1 1723 106 DYSREGULATION OF C-X-C MOTIF LIGAND 10 DURING AGING AND ASSOCIATION WITH COGNITIVE PERFORMANCE. CHRONIC LOW-GRADE INFLAMMATION DURING AGING (INFLAMMAGING) IS ASSOCIATED WITH COGNITIVE DECLINE AND NEURODEGENERATION; HOWEVER, THE MECHANISMS UNDERLYING INFLAMMAGING ARE UNCLEAR. WE STUDIED A POPULATION (N = 361) OF HEALTHY YOUNG AND OLD ADULTS FROM THE MYOAGE COHORT. PERIPHERAL LEVELS OF C-X-C MOTIF CHEMOKINE LIGAND 10 (CXCL10) WAS FOUND TO BE HIGHER IN OLDER ADULTS, COMPARED WITH YOUNG, AND NEGATIVELY ASSOCIATED WITH WORKING MEMORY PERFORMANCE. THIS COINCIDED WITH AN AGE-RELATED REDUCTION IN BLOOD DNA METHYLATION AT SPECIFIC CPGS WITHIN THE CXCL10 GENE PROMOTER. IN VITRO ANALYSIS SUPPORTED THE ROLE OF DNA METHYLATION IN REGULATING CXCL10 TRANSCRIPTION. A POLYMORPHISM (RS56061981) THAT ALTERED METHYLATION AT ONE OF THESE CPG SITES FURTHER ASSOCIATED WITH WORKING MEMORY PERFORMANCE IN 2 INDEPENDENT AGING COHORTS. STUDYING PREFRONTAL CORTEX SAMPLES, WE FOUND HIGHER CXCL10 PROTEIN LEVELS IN THOSE WITH ALZHEIMER'S DISEASE, COMPARED WITH AGED CONTROLS. THESE FINDINGS SUPPORT THE ASSOCIATION OF PERIPHERAL INFLAMMATION, AS DEMONSTRATED BY CXCL10, IN AGING AND COGNITIVE DECLINE. WE REVEAL AGE-RELATED EPIGENETIC AND GENETIC FACTORS WHICH CONTRIBUTE TO THE DYSREGULATION OF CXCL10. 2018 2 2297 30 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 3 6311 33 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP. 2017 4 6083 39 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS. 2014 5 344 39 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 6 3077 26 GENOME-WIDE METHYL-SEQ ANALYSIS OF BLOOD-BRAIN TARGETS OF GLUCOCORTICOID EXPOSURE. CHRONIC EXPOSURE TO GLUCOCORTICOIDS (GCS) CAN LEAD TO PSYCHIATRIC COMPLICATIONS THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION (DNAM). WE SOUGHT TO DETERMINE WHETHER EPIGENETIC CHANGES IN A PERIPHERAL TISSUE CAN SERVE AS A SURROGATE FOR THOSE IN A RELATIVELY INACCESSIBLE TISSUE SUCH AS THE BRAIN. DNA EXTRACTED FROM THE HIPPOCAMPUS AND BLOOD OF MICE TREATED WITH GCS OR VEHICLE SOLUTION WAS ASSAYED USING A GENOME-WIDE DNAM PLATFORM (METHYL-SEQ) TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) INDUCED BY GC TREATMENT. WE OBSERVED THAT APPROXIMATELY 70% OF THE DMRS IN BOTH TISSUES LOST METHYLATION FOLLOWING GC TREATMENT. OF THE 3,095 DMRS THAT MAPPED TO THE SAME GENES IN BOTH TISSUES, 1,853 DMRS UNDERWENT DNAM CHANGES IN THE SAME DIRECTION. INTERESTINGLY, ONLY 209 DMRS (<7%) OVERLAPPED IN GENOMIC COORDINATES BETWEEN THE 2 TISSUES, SUGGESTING TISSUE-SPECIFIC DIFFERENCES IN GC-TARGETED LOCI. PATHWAY ANALYSIS SHOWED THAT THE DMR-ASSOCIATED GENES WERE MEMBERS OF PATHWAYS INVOLVED IN METABOLISM, IMMUNE FUNCTION, AND NEURODEVELOPMENT. ALSO, CHANGES IN CELL TYPE COMPOSITION OF BLOOD AND BRAIN WERE EXAMINED BY FLUORESCENCE-ACTIVATED CELL SORTING. SEPARATION OF THE CORTEX INTO NEURONAL AND NON-NEURONAL FRACTIONS AND THE LEUKOCYTES INTO T-CELLS, B-CELLS, AND NEUTROPHILS SHOWED THAT GC-INDUCED METHYLATION CHANGES PRIMARILY OCCURRED IN NEURONS AND T-CELLS, WITH THE BLOOD TISSUE ALSO UNDERGOING A SHIFT IN THE PROPORTION OF CONSTITUENT CELL TYPES WHILE THE PROPORTION OF NEURONS AND GLIA IN THE BRAIN REMAINED STABLE. FROM THE CURRENT PILOT STUDY, WE FOUND THAT DESPITE TISSUE-SPECIFIC EPIGENETIC CHANGES AND CELLULAR HETEROGENEITY, BLOOD CAN SERVE AS A SURROGATE FOR GC-INDUCED CHANGES IN THE BRAIN. 