' HAS ADDED A NEW LAYER OF COMPLEXITY TO OUR UNDERSTANDING OF THIS CLINICALLY AND BIOLOGICALLY HETEROGENEOUS DISEASE. EARLY STUDIES IDENTIFIED ABERRANT DNA METHYLATION, OFTEN BASED ON SINGLE GENE PROMOTER ANALYSIS WITH BOTH BIOLOGICAL AND CLINICAL IMPACT. SUBSEQUENT GENOME-WIDE PROFILING STUDIES REVEALED DIFFERENTIAL DNA METHYLATION BETWEEN CLLS AND CONTROLS AND IN PROGNOSTICS SUBGROUPS OF THE DISEASE. FROM THESE STUDIES, IT BECAME APPARENT THAT DNA METHYLATION IN REGIONS OUTSIDE OF PROMOTERS, SUCH AS ENHANCERS, IS IMPORTANT FOR THE REGULATION OF CODING GENES AS WELL AS FOR THE REGULATION OF NON-CODING RNAS. ALTHOUGH DNA METHYLATION PROFILES ARE REPORTEDLY STABLE OVER TIME AND IN RELATION TO THERAPY, A HIGHER EPIGENETIC HETEROGENEITY OR 'BURDEN' IS SEEN IN MORE AGGRESSIVE CLL SUBGROUPS, ALBEIT AS NON-RECURRENT 'PASSENGER' EVENTS. MORE RECENTLY, DNA METHYLATION PROFILES IN CLL ANALYZED IN RELATION TO DIFFERENTIATING NORMAL B-CELL POPULATIONS REVEALED THAT THE MAJORITY OF THE CLL EPIGENOME REFLECTS THE EPIGENOMES PRESENT IN THE CELL OF ORIGIN AND THAT ONLY A SMALL FRACTION OF THE EPIGENETIC ALTERATIONS REPRESENTS TRULY CLL-SPECIFIC CHANGES. FURTHERMORE, CLL PATIENTS CAN BE GROUPED INTO AT LEAST THREE CLINICALLY RELEVANT EPIGENETIC SUBGROUPS, POTENTIALLY ORIGINATING FROM DIFFERENT CELLS AT VARIOUS STAGES OF DIFFERENTIATION AND ASSOCIATED WITH DISTINCT OUTCOMES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE DNA METHYLOME IN CLL, THE ROLE OF HISTONE MODIFYING ENZYMES, HIGHLIGHT INSIGHTS DERIVED FROM ANIMAL MODELS AND ATTEMPTS MADE TO TARGET EPIGENETIC REGULATORS IN CLL ALONG WITH THE FUTURE DIRECTIONS OF THIS RAPIDLY ADVANCING FIELD. 2018 17 2494 23 EPIGENETICS AND CHRONIC LYMPHOCYTIC LEUKEMIA. THE DNA METHYLATION LEVEL IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS GENERALLY LOWER THAN HEALTHY INDIVIDUALS. ALTHOUGH DNA METHYLATION IS GLOBALLY DECREASED, REGIONAL HYPERMETHYLATION OF GENE PROMOTERS LEADS TO GENE SILENCING. MANY OF THESE GENES HAVE TUMOR SUPPRESSOR PHENOTYPES. UNLIKE MUTATIONS OR DELETIONS, HYPERMETHYLATION IS POTENTIALLY REVERSIBLE AFTER INHIBITION WITH DNA METHYLATION MODULATORS. MYELODYSPLASTIC SYNDROME HAS BEEN A MODEL DISEASE IN WHICH TREATMENT OF PATIENTS RESULTS IN DEMETHYLATION OF SPECIFIC GENES. THE STORY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS SLOWLY UNRAVELING AS EPIGENETIC MODIFICATIONS LIKELY ALSO PLAY AN IMPORTANT ROLE. ONGOING CLINICAL TRIALS CORRELATING CLINICAL RESPONSE TO GENE EXPRESSION AFTER TREATMENT WITH DNA METHYLATION INHIBITORS WILL ULTIMATELY ALLOW US TO BETTER RISK STRATIFY AND PREDICT THE SUBGROUP OF PATIENTS WHO WILL BENEFIT FROM TREATMENT WITH THIS CLASS OF DRUGS. 