1 3981 148 LONG-TERM EPIGENETIC THERAPY WITH ORAL ZEBULARINE HAS MINIMAL SIDE EFFECTS AND PREVENTS INTESTINAL TUMORS IN MICE. RECENT SUCCESSES IN THE APPLICATION OF EPIGENETIC DRUGS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME HAVE RAISED QUESTIONS ON THE SAFETY OF LONG-TERM ADMINISTRATION OF DNA METHYLATION INHIBITORS. WE TREATED PREWEANED CANCER PRONE APC(MIN/+) (MIN) MICE CONTINUOUSLY WITH THE DNA METHYLATION INHIBITOR ZEBULARINE IN THEIR DRINKING WATER TO DETERMINE THE EFFECTS OF THE DRUG ON NORMAL MOUSE DEVELOPMENT AS WELL AS CANCER PREVENTION. ZEBULARINE CAUSED A TISSUE-SPECIFIC REDUCTION IN DNA METHYLATION AT B1 SHORT INTERSPERSED NUCLEOTIDE ELEMENTS IN THE SMALL AND LARGE INTESTINES OF FEMALE MIN MICE BUT NOT IN OTHER ORGANS EXAMINED AFTER CHRONIC ORAL TREATMENT. NO SIGNIFICANT DIFFERENCE IN THE AVERAGE WEIGHTS OF MICE WAS OBSERVED DURING THE TREATMENT. IN ADDITION, ANALYSIS OF GLOBAL GENE EXPRESSION OF COLONIC EPITHELIAL CELLS FROM THE FEMALES INDICATED THAT ONLY 3% TO 6% OF THE GENES WERE AFFECTED IN THEIR EXPRESSION. WE DID NOT DETECT TOXICITY AND ABNORMALITIES FROM THE HISTOPATHOLOGIC ANALYSIS OF LIVER AND INTESTINAL TISSUES. LASTLY, WE TESTED WHETHER PREVENTION OF TUMORIGENESIS CAN BE ACHIEVED WITH CHRONIC ORAL ADMINISTRATION OF ZEBULARINE IN MIN MICE. THE AVERAGE NUMBER OF POLYPS IN MIN FEMALES DECREASED FROM 58 TO 1, WHEREAS THE AVERAGE POLYP NUMBER REMAINED UNAFFECTED IN MIN MALES POSSIBLY DUE TO DIFFERENTIAL ACTIVITY OF ALDEHYDE OXIDASE. TAKEN TOGETHER, OUR RESULTS SHOW FOR THE FIRST TIME THAT LONG-TERM ORAL ADMINISTRATION OF ZEBULARINE CAUSES A GENDER-SPECIFIC ABROGATION OF INTESTINAL TUMORS WHILE CAUSING A TISSUE-SPECIFIC DNA DEMETHYLATION. IMPORTANTLY, PROLONGED TREATMENT OF MICE WITH EPIGENETIC DRUGS RESULTED IN ONLY MINOR DEVELOPMENTAL AND HISTOLOGIC CHANGES. 2008 2 3791 36 INTERLEUKIN 6 SUPPORTS THE MAINTENANCE OF P53 TUMOR SUPPRESSOR GENE PROMOTER METHYLATION. A STRONG ASSOCIATION EXISTS BETWEEN STATES OF CHRONIC INFLAMMATION AND CANCER, AND IT IS BELIEVED THAT MEDIATORS OF INFLAMMATION MAY BE RESPONSIBLE FOR THIS PHENOMENON. INTERLEUKIN 6 (IL-6) IS AN INFLAMMATORY CYTOKINE KNOWN TO PLAY A ROLE IN THE GROWTH AND SURVIVAL OF MANY TYPES OF TUMORS, YET THE MECHANISMS EMPLOYED BY THIS PLEOMORPHIC CYTOKINE TO ACCOMPLISH THIS FEAT ARE STILL POORLY UNDERSTOOD. ANOTHER IMPORTANT FACTOR IN TUMOR DEVELOPMENT SEEMS TO BE THE HYPERMETHYLATION OF CPG ISLANDS LOCATED WITHIN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. THIS COMMON EPIGENETIC ALTERATION ENABLES TUMOR CELLS TO REDUCE OR INACTIVATE THE EXPRESSION OF IMPORTANT TUMOR SUPPRESSOR AND CELL CYCLE REGULATORY GENES. HERE WE SHOW THAT IN THE IL-6-RESPONSIVE HUMAN MULTIPLE MYELOMA CELL LINE KAS 6/1, THE PROMOTER REGION OF P53 IS EPIGENETICALLY MODIFIED BY METHYLTRANSFERASES, RESULTING IN DECREASED LEVELS OF EXPRESSION. FURTHERMORE, CELLS TREATED WITH IL-6 EXHIBIT AN INCREASE IN THE EXPRESSION OF THE DNA MAINTENANCE METHYLATION ENZYME, DNMT-1. THE DNA METHYLTRANSFERASE INHIBITOR ZEBULARINE REVERSES THE METHYLATION OF THE P53 PROMOTER, ALLOWING THE RESUMPTION OF ITS EXPRESSION. HOWEVER, WHEN ZEBULARINE IS WITHDRAWN FROM THE CELLS, THE REESTABLISHMENT OF THE ORIGINAL CPG ISLAND METHYLATION WITHIN THE P53 PROMOTER DOES NOT OCCUR IN THE ABSENCE OF IL-6, AND CELLS WHICH DO NOT RECEIVE IL-6 EVENTUALLY DIE, AS P53 EXPRESSION CONTINUES UNCHECKED BY REMETHYLATION. INTERESTINGLY, THIS LOSS OF VIABILITY SEEMS TO INVOLVE NOT THE WITHDRAWAL OF CYTOKINE, BUT THE INABILITY OF THE CELL TO RESILENCE THE PROMOTER. CONSISTENT WITH THIS MODEL, WHEN CELLS THAT EXPRESS IL-6 IN AN AUTOCRINE FASHION ARE SUBJECTED TO IDENTICAL TREATMENT, P53 EXPRESSION IS REDUCED SHORTLY AFTER WITHDRAWAL OF ZEBULARINE. THEREFORE, IT SEEMS IL-6 IS CAPABLE OF MAINTAINING PROMOTER METHYLATION THUS REPRESENTING ONE OF THE POSSIBLE MECHANISMS USED BY INFLAMMATORY MEDIATORS IN THE GROWTH AND SURVIVAL OF TUMORS. 2005 3 2297 32 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 4 3726 41 INHIBITION OF HISTONE METHYLTRANSFERASE EZH2 SUPPRESSES ENDOMETRIOTIC VESICLE DEVELOPMENT IN A RAT MODEL OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A PAINFUL GYNECOLOGICAL DISEASE WITH NO CURE AND LIMITED THERAPEUTIC OPTIONS. IT HAS BEEN HYPOTHESIZED THAT EPIGENETIC DRUGS CAN BE USED AS A NONHORMONAL TREATMENT FOR ENDOMETRIOSIS. THIS STUDY WAS CONDUCTED TO STUDY THE EFFICACY OF AN INHIBITOR OF THE HISTONE METHYLTRANSFERASE EZH2 USING AN ESTABLISHED RAT MODEL OF ENDOMETRIOSIS. WE HYPOTHESIZED THAT TREATMENT WILL BLOCK OR REDUCE THE NUMBER OF ENDOMETRIOTIC VESICLES IN THIS MODEL. WE CONDUCTED A PRECLINICAL DRUG STUDY IN FEMALE RATS WITH EXPERIMENTAL ENDOMETRIOSIS (UTERINE TISSUE TRANSPLANTED NEXT TO THE INTESTINAL MESENTERY) OR CONTROL SHAM (SUTURES ONLY). RATS WITH ENDOMETRIOSIS OR SHAM SURGERY RECEIVED EITHER TREATMENT WITH EZH2 INHIBITOR (5 MG/KG OR 10 MG/KG) OR VEHICLE (0.1%, 67% DMSO) EVERY OTHER DAY DURING 4 WEEKS. AFTER TREATMENT COMPLETION, THE NUMBER, AREA, VOLUME, AND WEIGHT OF VESICLES WERE EVALUATED. RT [2] PROFILER ARRAYS FOR NEUROPATHIC AND INFLAMMATION, EPITHELIAL TO MESENCHYMAL TRANSITION, INFLAMMATORY RESPONSE, AND AUTOIMMUNITY PATHWAYS WERE USED TO EXAMINE GENE EXPRESSION CHANGES IN THE VESICLES THAT DEVELOPED. TREATMENT WITH EZH2 INHIBITOR (10 MG/KG) SUPPRESSED THE DEVELOPMENT OF VESICLES, BY SIGNIFICANTLY DECREASING THE TOTAL VESICLE NUMBER, AREA, VOLUME, AND WEIGHT. IN ADDITION, EZH2 INHIBITION SIGNIFICANTLY INCREASED THE EXPRESSION OF CACNA1B AND FKBP1A GENES, INVOLVED IN PAIN AND PROLIFERATION, RESPECTIVELY. EZH2 INHIBITION SUPPRESSES THE GROWTH OF VESICLES WITHOUT APPARENT DETRIMENTAL EFFECTS TO OTHER ORGANS. TREATMENT WITH THIS EPIGENETIC INHIBITOR LEADS TO UPREGULATION OF A LIMITED NUMBER OF GENES RELATED TO ENDOMETRIOSIS-RELEVANT PATHWAYS. IN CONCLUSION, THESE DATA SUPPORT FOLLOW-UP STUDIES TO EVALUATE ITS POTENTIAL AS A THERAPEUTIC APPROACH FOR ENDOMETRIOSIS. 2020 5 2683 42 EVALUATION OF THE IMPACT OF S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASE INHIBITOR, 3-DEAZANEPLANOCIN A, ON TISSUE INJURY AND COGNITIVE FUNCTION IN MICE. CANCER PATIENTS DISPLAY COGNITIVE IMPAIRMENT DUE, AT LEAST PARTLY, TO THE TREATMENTS. ADDITIONALLY, CHEMOTHERAPEUTIC TREATMENTS CAN LEAD TO ORGAN INJURY, LIMITING THEIR USE, AND ARE LIKELY TO HAVE NEGATIVE IMPACTS ON PATIENTS' QUALITY OF LIFE. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE TOXICITY OF 3-DEAZANEPLANOCIN A (DZNEP) ON SEVERAL TISSUES AND ORGANS, AS WELL AS ON COGNITIVE FUNCTIONS. DZNEP IS AN INHIBITOR OF S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASE (IN PARTICULAR OF THE HISTONE METHYLTRANSFERASE EZH2) WHICH SHOWED ANTITUMORAL FUNCTIONS IN PRECLINICAL TRIALS BUT WHOSE EFFECTS ON BEHAVIOR AND ON ORGANS (SIDE EFFECTS) ARE NOT KNOWN. CHRONIC INJECTIONS OF DZNEP WERE PERFORMED INTRAPERITONEALLY IN MALE NMRI MICE (2 MG/KG; I.P.; THREE TIMES PER WEEK) DURING 8 WEEKS. A FOLLOW-UP OF BODY WEIGHT WAS ASSESSED DURING ALL EXPERIMENTS. HISTOLOGICAL ANALYSIS WERE PERFORMED ON SEVERAL ORGANS. EZH2 EXPRESSION AND H3K27ME3 WERE ASSAYED BY WESTERN-BLOT. SEVERAL BEHAVIORAL TESTS WERE PERFORMED DURING TREATMENT AND 2 WEEKS AFTER. A PARTICULAR FOCUS WAS MADE ON SPONTANEOUS LOCOMOTOR ACTIVITY, COGNITIVE FUNCTIONS (SPONTANEOUS ALTERNATION AND RECOGNITION MEMORY), AND ANXIETY- AND DEPRESSION-RELATED BEHAVIOR. HEMATOLOGICAL MODIFICATIONS WERE ALSO ASSESSED. CHRONIC DZNEP TREATMENT TRANSIENTLY REDUCED ANIMAL GROWTH. IT HAD NO EFFECT ON MOST ORGANS BUT PROVOKED A REVERSIBLE SPLENOMEGALY, AND PERSISTENT TESTIS REDUCTION AND ERYTHROPOIESIS. DZNEP ADMINISTRATION DID NOT ALTER ANIMAL BEHAVIOR. IN CONCLUSION, THIS STUDY IS ENCOURAGING FOR THE USE OF DZNEP FOR CANCER TREATMENT. INDEED, IT HAS NO EFFECT ON ANIMAL BEHAVIOR, CONFERRING AN ADVANTAGEOUS SAFETY, AND INDUCES IRREVERSIBLE SIDE EFFECTS LIMITED ON TESTIS WHICH ARE UNFORTUNATELY FOUND IN MOST CHEMOTHERAPY TREATMENTS. 2018 6 4224 44 METHYLATION CHANGES IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE EXPOSED TO ACUTE AND CHRONIC LOW-DOSE X-RAY-IRRADIATION. THE BIOLOGICAL AND GENETIC EFFECTS OF CHRONIC LOW-DOSE RADIATION (LDR) EXPOSURE AND ITS RELATIONSHIP TO CARCINOGENESIS HAVE RECEIVED A LOT OF ATTENTION IN THE RECENT YEARS. FOR EXAMPLE, RADIATION-INDUCED GENOME INSTABILITY, WHICH IS THOUGHT TO BE A PRECURSOR OF TUMOROGENESIS, WAS SHOWN TO HAVE A TRANSGENERATIONAL NATURE. THIS INDICATES A POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LDR-INDUCED GENOME INSTABILITY. GENOMIC DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MECHANISMS. EXISTING DATA ON RADIATION EFFECTS ON DNA METHYLATION PATTERNS IS LIMITED, AND NO ONE HAS SPECIFICALLY STUDIED THE EFFECTS OF THE LDR. WE REPORT THE FIRST STUDY OF THE EFFECTS OF WHOLE-BODY LDR EXPOSURE ON GLOBAL GENOME METHYLATION IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE. IN PARALLEL, WE EVALUATED CHANGES IN PROMOTER METHYLATION AND EXPRESSION OF THE TUMOR SUPPRESSOR GENE P16(INKA) AND DNA REPAIR GENE O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT). WE OBSERVED DIFFERENT PATTERNS OF RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION IN THE LIVER AND MUSCLE OF EXPOSED MALES AND FEMALES. WE ALSO FOUND SEX AND TISSUE-SPECIFIC DIFFERENCES IN P16(INKA) PROMOTER METHYLATION UPON LDR EXPOSURE. IN MALE LIVER TISSUE, P16(INKA) PROMOTER METHYLATION WAS MORE PRONOUNCED THAN IN FEMALE TISSUE. IN CONTRAST, NO SIGNIFICANT RADIATION-INDUCED CHANGES IN P16(INKA) PROMOTER METHYLATION WERE NOTED IN THE MUSCLE TISSUE OF EXPOSED MALES AND FEMALES. RADIATION ALSO DID NOT SIGNIFICANTLY AFFECT METHYLATION STATUS OF MGMT PROMOTER. WE ALSO OBSERVED SUBSTANTIAL SEX DIFFERENCES IN ACUTE AND CHRONIC RADIATION-INDUCED EXPRESSION OF P16(INKA) AND MGMT GENES. ANOTHER IMPORTANT OUTCOME OF OUR STUDY WAS THE FACT THAT CHRONIC LOW-DOSE RADIATION EXPOSURE PROVED TO BE A MORE POTENT INDUCER OF EPIGENETIC EFFECTS THAN THE ACUTE EXPOSURE. THIS SUPPORTS PREVIOUS FINDINGS THAT CHRONIC EXPOSURE LEADS TO GREATER GENOME DESTABILIZATION THAN ACUTE EXPOSURE. 