2017 7 5894 35 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 8 1503 30 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 9 1537 31 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD. 2018 10 4879 23 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 11 3914 43 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK. 2015 12 5710 37 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 13 5768 33 SPECIFIC ALTERATIONS IN THE CIRCULATING LEVELS OF THE SIRT1, TLR4, AND IL7 PROTEINS IN PATIENTS WITH DEMENTIA. SIRTUINS HAVE GAINED CONSIDERABLE ATTENTION AS EPIGENETIC REGULATORS FOR SLOWING AGING AND AGE-RELATED DISORDERS. THE GROWING ASSOCIATION BETWEEN NEURODEGENERATION AND INFLAMMATION HAS LED RESEARCHERS TO INVESTIGATE INTERACTIONS OF SIRTUINS WITH INFLAMMATORY MARKERS IN NEURODEGENERATIVE DISEASES. WE ANALYZED SIRT1'S ASSOCIATION WITH CHRONIC INFLAMMATION IN DEMENTIA AS AN AGE-RELATED NEURODEGENERATIVE CONDITION THROUGH TOLL-LIKE RECEPTOR 4 (TLR4) AND INTERLEUKIN-7 (IL7) FOR THE FIRST TIME. IN THE PRESENT STUDY, WE OBSERVED A SIGNIFICANT INCREASE IN THE LEVEL OF SIRT1 IN PATIENTS WITH ALL TYPES OF DEMENTIA. INTERESTINGLY, THE LEVEL OF TLR4 PROTEIN WAS SIGNIFICANTLY LOWER IN ONLY THE PATIENTS WITH ALZHEIMER'S DISEASE (AD) COMPARED TO THE HEALTHY ELDERLY SUBJECTS. THERE WAS NO SIGNIFICANT CHANGE IN THE LEVEL OF IL7 BETWEEN THE DISEASED AND HEALTHY ELDERLY SUBJECTS. A SIGNIFICANT POSITIVE CORRELATION BETWEEN SIRT1 LEVEL AND AGE IN HEALTHY ELDERLY SUBJECTS WAS EVIDENT ACCORDING TO PEARSON'S CORRELATION TEST. HOWEVER, THIS CORRELATION WAS NOT OBSERVED IN THE DEMENTIA PATIENTS. FURTHERMORE, THE POSITIVE CORRELATION BETWEEN THE LEVELS OF IL7 AND TLR4 IN THE HEALTHY ELDERLY SUBJECTS WAS ABSENT IN THE DEMENTIA PATIENTS. HOWEVER, THERE WAS NO DIRECT ASSOCIATION BETWEEN THE EXAMINED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND DEMENTIA AT THE MOLECULAR LEVEL. ACCORDING TO LOGISTIC REGRESSION ANALYSIS, DEMENTIA RISK INCREASES 1.16 TIMES DUE TO AN INCREASE IN THE SIRT1 LEVEL AND 24.23 TIMES DUE TO A DECREASE IN THE TLR4 LEVEL. INTERESTINGLY, A HIGH LEVEL IN THE TOTAL ANTIOXIDANT STATUS (TAS) INCREASES THE RISK OF DEMENTIA APPROXIMATELY 33.32 TIMES. THEREFORE, THE CURRENT STUDY, FOR THE FIRST TIME, PROVIDES A MUCH BETTER MOLECULAR UNDERSTANDING OF THE INTERACTION BETWEEN DECREASING TLR4 LEVELS AND INCREASING SIRT1 LEVELS IN DEMENTIA, ESPECIALLY IN AD. FURTHERMORE, IT HIGHLIGHTS THE IMPORTANCE OF EPIGENETICS IN SEVERAL AGE-RELATED DISEASES AND SUGGESTS THAT DEVELOPING NOVEL THERAPIES TO PREVENT OR SLOW DOWN THE PROGRESSION OF DEMENTIA MAY SUPPORT HEALTHY AGING. 