2006 18 3005 28 GENETIC, EPIGENETIC, AND STEROIDOGENIC MODULATION MECHANISMS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE, AFFECTING UP TO 10% OF REPRODUCTIVE-AGE WOMEN. THE EXACT CAUSE OF THE DISEASE IS UNKNOWN; HOWEVER, IT IS A HERITABLE CONDITION AFFECTED BY MULTIPLE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. PREVIOUS STUDIES REPORTED VARIATIONS IN THE EPIGENETIC PATTERNS OF NUMEROUS GENES KNOWN TO BE INVOLVED IN THE ABERRANT MODULATION OF CELL CYCLE STEROIDOGENESIS, ABNORMAL HORMONAL, IMMUNE AND INFLAMMATORY STATUS IN ENDOMETRIOSIS, APOPTOSIS, ADHESION, ANGIOGENESIS, PROLIFERATION, IMMUNE AND INFLAMMATORY PROCESSES, RESPONSE TO HYPOXIA, STEROIDOGENIC PATHWAY AND HORMONE SIGNALING ARE INVOLVED IN THE PATHOGENESIS OF ENDOMETRIOSIS. ACCUMULATING EVIDENCE SUGGEST THAT VARIOUS EPIGENETIC ABERRATIONS MAY CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. AMONG THEM, DNA METHYLTRANSFERASES, HISTONE DEACETYLATORS, AND NON-CODING MICRORNAS DEMONSTRATE DIFFERENTIAL EXPRESSION WITHIN ENDOMETRIOTIC LESIONS AND IN THE ENDOMETRIUM OF PATIENTS WITH ENDOMETRIOSIS. IT HAS BEEN INDICATED THAT THE IDENTIFICATION OF EPIGENETIC DIFFERENCES WITHIN THE DNA OR HISTONE PROTEINS MAY CONTRIBUTE TO THE DISCOVERY OF A USEFUL PROGNOSTIC BIOMARKER, WHICH COULD AID IN THE FUTURE EARLIER DETECTION, TIMELY DIAGNOSIS, AND INITIATION OF A NEW APPROACH TO THE TREATMENT OF ENDOMETRIOSIS, AS WELL AS INFORM US ABOUT THE EFFECTIVENESS OF TREATMENT AND THE STAGE OF THE DISEASE. AS THE ETIOLOGY OF ENDOMETRIOSIS IS HIGHLY COMPLEX AND STILL FAR FROM BEING FULLY ELUCIDATED, THE PRESENTED REVIEW FOCUSES ON DIFFERENT APPROACHES TO IDENTIFY THE GENETIC AND EPIGENETIC LINKS OF ENDOMETRIOSIS AND ITS PATHOGENESIS. 2020 19 6854 27 [NEW ADVANCES OF EPIGENETIC STUDY IN TUMORS OF LYMPHATIC SYSTEM---REVIEW]. EPIGENETICS IS AIMED TO STUDY THE HERITABLE CHANGES IN GENE EXPRESSION PATTERNS INDEPENDENT OF ALTERATIONS IN GENOMIC DNA SEQUENCE STRUCTURE, AND THE MECHANISMS OF TRANSLATION FROM GENOTYPE TO PHENOTYPE. IN RECENT YEARS, COMPELLING EVIDENCE GATHERED SUPPORTS A ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF LYMPHATIC SYSTEM TUMORS. FOR EXAMPLE, RECENT DATA FROM MULTIPLE LABORATORIES INDICATE THAT SEVERAL HUNDRED GENES, INVOLVING DOZENS OF CRITICAL MOLECULAR PATHWAYS, ARE EPIGENETICALLY