2004 7 4604 30 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 8 5067 26 PHYSICAL ACTIVITY AND DNA METHYLATION IN HUMANS. PHYSICAL ACTIVITY IS A STRONG STIMULUS INFLUENCING THE OVERALL PHYSIOLOGY OF THE HUMAN BODY. EXERCISES LEAD TO BIOCHEMICAL CHANGES IN VARIOUS TISSUES AND EXERT AN IMPACT ON GENE EXPRESSION. EXERCISE-INDUCED CHANGES IN GENE EXPRESSION MAY BE MEDIATED BY EPIGENETIC MODIFICATIONS, WHICH REARRANGE THE CHROMATIN STRUCTURE AND THEREFORE MODULATE ITS ACCESSIBILITY FOR TRANSCRIPTION FACTORS. ONE OF SUCH EPIGENETIC MARK IS DNA METHYLATION THAT INVOLVES AN ATTACHMENT OF A METHYL GROUP TO THE FIFTH CARBON OF CYTOSINE RESIDUE PRESENT IN CG DINUCLEOTIDES (CPG). DNA METHYLATION IS CATALYZED BY A FAMILY OF DNA METHYLTRANSFERASES. THIS REVERSIBLE DNA MODIFICATION RESULTS IN THE RECRUITMENT OF PROTEINS CONTAINING METHYL BINDING DOMAIN AND FURTHER TRANSCRIPTIONAL CO-REPRESSORS LEADING TO THE SILENCING OF GENE EXPRESSION. THE ACCUMULATION OF CPG DINUCLEOTIDES, REFERRED AS CPG ISLANDS, OCCURS AT THE PROMOTER REGIONS IN A GREAT MAJORITY OF HUMAN GENES. THEREFORE, CHANGES IN DNA METHYLATION PROFILE AFFECT THE TRANSCRIPTION OF MULTIPLE GENES. A GROWING BODY OF EVIDENCE INDICATES THAT EXERCISE TRAINING MODULATES DNA METHYLATION IN MUSCLES AND ADIPOSE TISSUE. SOME OF THESE EPIGENETIC MARKERS WERE ASSOCIATED WITH A REDUCED RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE INFLUENCE OF PHYSICAL ACTIVITY ON THE DNA METHYLATION STATUS IN HUMANS. 2021 9 1967 31 EPIGENETIC ALTERATION OF THE DOPAMINE TRANSPORTER GENE IN ALCOHOL-DEPENDENT PATIENTS IS ASSOCIATED WITH AGE. CHRONIC ALCOHOL ABUSE AND DEPENDENCE ARE ASSOCIATED WITH DYSFUNCTIONAL DOPAMINERGIC NEUROTRANSMISSION IN MESOCORTICOLIMBIC CIRCUITS. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN SHOWN TO MODULATE SUSCEPTIBILITY TO ALCOHOL DEPENDENCE, AND BOTH MAY ACT THROUGH EPIGENETIC MECHANISMS THAT CAN MODULATE GENE EXPRESSION, E.G. DNA METHYLATION AT CPG SITES. RECENT STUDIES HAVE SUGGESTED THAT DNA METHYLATION PATTERNS MAY CHANGE OVER TIME. HOWEVER, FEW DATA ARE AVAILABLE CONCERNING THE RATE OF THESE CHANGES IN SPECIFIC GENES. A RECENT STUDY FOUND THAT HYPERMETHYLATION OF THE PROMOTER OF THE DOPAMINE TRANSPORTER (DAT) GENE WAS POSITIVELY CORRELATED WITH ALCOHOL DEPENDENCE AND NEGATIVELY CORRELATED WITH ALCOHOL CRAVING. THE AIM OF THE PRESENT STUDY WAS TO REPLICATE THESE FINDINGS IN A LARGER SAMPLE OF ALCOHOL-DEPENDENT PATIENTS AND POPULATION-BASED CONTROLS MATCHED FOR AGE AND SEX. NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BETWEEN PATIENTS AND CONTROLS, AND NO DIFFERENCE IN METHYLATION LEVEL WAS OBSERVED BEFORE AND AFTER ALCOHOL WITHDRAWAL IN PATIENTS. HOWEVER, PATIENTS WITH MORE SEVERE CRAVING SHOWED A TREND TOWARDS LOWER DAT METHYLATION LEVELS (P = 0.07), WHICH IS CONSISTENT WITH PREVIOUS FINDINGS. FURTHERMORE, IN OUR OVERALL SAMPLE, DAT METHYLATION LEVELS INCREASED WITH AGE. INTERESTINGLY, A SEPARATE ANALYSIS OF PATIENTS SUGGESTED THAT THIS FINDING WAS MAINLY DRIVEN BY THE PATIENT GROUP. ALTHOUGH THE PRESENT DATA DO NOT CLARIFY WHETHER CHRONIC ALCOHOL ABUSE IS RESPONSIBLE FOR THIS PHENOMENON OR MERELY ENHANCES AN AGEING-SPECIFIC PROCESS, OUR FINDINGS SUGGEST THAT HYPERMETHYLATION IN ALCOHOL-DEPENDENT PATIENTS IS A CONSEQUENCE, RATHER THAN A CAUSE, OF THE DISORDER. 2014 10 904 40 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE. 2021 11 1655 25 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 12 990 33 CHRONIC SOCIAL STRESS INDUCES DNA METHYLATION CHANGES AT AN EVOLUTIONARY CONSERVED INTERGENIC REGION IN CHROMOSOME X. CHRONIC STRESS RESULTING FROM PROLONGED EXPOSURE TO NEGATIVE LIFE EVENTS INCREASES THE RISK OF MOOD AND ANXIETY DISORDERS. ALTHOUGH CHRONIC STRESS CAN CHANGE GENE EXPRESSION RELEVANT FOR BEHAVIOR, MOLECULAR REGULATORS OF THIS CHANGE HAVE NOT BEEN FULLY DETERMINED. ONE PROCESS THAT COULD PLAY A ROLE IS DNA METHYLATION, AN EPIGENETIC PROCESS WHEREBY A METHYL GROUP IS ADDED ONTO NUCLEOTIDES, PREDOMINANTLY CYTOSINE IN THE CPG CONTEXT, AND WHICH CAN BE INDUCED BY CHRONIC STRESS. IT IS UNKNOWN TO WHAT EXTENT CHRONIC SOCIAL DEFEAT, A MODEL OF HUMAN SOCIAL STRESS, INFLUENCES DNA METHYLATION PATTERNS ACROSS THE GENOME. OUR STUDY ADDRESSED THIS QUESTION BY USING A TARGETED-CAPTURE APPROACH CALLED METHYL-SEQ TO INVESTIGATE DNA METHYLATION PATTERNS OF THE DENTATE GYRUS AT PUTATIVE REGULATORY REGIONS ACROSS THE MOUSE GENOME FROM MICE EXPOSED TO 14 DAYS OF SOCIAL DEFEAT. FINDINGS WERE REPLICATED IN INDEPENDENT COHORTS BY BISULFITE-PYROSEQUENCING. TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE IDENTIFIED. ONE DMR WAS LOCATED AT INTRON 9 OF DROSHA, AND IT SHOWED REDUCED METHYLATION IN STRESSED MICE. THIS OBSERVATION REPLICATED IN ONE OF TWO INDEPENDENT COHORTS. A SECOND DMR WAS IDENTIFIED AT AN INTERGENIC REGION OF CHROMOSOME X, AND METHYLATION IN THIS REGION WAS INCREASED IN STRESSED MICE. THIS METHYLATION DIFFERENCE REPLICATED IN TWO INDEPENDENT COHORTS AND IN MAJOR DEPRESSIVE DISORDER (MDD) POSTMORTEM BRAINS. THESE RESULTS HIGHLIGHT A REGION NOT PREVIOUSLY KNOWN TO BE DIFFERENTIALLY METHYLATED BY CHRONIC SOCIAL DEFEAT STRESS AND WHICH MAY BE INVOLVED IN MDD. 2018 13 4093 36 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 14 3795 32 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 15 1815 31 EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN ON EPIGENETIC REGULATORY GENES EXPRESSION AND EPIGENETIC CODE IN HUMAN PROSTATE EPITHELIAL CELLS. CHRONIC EXPOSURES TO ARSENIC AND ESTROGEN ARE KNOWN RISK FACTORS FOR PROSTATE CANCER. THOUGH THE EVIDENCE SUGGESTS THAT EXPOSURE TO ARSENIC OR ESTROGENS CAN DISRUPT NORMAL DNA METHYLATION PATTERNS AND HISTONE MODIFICATIONS, THE MECHANISMS BY WHICH THESE CHEMICALS INDUCE EPIGENETIC CHANGES ARE NOT FULLY UNDERSTOOD. MOREOVER, THE EPIGENETIC EFFECTS OF CO-EXPOSURE TO THESE TWO CHEMICALS ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN, BOTH ALONE AND IN COMBINATION, ON THE EXPRESSION OF EPIGENETIC REGULATORY GENES, THEIR CONSEQUENCES ON DNA METHYLATION, AND HISTONE MODIFICATIONS. HUMAN PROSTATE EPITHELIAL CELLS, RWPE-1, CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION WERE USED FOR ANALYSIS OF EPIGENETIC REGULATORY GENES EXPRESSION, GLOBAL DNA METHYLATION CHANGES, AND HISTONE MODIFICATIONS AT PROTEIN LEVEL. THE RESULT OF THIS STUDY REVEALED THAT EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION ALTERS THE EXPRESSION OF EPIGENETIC REGULATORY GENES AND CHANGES GLOBAL DNA METHYLATION AND HISTONE MODIFICATION PATTERNS IN RWPE-1 CELLS. THESE CHANGES WERE SIGNIFICANTLY GREATER IN ARSENIC AND ESTROGEN COMBINATION TREATED GROUP THAN INDIVIDUALLY TREATED GROUP. THE FINDINGS OF THIS STUDY WILL HELP EXPLAIN THE EPIGENETIC MECHANISM OF ARSENIC- AND/OR ESTROGEN-INDUCED PROSTATE CARCINOGENESIS. 2012 16 1503 33 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 17 344 32 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY. 2020 18 2494 28 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 19 4879 22 OVERLAPPING SIGNATURES OF CHRONIC PAIN IN THE DNA METHYLATION LANDSCAPE OF PREFRONTAL CORTEX AND PERIPHERAL T CELLS. WE TESTED THE HYPOTHESIS THAT EPIGENETIC MECHANISMS IN THE BRAIN AND THE IMMUNE SYSTEM ARE ASSOCIATED WITH CHRONIC PAIN. GENOME-WIDE DNA METHYLATION ASSESSED IN 9 MONTHS POST NERVE-INJURY (SNI) AND SHAM RATS, IN THE PREFRONTAL CORTEX (PFC) AS WELL AS IN T CELLS REVEALED A VAST DIFFERENCE IN THE DNA METHYLATION LANDSCAPE IN THE BRAIN BETWEEN THE GROUPS AND A REMARKABLE OVERLAP (72%) BETWEEN DIFFERENTIALLY METHYLATED PROBES IN T CELLS AND PREFRONTAL CORTEX. DNA METHYLATION STATES IN THE PFC SHOWED ROBUST CORRELATION WITH PAIN SCORE OF ANIMALS IN SEVERAL GENES INVOLVED IN PAIN. FINALLY, ONLY 11 DIFFERENTIALLY METHYLATED PROBES IN T CELLS WERE SUFFICIENT TO DISTINGUISH SNI OR SHAM INDIVIDUAL RATS. THIS STUDY SUPPORTS THE PLAUSIBILITY OF DNA METHYLATION INVOLVEMENT IN CHRONIC PAIN AND DEMONSTRATES THE POTENTIAL FEASIBILITY OF DNA METHYLATION MARKERS IN T CELLS AS NONINVASIVE BIOMARKERS OF CHRONIC PAIN SUSCEPTIBILITY. 2016 20 476 39 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019