1 2130 81 EPIGENETIC INACTIVATION OF THE AUTOPHAGY-LYSOSOMAL SYSTEM IN APPENDIX IN PARKINSON'S DISEASE. THE GASTROINTESTINAL TRACT MAY BE A SITE OF ORIGIN FOR ALPHA-SYNUCLEIN PATHOLOGY IN IDIOPATHIC PARKINSON'S DISEASE (PD). DISRUPTION OF THE AUTOPHAGY-LYSOSOME PATHWAY (ALP) MAY CONTRIBUTE TO ALPHA-SYNUCLEIN AGGREGATION. HERE WE EXAMINED EPIGENETIC ALTERATIONS IN THE ALP IN THE APPENDIX BY DEEP SEQUENCING DNA METHYLATION AT 521 ALP GENES. WE IDENTIFIED ABERRANT METHYLATION AT 928 CYTOSINES AFFECTING 326 ALP GENES IN THE APPENDIX OF INDIVIDUALS WITH PD AND WIDESPREAD HYPERMETHYLATION THAT IS ALSO SEEN IN THE BRAIN OF INDIVIDUALS WITH PD. IN MICE, WE FIND THAT DNA METHYLATION CHANGES AT ALP GENES INDUCED BY CHRONIC GUT INFLAMMATION ARE GREATLY EXACERBATED BY ALPHA-SYNUCLEIN PATHOLOGY. DNA METHYLATION CHANGES AT ALP GENES INDUCED BY SYNUCLEINOPATHY ARE ASSOCIATED WITH THE ALP ABNORMALITIES OBSERVED IN THE APPENDIX OF INDIVIDUALS WITH PD SPECIFICALLY INVOLVING LYSOSOMAL GENES. OUR WORK IDENTIFIES EPIGENETIC DYSREGULATION OF THE ALP WHICH MAY SUGGEST A POTENTIAL MECHANISM FOR ACCUMULATION OF ALPHA-SYNUCLEIN PATHOLOGY IN IDIOPATHIC PD. 2021 2 330 28 ALPHA-SYNUCLEIN AND MECHANISMS OF EPIGENETIC REGULATION. SYNUCLEINOPATHIES ARE A GROUP OF NEURODEGENERATIVE DISEASES WITH COMMON PATHOLOGICAL LESIONS ASSOCIATED WITH THE EXCESSIVE ACCUMULATION AND ABNORMAL INTRACELLULAR DEPOSITION OF TOXIC SPECIES OF ALPHA-SYNUCLEIN. THE SHARED CLINICAL FEATURES ARE CHRONIC PROGRESSIVE DECLINE OF MOTOR, COGNITIVE, AND BEHAVIORAL FUNCTIONS. THESE DISORDERS INCLUDE PARKINSON'S DISEASE, DEMENTIA WITH LEWY BODY, AND MULTIPLE SYSTEM ATROPHY. VIGOROUS RESEARCH IN THE MECHANISMS OF PATHOLOGY OF THESE ILLNESSES IS CURRENTLY UNDER WAY TO FIND DISEASE-MODIFYING TREATMENT AND MOLECULAR MARKERS FOR EARLY DIAGNOSIS. ALPHA-SYNUCLEIN IS A PRONE-TO-AGGREGATE, SMALL AMYLOIDOGENIC PROTEIN WITH MULTIPLE ROLES IN SYNAPTIC VESICLE TRAFFICKING, NEUROTRANSMITTER RELEASE, AND INTRACELLULAR SIGNALING EVENTS. ITS EXPRESSION IS CONTROLLED BY SEVERAL MECHANISMS, ONE OF WHICH IS EPIGENETIC REGULATION. WHEN TRANSMITTED TO THE NUCLEUS, ALPHA-SYNUCLEIN BINDS TO DNA AND HISTONES AND PARTICIPATES IN EPIGENETIC REGULATORY FUNCTIONS CONTROLLING SPECIFIC GENE TRANSCRIPTION. HERE, WE DISCUSS THE VARIOUS ASPECTS OF ALPHA-SYNUCLEIN INVOLVEMENT IN EPIGENETIC REGULATION IN HEALTH AND DISEASES. 2023 3 3137 30 GLOBAL DNA METHYLATION PROFILING OF MANGANESE-EXPOSED HUMAN NEUROBLASTOMA SH-SY5Y CELLS REVEALS EPIGENETIC ALTERATIONS IN PARKINSON'S DISEASE-ASSOCIATED GENES. MANGANESE (MN) IS AN ESSENTIAL TRACE ELEMENT REQUIRED FOR OPTIMAL FUNCTIONING OF CELLULAR BIOCHEMICAL PATHWAYS IN THE CENTRAL NERVOUS SYSTEM. ELEVATED EXPOSURE TO MN THROUGH ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE CAN CAUSE NEUROTOXIC EFFECTS RESULTING IN MANGANISM, A CONDITION WITH CLINICAL SYMPTOMS IDENTICAL TO IDIOPATHIC PARKINSON'S DISEASE. EPIGENETICS IS NOW RECOGNIZED AS A BIOLOGICAL MECHANISM INVOLVED IN THE ETIOLOGY OF VARIOUS DISEASES. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION ALTERATIONS INDUCED BY CHRONIC MN (100 MICROM) EXPOSURE IN HUMAN NEUROBLASTOMA (SH-SY5Y) CELLS IN RELEVANCE TO PARKINSON'S DISEASE. A COMBINED ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA FOR PARKINSON'S DISEASE-ASSOCIATED GENES WAS CARRIED OUT. WHOLE-GENOME BISULFITE CONVERSION AND SEQUENCING INDICATE EPIGENETIC PERTURBATION OF KEY GENES INVOLVED IN BIOLOGICAL PROCESSES ASSOCIATED WITH NEURONAL CELL HEALTH. INTEGRATION OF DNA METHYLATION DATA WITH GENE EXPRESSION REVEALS EPIGENETIC ALTERATIONS TO PINK1, PARK2 AND TH GENES THAT PLAY CRITICAL ROLES IN THE ONSET OF PARKINSONISM. THE PRESENT STUDY SUGGESTS THAT MN-INDUCED ALTERATION OF DNA METHYLATION OF PINK1-PARK2 MAY INFLUENCE MITOCHONDRIAL FUNCTION AND PROMOTE PARKINSONISM. OUR FINDINGS PROVIDE A BASIS TO FURTHER EXPLORE AND VALIDATE THE EPIGENETIC BASIS OF MN-INDUCED NEUROTOXICITY . 2017 4 3 30 "EPIGENOME-WIDE METHYLATION PROFILE OF CHRONIC KIDNEY DISEASE-DERIVED ARTERIAL DNA UNCOVERS NOVEL PATHWAYS IN DISEASE-ASSOCIATED CARDIOVASCULAR PATHOLOGY.". CHRONIC KIDNEY DISEASE (CKD) RELATED CARDIOVASCULAR DISEASE (CVD) IS CHARACTERIZED BY VASCULAR REMODELLING WITH WELL-ESTABLISHED STRUCTURAL AND FUNCTIONAL CHANGES IN THE VASCULAR WALL SUCH AS ARTERIAL STIFFNESS, MATRIX DEPOSITION, AND CALCIFICATION. THESE PHENOTYPIC CHANGES RESEMBLE PATHOLOGY SEEN IN AGEING, AND ARE LIKELY TO BE MEDIATED BY SUSTAINED ALTERATIONS IN GENE EXPRESSION, WHICH MAY BE CAUSED BY EPIGENETIC CHANGES SUCH AS TISSUE-SPECIFIC DNA METHYLATION. WE AIMED TO INVESTIGATE TISSUE SPECIFIC CHANGES IN DNA METHYLATION THAT OCCUR IN CKD-RELATED CVD. GENOME-WIDE DNA METHYLATION CHANGES WERE EXAMINED IN BISULPHITE CONVERTED GENOMIC DNA ISOLATED FROM THE VASCULAR MEDIA OF CKD AND HEALTHY ARTERIES. METHYLATION-SPECIFIC PCR WAS USED TO VALIDATE THE ARRAY DATA, AND THE ASSOCIATION BETWEEN DNA METHYLATION AND GENE AND PROTEIN EXPRESSION WAS EXAMINED. THE DNA METHYLATION AGE WAS COMPARED TO THE CHRONOLOGICAL AGE IN BOTH CASES AND CONTROLS. THREE HUNDRED AND NINETEEN DIFFERENTIALLY METHYLATED REGIONS (DMR) WERE IDENTIFIED SPREAD ACROSS THE GENOME. PATHWAY ANALYSIS REVEALED THAT DMRS ASSOCIATED WITH GENES WERE INVOLVED IN EMBRYONIC AND VASCULAR DEVELOPMENT, AND SIGNALLING PATHWAYS SUCH AS TGFBETA AND FGF. EXPRESSION OF TOP DIFFERENTIALLY METHYLATED GENE HOXA5 SHOWED A SIGNIFICANT NEGATIVE CORRELATION WITH DNA METHYLATION. INTERESTINGLY, DNA METHYLATION AGE AND CHRONOLOGICAL AGE WERE HIGHLY CORRELATED, BUT THERE WAS NO EVIDENCE OF ACCELERATED AGE-RELATED DNA METHYLATION IN THE ARTERIES OF CKD PATIENTS. IN CONCLUSION, WE DEMONSTRATED THAT DIFFERENTIAL DNA METHYLATION IN THE ARTERIAL TISSUE OF CKD PATIENTS REPRESENTS A POTENTIAL MEDIATOR OF ARTERIAL PATHOLOGY AND MAY BE USED TO UNCOVER NOVEL PATHWAYS IN THE GENESIS OF CKD-ASSOCIATED COMPLICATIONS. 2021 5 2483 29 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 6 665 26 BLOOD TRANSCRIPTOMICS OF DRUG-NAIVE SPORADIC PARKINSON'S DISEASE PATIENTS. BACKGROUND: PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISORDER THAT IS CLINICALLY DEFINED IN TERMS OF MOTOR SYMPTOMS. THESE ARE PRECEDED BY PRODROMAL NON-MOTOR MANIFESTATIONS THAT PROVE THE SYSTEMIC NATURE OF THE DISEASE. IDENTIFYING GENES AND PATHWAYS ALTERED IN LIVING PATIENTS PROVIDE NEW INFORMATION ON THE DIAGNOSIS AND PATHOGENESIS OF SPORADIC PD. METHODS: CHANGES IN GENE EXPRESSION IN THE BLOOD OF 40 SPORADIC PD PATIENTS AND 20 HEALTHY CONTROLS ("DISCOVERY SET") WERE ANALYZED BY TAKING ADVANTAGE OF THE AFFYMETRIX PLATFORM. PATIENTS WERE AT THE ONSET OF MOTOR SYMPTOMS AND BEFORE INITIATING ANY PHARMACOLOGICAL TREATMENT. DATA ANALYSIS WAS PERFORMED BY APPLYING RANKING-PRINCIPAL COMPONENT ANALYSIS, PUMA AND SIGNIFICANCE ANALYSIS OF MICROARRAYS. FUNCTIONAL ANNOTATIONS WERE ASSIGNED USING GO, DAVID, GSEA TO UNVEIL SIGNIFICANT ENRICHED BIOLOGICAL PROCESSES IN THE DIFFERENTIALLY EXPRESSED GENES. THE EXPRESSIONS OF SELECTED GENES WERE VALIDATED USING RT-QPCR AND SAMPLES FROM AN INDEPENDENT COHORT OF 12 PATIENTS AND CONTROLS ("VALIDATION SET"). RESULTS: GENE EXPRESSION PROFILING OF BLOOD SAMPLES DISCRIMINATES PD PATIENTS FROM HEALTHY CONTROLS AND IDENTIFIES DIFFERENTIALLY EXPRESSED GENES IN BLOOD. THE MAJORITY OF THESE ARE ALSO PRESENT IN DOPAMINERGIC NEURONS OF THE SUBSTANTIA NIGRA, THE KEY SITE OF NEURODEGENERATION. TOGETHER WITH NEURONAL APOPTOSIS, LYMPHOCYTE ACTIVATION AND MITOCHONDRIAL DYSFUNCTION, ALREADY FOUND IN PREVIOUS ANALYSIS OF PD BLOOD AND POST-MORTEM BRAINS, WE UNVEILED TRANSCRIPTOME CHANGES ENRICHED IN BIOLOGICAL TERMS RELATED TO EPIGENETIC MODIFICATIONS INCLUDING CHROMATIN REMODELING AND METHYLATION. CANDIDATE TRANSCRIPTS AS CBX5, TCF3, MAN1C1 AND DOCK10 WERE VALIDATED BY RT-QPCR. CONCLUSIONS: OUR DATA SUPPORT THE USE OF BLOOD TRANSCRIPTOMICS TO STUDY NEURODEGENERATIVE DISEASES. IT IDENTIFIES CHANGES IN CRUCIAL COMPONENTS OF CHROMATIN REMODELING AND METHYLATION MACHINERIES AS EARLY EVENTS IN SPORADIC PD SUGGESTING EPIGENETICS AS TARGET FOR THERAPEUTIC INTERVENTION. 2015 7 1269 27 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 8 822 28 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 9 5067 24 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 10 5894 26 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 11 2873 23 FUNCTIONAL METHYLOME ANALYSIS OF HUMAN DIABETIC KIDNEY DISEASE. IN PATIENTS WITH DIABETES MELLITUS, POOR METABOLIC CONTROL HAS A LONG-LASTING IMPACT ON KIDNEY DISEASE DEVELOPMENT. EPIGENETIC CHANGES, INCLUDING CYTOSINE METHYLATION, HAVE BEEN PROPOSED AS POTENTIAL MEDIATORS OF THE LONG-LASTING EFFECT OF ADVERSE METABOLIC EVENTS. OUR UNDERSTANDING OF THE PRESENCE AND CONTRIBUTION OF METHYLATION CHANGES TO DISEASE DEVELOPMENT IS LIMITED BECAUSE OF THE LACK OF COMPREHENSIVE BASE-RESOLUTION METHYLOME INFORMATION OF HUMAN KIDNEY TISSUE SAMPLES AND SITE-SPECIFIC METHYLATION EDITING. BASE RESOLUTION, WHOLE-GENOME BISULFITE SEQUENCING METHYLOME MAPS OF HUMAN DIABETIC KIDNEY DISEASE (DKD) TUBULE SAMPLES, AND ASSOCIATED GENE EXPRESSION MEASURED BY RNA SEQUENCING HIGHLIGHTED WIDESPREAD METHYLATION CHANGES IN DKD. PATHWAY ANALYSIS HIGHLIGHTED COORDINATED (METHYLATION AND GENE EXPRESSION) CHANGES IN IMMUNE SIGNALING, INCLUDING TUMOR NECROSIS FACTOR ALPHA (TNF). CHANGES IN TNF METHYLATION CORRELATED WITH KIDNEY FUNCTION DECLINE. DCAS9-TET1-BASED LOWERING OF THE CYTOSINE METHYLATION LEVEL OF THE TNF DIFFERENTIALLY METHYLATED REGION RESULTED IN AN INCREASE IN THE TNF TRANSCRIPT LEVEL, INDICATING THAT METHYLATION OF THIS LOCUS PLAYS AN IMPORTANT ROLE IN CONTROLLING TNF EXPRESSION. INCREASING THE TNF LEVEL IN DIABETIC MICE INCREASED DISEASE SEVERITY, SUCH AS ALBUMINURIA. IN SUMMARY, OUR RESULTS INDICATE WIDESPREAD METHYLATION DIFFERENCES IN DKD KIDNEYS AND HIGHLIGHTS EPIGENETIC CHANGES IN THE TNF LOCUS AND ITS CONTRIBUTION TO THE DEVELOPMENT OF NEPHROPATHY IN PATIENTS WITH DIABETES MELLITUS. 2019 12 925 26 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 13 5710 24 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 14 315 25 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 15 1655 19 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 16 1583 28 DNA METHYLATION PROFILES OF BLOOD CELLS ARE DISTINCT BETWEEN EARLY-ONSET OBESE AND CONTROL INDIVIDUALS. OBESITY IS A HIGHLY PREVALENT, CHRONIC DISORDER THAT HAS BEEN INCREASING IN INCIDENCE IN YOUNG PATIENTS. BOTH EPIGENETIC AND GENETIC ABERRATIONS MAY PLAY A ROLE IN THE PATHOGENESIS OF OBESITY. THEREFORE, IN-DEPTH EPIGENOMIC AND GENOMIC ANALYSES WILL ADVANCE OUR UNDERSTANDING OF THE DETAILED MOLECULAR MECHANISMS UNDERLYING OBESITY AND AID IN THE SELECTION OF POTENTIAL BIOMARKERS FOR OBESITY IN YOUTH. HERE, WE PERFORMED MICROARRAY-BASED DNA METHYLATION AND GENE EXPRESSION PROFILING OF PERIPHERAL WHITE BLOOD CELLS OBTAINED FROM SIX YOUNG, OBESE INDIVIDUALS AND SIX HEALTHY CONTROLS. WE OBSERVED THAT THE HIERARCHICAL CLUSTERING OF DNA METHYLATION, BUT NOT GENE EXPRESSION, CLEARLY SEGREGATES THE OBESE INDIVIDUALS FROM THE CONTROLS, SUGGESTING THAT THE METABOLIC DISTURBANCE THAT OCCURS AS A RESULT OF OBESITY AT A YOUNG AGE MAY AFFECT THE DNA METHYLATION OF PERIPHERAL BLOOD CELLS WITHOUT ACCOMPANYING TRANSCRIPTIONAL CHANGES. TO EXAMINE THE GENOME-WIDE DIFFERENCES IN THE DNA METHYLATION PROFILES OF YOUNG OBESE AND CONTROL INDIVIDUALS, WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES AND INVESTIGATED THEIR GENOMIC AND EPIGENOMIC CONTEXTS. THE ABERRANT DNA METHYLATION PATTERNS IN OBESE INDIVIDUALS CAN BE SUMMARIZED AS RELATIVE GAINS AND LOSSES OF DNA METHYLATION IN GENE PROMOTERS AND GENE BODIES, RESPECTIVELY. WE ALSO OBSERVED THAT THE CPG ISLANDS OF OBESE INDIVIDUALS ARE MORE SUSCEPTIBLE TO DNA METHYLATION COMPARED TO CONTROLS. OUR PILOT STUDY SUGGESTS THAT THE GENOME-WIDE ABERRANT DNA METHYLATION PATTERNS OF OBESE INDIVIDUALS MAY ADVANCE NOT ONLY OUR UNDERSTANDING OF THE EPIGENOMIC PATHOGENESIS BUT ALSO EARLY SCREENING OF OBESITY IN YOUTH. 2017 17 1794 26 EFFECT OF DIABETES STATUS AND HYPERGLYCEMIA ON GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION. TYPE 2 DIABETES MELLITUS (T2DM) IS CHARACTERIZED BY OXIDATIVE STRESS THAT COULD LEAD TO CHRONIC MICRO- AND MACROVASCULAR COMPLICATIONS. WE HYPOTHESIZED THAT SOME OF THE TARGET ORGAN DAMAGE IS MEDIATED BY OXIDATIVE ALTERATIONS IN EPIGENETIC MECHANISMS INVOLVING DNA METHYLATION (5MC) AND DNA HYDROXYMETHYLATION (5HMC). WE ANALYZED GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION IN PERIPHERAL BLOOD CELLS IN WELL-CONTROLLED AND POORLY CONTROLLED PATIENTS WITH T2DM AND COMPARED THEM WITH HEALTHY CONTROLS. WE ALSO ANALYZED MICROARRAYS OF DNA METHYLATION AND GENE EXPRESSION OF OTHER IMPORTANT TISSUES IN THE CONTEXT OF DIABETES FROM THE GEO DATABASE REPOSITORY AND THEN COMPARED THESE RESULTS WITH OUR EXPERIMENTAL GENE EXPRESSION DATA. DNA METHYLATION AND, MORE IMPORTANTLY, DNA HYDROXYMETHYLATION LEVELS WERE INCREASED IN POORLY CONTROLLED PATIENTS COMPARED TO WELL-CONTROLLED AND HEALTHY INDIVIDUALS. BOTH 5MC AND 5HMC MEASUREMENTS WERE CORRELATED WITH THE PERCENTAGE OF GLYCATED HEMOGLOBIN, INDICATING A DIRECT IMPACT OF HYPERGLYCEMIA ON CHANGES OVER THE EPIGENOME. THE ANALYSIS OF METHYLATION MICROARRAYS WAS CONCORDANT, AND 5MC LEVELS WERE INCREASED IN THE PERIPHERAL BLOOD OF T2DM PATIENTS. HOWEVER, THE DNA METHYLATION LEVELS WERE THE OPPOSITE OF THOSE IN OTHER TISSUES, SUCH AS THE PANCREAS, ADIPOSE TISSUE AND SKELETAL MUSCLE. WE HYPOTHESIZE THAT A PROCESS OF DNA OXIDATION ASSOCIATED WITH HYPERGLYCEMIA MAY EXPLAIN THE DNA DEMETHYLATION IN WHICH THE ACTIVITY OF TEN-ELEVEN TRANSLOCATION (TET) PROTEINS IS NOT SUFFICIENT TO COMPLETE THE PROCESS. HIGH LEVELS OF GLUCOSE LEAD TO CELLULAR OXIDATION, WHICH TRIGGERS THE PROCESS OF DNA DEMETHYLATION AIDED BY TET ENZYMES, RESULTING IN EPIGENETIC DYSREGULATION OF THE DAMAGED TISSUES. 2017 18 948 28 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 19 3659 26 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 20 287 27 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010