SUPPRESSED IN ACUTE LYMPHOCYTIC LEUKEMIA; A PANEL OF METHYLATION MARKERS CAN BE USED FOR ADDITIONAL RISK STRATIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS; BASED ON THE EPIGENETIC PROFILES, THE CLASS PREDICTION MODELS IN GRAY ZONE LYMPHOMA CAN BE ESTABLISHED; THE EPIGENETIC SILENCING OF MICRORNAS IN MULTIPLE MYELOMA GENERALLY APPEARS TO HAVE INTACT P53 FUNCTION; EPIGENETIC THERAPIES HAVE BROADER IMPLICATION AND HIGH POTENTIAL FOR THE DEVELOPMENT OF IMMUNOTHERAPEUTIC STRATEGIES AND SO ON. IN THIS REVIEW, THE LATEST ADVANCES OF EPIGENETIC STUDY AND THE PROSPECT OF EPIGENETIC THERAPY FOR TUMORS IN LYMPHATIC SYSTEM ARE SUMMARIZED. 2012 20 1202 30 COULD DNA HYDROXYMETHYLATION BE CRUCIAL IN INFLUENCING STEROID HORMONE SIGNALING IN ENDOMETRIAL BIOLOGY AND ENDOMETRIOSIS? ENDOMETRIOSIS AFFECTS 10% OF REPRODUCTIVE-AGED WOMEN. IT IS CHARACTERIZED BY THE GROWTH OF THE ENDOMETRIUM, OUTSIDE THE UTERUS AND IS ASSOCIATED WITH INFERTILITY AND CHRONIC ABDOMINAL PAIN. LACK OF NONINVASIVE DIAGNOSTIC TOOLS AND EARLY SCREENING TESTS RESULTS IN DELAYED TREATMENT AND SUBSEQUENTLY INCREASED DISEASE SEVERITY. ENDOMETRIOSIS IS A DISEASE ASSOCIATED WITH A DEREGULATED HORMONAL RESPONSE, THEREFORE, UNDERSTANDING THE MOLECULAR MECHANISMS THAT GOVERN THIS HORMONAL INTERPLAY IS OF PARAMOUNT IMPORTANCE. DNA METHYLATION IS AN EPIGENETIC MARK THAT REGULATES GENE EXPRESSION AND IS OFTEN ASSOCIATED WITH GENES THAT CODE FOR STEROID RECEPTORS AND ENZYMES ASSOCIATED WITH ESTROGEN SYNTHESIS AND METABOLISM IN ENDOMETRIOSIS. DNA HYDROXYMETHYLATION, WHICH IS STRUCTURALLY SIMILAR TO METHYLATION BUT FUNCTIONALLY DIFFERENT, IS A BIOLOGICALLY CRITICAL MECHANISM THAT IS ALSO KNOWN TO REGULATE GENE EXPRESSION. TEN ELEVEN TRANSLOCATION (TET) PROTEINS MEDIATE HYDROXYMETHYLATION. HOWEVER, THE ROLE OF DNA HYDROXYMETHYLATION OR TETS IN THE ENDOMETRIUM REMAINS RELATIVELY UNEXPLORED. CURRENTLY, THE "GOLD STANDARD" TECHNIQUE USED TO STUDY METHYLATION PATTERNS IS BISULFITE GENOMIC SEQUENCING. THIS TECHNIQUE ALSO DETECTS HYDROXYMETHYLATION BUT FAILS TO DISTINGUISH BETWEEN THE TWO, THEREBY LIMITING OUR UNDERSTANDING OF THESE TWO PROCESSES. THE PRESENCE OF TETS IN THE MALE AND FEMALE REPRODUCTIVE TRACT AND ITS CONTRIBUTION TO ENDOMETRIAL CANCER MAKES IT AN IMPORTANT FACTOR TO STUDY IN ENDOMETRIOSIS. THIS REVIEW SUMMARIZES THE ROLE OF DNA METHYLATION IN ABERRANT STEROID HORMONE SIGNALING AND HYPOTHESIZES THAT HYDROXYMETHYLATION COULD BE A FACTOR INFLUENCING HORMONAL INSTABILITY SEEN IN ENDOMETRIOSIS. 2020