2018 14 4255 26 METHYLOME-WIDE ANALYSIS OF CHRONIC HIV INFECTION REVEALS FIVE-YEAR INCREASE IN BIOLOGICAL AGE AND EPIGENETIC TARGETING OF HLA. HIV-INFECTED INDIVIDUALS ARE LIVING LONGER ON ANTIRETROVIRAL THERAPY, BUT MANY PATIENTS DISPLAY SIGNS THAT IN SOME WAYS RESEMBLE PREMATURE AGING. TO INVESTIGATE AND QUANTIFY THE IMPACT OF CHRONIC HIV INFECTION ON AGING, WE REPORT A GLOBAL ANALYSIS OF THE WHOLE-BLOOD DNA METHYLOMES OF 137 HIV+ INDIVIDUALS UNDER SUSTAINED THERAPY ALONG WITH 44 MATCHED HIV- INDIVIDUALS. FIRST, WE DEVELOP AND VALIDATE EPIGENETIC MODELS OF AGING THAT ARE INDEPENDENT OF BLOOD CELL COMPOSITION. USING THESE MODELS, WE FIND THAT BOTH CHRONIC AND RECENT HIV INFECTION LEAD TO AN AVERAGE AGING ADVANCEMENT OF 4.9 YEARS, INCREASING EXPECTED MORTALITY RISK BY 19%. IN ADDITION, SUSTAINED INFECTION RESULTS IN GLOBAL DEREGULATION OF THE METHYLOME ACROSS >80,000 CPGS AND SPECIFIC HYPOMETHYLATION OF THE REGION ENCODING THE HUMAN LEUKOCYTE ANTIGEN LOCUS (HLA). WE FIND THAT DECREASED HLA METHYLATION IS PREDICTIVE OF LOWER CD4 / CD8 T CELL RATIO, LINKING MOLECULAR AGING, EPIGENETIC REGULATION, AND DISEASE PROGRESSION. 2016 15 519 35 ASSOCIATIONS BETWEEN GENETIC AND EPIGENETIC VARIATIONS IN CYTOKINE GENES AND MILD PERSISTENT BREAST PAIN IN WOMEN FOLLOWING BREAST CANCER SURGERY. PERSISTENT PAIN FOLLOWING BREAST CANCER SURGERY IS A SIGNIFICANT PROBLEM. BOTH INHERITED AND ACQUIRED MECHANISMS OF INFLAMMATION APPEAR TO PLAY A ROLE IN THE DEVELOPMENT AND MAINTENANCE OF PERSISTENT PAIN. IN THIS LONGITUDINAL STUDY, GROWTH MIXTURE MODELING WAS USED TO IDENTIFY PERSISTENT BREAST PAIN PHENOTYPES BASED ON PAIN ASSESSMENTS OBTAINED PRIOR TO AND MONTHLY FOR 6MONTHS FOLLOWING BREAST CANCER SURGERY. ASSOCIATIONS BETWEEN THE "NO PAIN" AND "MILD PAIN" PHENOTYPES AND SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) SPANNING 15 CYTOKINE GENES WERE EVALUATED. THE METHYLATION STATUS OF THE CPG SITES FOUND IN THE PROMOTERS OF GENES ASSOCIATED WITH PAIN GROUP MEMBERSHIP WAS DETERMINED USING BISULFITE SEQUENCING. IN THE MULTIVARIATE ANALYSIS, THREE SNPS (I.E., INTERLEUKIN 6 (IL6) RS2069840, C-X-C MOTIF CHEMOKINE LIGAND 8 (CXCL8) RS4073, TUMOR NECROSIS FACTOR (TNF) RS1800610) AND TWO TNF CPG SITES (I.E., C.-350C, C.-344C) WERE ASSOCIATED WITH PAIN GROUP MEMBERSHIP. THESE FINDINGS SUGGEST THAT VARIATIONS IN IL6, CXCL8, AND TNF ARE ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF MILD PERSISTENT BREAST PAIN. CPG METHYLATION WITHIN THE TNF PROMOTER MAY PROVIDE AN ADDITIONAL MECHANISM THROUGH WHICH TNF ALTERS THE RISK FOR MILD PERSISTENT BREAST PAIN AFTER BREAST CANCER SURGERY. THESE GENETIC AND EPIGENETIC VARIATIONS MAY HELP TO IDENTIFY INDIVIDUALS WHO ARE PREDISPOSED TO THE DEVELOPMENT OF MILD LEVELS OF PERSISTENT BREAST PAIN FOLLOWING BREAST CANCER SURGERY. 2017 16 990 30 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 17 1909 41 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS