1   344 153 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  1967  51 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3  5034  37 PHARMACOEPIGENETICS OF THE ROLE OF DNA METHYLATION IN MU-OPIOID RECEPTOR EXPRESSION IN DIFFERENT HUMAN BRAIN REGIONS. AIM: EXPOSURE TO OPIOIDS HAS BEEN ASSOCIATED WITH EPIGENETIC EFFECTS. STUDIES IN RODENTS SUGGESTED A ROLE OF VARYING DEGREES OF DNA METHYLATION IN THE DIFFERENTIAL REGULATION OF MU-OPIOID RECEPTOR EXPRESSION ACROSS THE BRAIN. METHODS: IN A TRANSLATIONAL INVESTIGATION, USING TISSUE ACQUIRED POSTMORTEM FROM 21 BRAIN REGIONS OF FORMER OPIATE ADDICTS, REPRESENTING A HUMAN COHORT WITH CHRONIC OPIOID EXPOSURE, MU-OPIOID RECEPTOR EXPRESSION WAS ANALYZED AT THE LEVEL OF DNA METHYLATION, MRNA AND PROTEIN. RESULTS & CONCLUSION: WHILE HIGH OR LOW MU-OPIOID RECEPTOR EXPRESSION SIGNIFICANTLY CORRELATED WITH LOCAL OPRM1 MRNA LEVELS, THERE WAS NO CORRESPONDING ASSOCIATION WITH OPRM1 METHYLATION STATUS. ADDITIONAL EXPERIMENTS IN HUMAN CELL LINES SHOWED THAT CHANGES IN DNA METHYLATION ASSOCIATED WITH CHANGES IN MU-OPIOID EXPRESSION WERE AN ORDER OF MAGNITUDE GREATER THAN DIFFERENCES IN BRAIN. HENCE, DIFFERENT DEGREES OF DNA METHYLATION ASSOCIATED WITH CHRONIC OPIOID EXPOSURE ARE UNLIKELY TO EXERT A MAJOR ROLE IN THE REGION-SPECIFICITY OF MU-OPIOID RECEPTOR EXPRESSION IN THE HUMAN BRAIN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  2281  45 EPIGENETIC REGULATION IN EARLY CHILDHOOD: A MINIATURIZED AND VALIDATED METHOD TO ASSESS HISTONE ACETYLATION. INTRODUCTION: CHRONIC INFLAMMATORY DISEASES INCLUDING ALLERGIES AND ASTHMA ARE THE RESULT OF COMPLEX INTERACTIONS BETWEEN GENES AND ENVIRONMENTAL FACTORS. EPIGENETIC MECHANISMS COMPRISE A SET OF BIOCHEMICAL REACTIONS THAT REGULATE GENE EXPRESSION. IN ORDER TO UNDERSTAND THE CAUSE-EFFECT RELATIONSHIP BETWEEN ENVIRONMENTAL EXPOSURES AND DISEASE DEVELOPMENT, METHODS CAPABLE OF ASSESSING EPIGENETIC REGULATION (ALSO) IN LARGE COHORTS ARE NEEDED. METHODS: FOR THIS PURPOSE, WE DEVELOPED AND EVALUATED A MINIATURIZED CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY ALLOWING FOR A COST-EFFECTIVE ASSESSMENT OF HISTONE ACETYLATION OF CANDIDATE GENES IN A QUANTITATIVE FASHION. THIS METHOD WAS THEN APPLIED TO ASSESS H3 AND H4 HISTONE ACETYLATION CHANGES IN CORD BLOOD (CB) SAMPLES FROM AN ESTABLISHED COHORT OF AUSTRALIAN CHILDREN EXPOSED IN THE FETAL PERIOD TO EITHER VERY LOW OR VERY HIGH LEVELS OF MATERNAL FOLATE. RESULTS: OUR CHIP ASSAY WAS VALIDATED FOR A MINIMUM REQUIREMENT OF 1 X 105 TARGET CELLS (E.G. CD4+ T CELLS). VERY HIGH LEVELS OF MATERNAL FOLATE WERE SIGNIFICANTLY ASSOCIATED WITH INCREASED H3/H4 ACETYLATION AT GATA3 AND/OR IL9 PROMOTER REGIONS IN CD4+ T CELLS IN CB. CONCLUSION: WE DEVELOPED A CHIP METHOD ALLOWING RELIABLE ASSESSMENT OF H3/H4 ACETYLATION USING 1 X 105 CELLS ONLY. PRACTICAL APPLICATION OF THIS ASSAY DEMONSTRATED AN ASSOCIATION BETWEEN HIGH MATERNAL FOLATE EXPOSURE AND INCREASED HISTONE ACETYLATION, CORRESPONDING TO A MORE TRANSCRIPTIONALLY PERMISSIVE CHROMATIN STATUS IN THE PROMOTER REGIONS OF SOME TH2-RELATED GENES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5   287  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  2766  45 EXPRESSION, POLYMORPHISM AND METHYLATION PATTERN OF INTERLEUKIN-6 IN PERIODONTAL TISSUES. PERIODONTITIS IS CONSIDERED AN INFLAMMATORY DISORDER OF BACTERIAL ETIOLOGY THAT RESULTS IN PERIODONTAL TISSUE DESTRUCTION, AS A RESULT OF COMPLEX INTERACTIONS BETWEEN PERIODONTAL PATHOGENS, HOST AND IMMUNE RESPONSE. GENETIC AND EPIGENETIC MECHANISMS MAY MODULATE THE INDIVIDUAL RESPONSE SINCE IT IS ABLE TO INFLUENCE THE GENE EXPRESSION. THE AIM OF THIS STUDY WAS TO EVALUATE THE IMPACT OF -174 G/C POLYMORPHISM AND THE METHYLATION STATUS OF THE PROMOTER REGION OF IL-6 GENE ON THE EXPRESSION OF IL-6 IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS. GINGIVAL BIOPSIES WERE COLLECTED FROM 21 PATIENTS WITH CHRONIC PERIODONTITIS AND 21 CONTROLS. HISTOLOGIC SECTIONS STAINED BY HEMATOXYLIN-EOSIN WERE USED FOR HISTOPATHOLOGICAL EVALUATION. THE IL-6 GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. THE POLYMORPHISM IL-6 -174 C/G WAS STUDIED BY POLYMERASE CHAIN REACTION (PCR) AMPLIFICATION AND RESTRICTION ENDONUCLEASE DIGESTION (HSPII). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS USED TO VERIFY THE DNA METHYLATION PATTERN. THE NUMBER OF INFLAMMATORY CELLS IN TISSUE FRAGMENTS FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS WAS HIGHER THAN IN THE CONTROL GROUP AND THE INFLAMMATORY INFILTRATE WAS PREDOMINANTLY MONONUCLEAR. THE EXPRESSION OF IL-6 WAS HIGHER IN THE GROUP WITH PERIODONTITIS. IN POLYMORPHISM ASSAY, NO STATISTICAL DIFFERENCE IN THE DISTRIBUTION OF GENOTYPES AND ALLELES IN BOTH GROUPS WERE OBSERVED. THE MOST OF SAMPLES WERE PARTIALLY METHYLATED. NO DIFFERENCE WAS OBSERVED IN METHYLATION PATTERN FROM TWO DIFFERENT REGIONS OF THE IL-6 GENE AMONG GROUPS. THE HIGH EXPRESSION OF IL-6 IS AN IMPORTANT FACTOR RELATED TO CHRONIC PERIODONTITIS, BUT WAS NOT ASSOCIATED WITH METHYLATION STATUS OR THE -174 (G/C) GENETIC POLYMORPHISM, SUGGESTING THAT OTHER MECHANISMS ARE INVOLVED IN THIS GENE TRANSCRIPTION REGULATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  1566  39 DNA METHYLATION OF TH1/TH2 CYTOKINE GENES AFFECTS SENSITIZATION AND PROGRESS OF EXPERIMENTAL ASTHMA. BACKGROUND: EPIGENETIC CHANGES IN DNA METHYLATION HAVE RECENTLY BEEN DEMONSTRATED TO BE INVOLVED IN EFFECTOR T-CELL POLARIZATION, RESULTING IN DIFFERENTIAL SECRETION OF T(H)1 AND T(H)2 CYTOKINES. HOWEVER, THE CONTRIBUTION TO THE DEVELOPMENT OF A CHRONIC INFLAMMATORY PHENOTYPE REMAINS STILL UNCLEAR. OBJECTIVE: WE SOUGHT TO INVESTIGATE CHANGES IN DNA METHYLATION IN MARKER GENES OF T-CELL SUBSETS DURING ALLERGEN SENSITIZATION/CHALLENGE AND THEIR INFLUENCE ON THE DEVELOPMENT OF AN ALLERGIC AIRWAY INFLAMMATORY RESPONSE. METHODS: THE RELATIONSHIP BETWEEN CHANGES IN DNA METHYLATION AND PHENOTYPE DEVELOPMENT WERE EXAMINED IN A WELL-ESTABLISHED MODEL OF EXPERIMENTAL ASTHMA. DNA METHYLATION WAS INVESTIGATED AT GENOMIC LOCI ASSOCIATED WITH T(H)1 (IFNG PROMOTER) OR T(H)2 (CONSERVED NONCODING SEQUENCE 1 [CNS1]) CYTOKINE PRODUCTION BY USING BISULFITE PYROSEQUENCING. RESULTS: ANALYSIS OF CD4(+) T CELLS REVEALED A SIGNIFICANT INCREASE IN DNA METHYLATION AT THE IFNG PROMOTER AFTER ALLERGEN SENSITIZATION/CHALLENGE, WHICH CORRELATED WITH DECREASED IFN-GAMMA CYTOKINE EXPRESSION, WHEREAS ONLY MINOR CHANGES WERE OBSERVED AT THE CNS1 LOCUS. FURTHERMORE, THE INCREASE IN DNA METHYLATION AT THE IFNG PROMOTER COULD BE REVERSED WITH A DNA METHYLTRANSFERASE (DNMT) INHIBITOR IN VITRO AND IN VIVO WITH BENEFICIAL EFFECTS ON SENSITIZATION STATUS AND ALLERGIC PHENOTYPE. THE SPECIFIC IMPORTANCE OF THE DNA METHYLATION STATUS IN CD4(+) T CELLS COULD BE CONFIRMED BY USING ADOPTIVE TRANSFER EXPERIMENTS. CONCLUSION: WE HERE REPORT THE NOVEL FINDING THAT EPIGENETIC REGULATION IN T CELLS CONTRIBUTES TO THE DEVELOPMENT OF EXPERIMENTAL ASTHMA AND CAN BE TARGETED PHARMACOLOGICALLY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8   531  42 ASTROCYTE REACTIVITY FOLLOWING BLAST EXPOSURE INVOLVES ABERRANT HISTONE ACETYLATION. BLAST INDUCED NEUROTRAUMA (BINT) IS A PREVALENT INJURY WITHIN MILITARY AND CIVILIAN POPULATIONS. THE INJURY IS CHARACTERIZED BY PERSISTENT INFLAMMATION AT THE CELLULAR LEVEL WHICH MANIFESTS AS A MULTITUDE OF COGNITIVE AND FUNCTIONAL IMPAIRMENTS. EPIGENETIC REGULATION OF TRANSCRIPTION OFFERS AN IMPORTANT CONTROL MECHANISM FOR GENE EXPRESSION AND CELLULAR FUNCTION WHICH MAY UNDERLIE CHRONIC INFLAMMATION AND RESULT IN NEURODEGENERATION. WE HYPOTHESIZE THAT ALTERED HISTONE ACETYLATION PATTERNS MAY BE INVOLVED IN BLAST INDUCED INFLAMMATION AND THE CHRONIC ACTIVATION OF GLIAL CELLS. THIS STUDY AIMED TO ELUCIDATE CHANGES TO HISTONE ACETYLATION OCCURRING FOLLOWING INJURY AND THE ROLES THESE CHANGES MAY HAVE WITHIN THE PATHOLOGY. SPRAGUE DAWLEY RATS WERE SUBJECTED TO EITHER A 10 OR 17 PSI BLAST OVERPRESSURE WITHIN AN ADVANCED BLAST SIMULATOR (ABS). SHAM ANIMALS UNDERWENT THE SAME PROCEDURES WITHOUT BLAST EXPOSURE. MEMORY IMPAIRMENTS WERE MEASURED USING THE NOVEL OBJECT RECOGNITION (NOR) TEST AT 2 AND 7 DAYS POST-INJURY. TISSUES WERE COLLECTED AT 7 DAYS FOR WESTERN BLOT AND IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS. SHAM ANIMALS SHOWED INTACT MEMORY AT EACH TIME POINT. THE NOVEL OBJECT DISCRIMINATION DECREASED SIGNIFICANTLY BETWEEN TWO AND 7 DAYS FOR EACH INJURY GROUP (P < 0.05). THIS IS INDICATIVE OF THE ONSET OF MEMORY IMPAIRMENT. WESTERN BLOT ANALYSIS SHOWED GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), A KNOWN MARKER OF ACTIVATED ASTROCYTES, WAS ELEVATED IN THE PREFRONTAL CORTEX (PFC) FOLLOWING BLAST EXPOSURE FOR BOTH INJURY GROUPS. ANALYSIS OF HISTONE PROTEIN EXTRACT SHOWED NO CHANGES IN THE LEVEL OF ANY TOTAL HISTONE PROTEINS WITHIN THE PFC. HOWEVER, ACETYLATION LEVELS OF HISTONE H2B, H3, AND H4 WERE DECREASED IN BOTH GROUPS (P < 0.05). CO-LOCALIZATION IMMUNOFLUORESCENCE WAS USED TO FURTHER INVESTIGATE ANY POTENTIAL CORRELATION BETWEEN DECREASED HISTONE ACETYLATION AND ASTROCYTE ACTIVATION. THESE EXPERIMENTS SHOWED A SIMILAR DECREASE IN H3 ACETYLATION IN ASTROCYTES EXPOSED TO A 17 PSI BLAST BUT NOT A 10 PSI BLAST. FURTHER INVESTIGATION OF GENE EXPRESSION BY POLYMERASE CHAIN REACTION (PCR) ARRAY, SHOWED DYSREGULATION OF SEVERAL CYTOKINE AND CYTOKINE RECEPTORS THAT ARE INVOLVED IN NEUROINFLAMMATORY PROCESSES. WE HAVE SHOWN ABERRANT HISTONE ACETYLATION PATTERNS INVOLVED IN BLAST INDUCED ASTROGLIOSIS AND COGNITIVE IMPAIRMENTS. FURTHER UNDERSTANDING OF THEIR ROLE IN THE INJURY PROGRESSION MAY LEAD TO NOVEL THERAPEUTIC TARGETS.	2016	

9   976  40 CHRONIC OPIOID USE IS ASSOCIATED WITH INCREASED DNA METHYLATION CORRELATING WITH INCREASED CLINICAL PAIN. ENVIRONMENTALLY CAUSED CHANGES IN CHROMOSOMES THAT DO NOT ALTER THE DNA SEQUENCE BUT CAUSE PHENOTYPIC CHANGES BY ALTERING GENE TRANSCRIPTION ARE SUMMARIZED AS EPIGENETICS. A MAJOR EPIGENETIC MECHANISM IS METHYLATION OR DEMETHYLATION AT CPG-RICH DNA ISLANDS. DNA METHYLATION TRIGGERED BY DRUGS HAS LARGELY UNEXPLORED THERAPEUTIC CONSEQUENCES. HERE WE REPORT INCREASED METHYLATION AT A CPG RICH ISLAND IN THE OPRM1 GENE CODING FOR MU-OPIOID RECEPTORS AND AT A GLOBAL METHYLATION SITE (LINE-1) IN LEUKOCYTES OF METHADONE-SUBSTITUTED FORMER OPIATE ADDICTS COMPARED WITH MATCHED HEALTHY CONTROLS. HIGHER DNA METHYLATION ASSOCIATED WITH CHRONIC OPIOID EXPOSURE WAS REPRODUCED IN AN INDEPENDENT COHORT OF OPIOID-TREATED AS COMPARED TO NON-OPIOID-TREATED PAIN PATIENTS. THIS SUGGESTS THAT OPIOIDS MAY STIMULATE DNA METHYLATION. THE OPRM1 METHYLATION HAD NO IMMEDIATE EFFECT ON MU-OPIOID RECEPTOR TRANSCRIPTION AND WAS NOT ASSOCIATED WITH OPIOID DOSING REQUIREMENTS. HOWEVER, THE GLOBAL DNA METHYLATION AT LINE-1 WAS SIGNIFICANTLY CORRELATED WITH INCREASED CHRONIC PAIN. THIS SUGGESTS INHIBITORY EFFECTS ON THE TRANSCRIPTION OF STILL UNSPECIFIED NOCIFENSIVE GENE PRODUCTS. IT FURTHER IMPLIES THAT OPIOIDS MAY BE CAUSALLY ASSOCIATED WITH INCREASED GENOME-WIDE DNA METHYLATION, ALTHOUGH CURRENTLY THERE IS NO DIRECT EVIDENCE OF THIS. THIS HAS PHENOTYPIC CONSEQUENCES FOR PAIN AND MAY PROVIDE A NEW, EPIGENETICS-ASSOCIATED MECHANISM OF OPIOID-INDUCED HYPERALGESIA. THE RESULTS INDICATE A POTENTIAL INFLUENCE OF OPIOID ANALGESICS ON THE PATIENTS' EPIGENOME. THEY EMPHASIZE THE NEED FOR RELIABLE AND COST-EFFECTIVE SCREENING TOOLS AND MAY IMPLY THAT HIGH-THROUGHPUT SCREENING FOR LEAD COMPOUNDS IN ARTIFICIAL EXPRESSION SYSTEMS MAY NOT PROVIDE THE BEST TOOLS FOR IDENTIFYING NEW PAIN MEDICATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10   990  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  5305  49 PROTEOMICS ANALYSIS OF HUMAN OBESITY REVEALS THE EPIGENETIC FACTOR HDAC4 AS A POTENTIAL TARGET FOR OBESITY. SEDENTARY LIFESTYLE AND EXCESSIVE ENERGY INTAKE ARE PROMINENT CONTRIBUTORS TO OBESITY; A MAJOR RISK FACTORS FOR THE DEVELOPMENT OF INSULIN RESISTANCE, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. ELUCIDATING THE MOLECULAR MECHANISMS UNDERLYING THESE CHRONIC CONDITIONS IS OF RELEVANT IMPORTANCE AS IT MIGHT LEAD TO THE IDENTIFICATION OF NOVEL ANTI-OBESITY TARGETS. THE PURPOSE OF THE CURRENT STUDY IS TO INVESTIGATE DIFFERENTIALLY EXPRESSED PROTEINS BETWEEN LEAN AND OBESE SUBJECTS THROUGH A SHOT-GUN QUANTITATIVE PROTEOMICS APPROACH USING PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) EXTRACTS AS WELL AS POTENTIAL MODULATION OF THOSE PROTEINS BY PHYSICAL EXERCISE. USING THIS APPROACH, A TOTAL OF 47 PROTEINS SHOWED AT LEAST 1.5 FOLD CHANGE BETWEEN LEAN AND OBESE SUBJECTS. IN OBESE, THE PROTEOMIC PROFILING BEFORE AND AFTER 3 MONTHS OF PHYSICAL EXERCISE SHOWED DIFFERENTIAL EXPRESSION OF 38 PROTEINS. THROMBOSPONDIN 1 (TSP1) WAS AMONG THE PROTEINS THAT WERE UPREGULATED IN OBESE SUBJECTS AND THEN DECREASED BY PHYSICAL EXERCISE. CONVERSELY, THE HISTONE DEACETYLASE 4 (HDAC4) WAS DOWNREGULATED IN OBESE SUBJECTS AND THEN INDUCED BY PHYSICAL EXERCISE. THE PROTEOMIC DATA WAS FURTHER VALIDATED BY QRT-PCR, WESTERN BLOT AND IMMUNOHISTOCHEMISTRY IN BOTH PBMCS AND ADIPOSE TISSUE. WE ALSO SHOWED THAT HDAC4 LEVELS CORRELATED POSITIVELY WITH MAXIMUM OXYGEN CONSUMPTION (VO2 MAX) BUT NEGATIVELY WITH BODY MASS INDEX, PERCENT BODY FAT, AND THE INFLAMMATORY CHEMOKINE RANTES. IN FUNCTIONAL ASSAYS, OUR DATA INDICATED THAT ECTOPIC EXPRESSION OF HDAC4 SIGNIFICANTLY IMPAIRED TNF-ALPHA-DEPENDENT ACTIVATION OF NF-KAPPAB, ESTABLISHING THUS A LINK BETWEEN HDAC4 AND REGULATION OF THE IMMUNE SYSTEM. TOGETHER, THE EXPRESSION PATTERN OF HDAC4 IN OBESE SUBJECTS BEFORE AND AFTER PHYSICAL EXERCISE, ITS CORRELATION WITH VARIOUS PHYSICAL, CLINICAL AND METABOLIC PARAMETERS ALONG WITH ITS INHIBITORY EFFECT ON NF-KAPPAB ARE SUGGESTIVE OF A PROTECTIVE ROLE OF HDAC4 AGAINST OBESITY. HDAC4 COULD THEREFORE REPRESENT A POTENTIAL THERAPEUTIC TARGET FOR THE CONTROL AND MANAGEMENT OF OBESITY AND PRESUMABLY INSULIN RESISTANCE.	2013	
                                                                                                                                                                                                                                                                                                                                     
12  2297  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  4604  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  3981  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  3440  34 HYPERMETHYLATION AND LOW TRANSCRIPTION OF TLR2 GENE IN CHRONIC PERIODONTITIS. PERIODONTITIS IS AN INFLAMMATORY DISORDER CHARACTERIZED BY INTERACTIONS BETWEEN PERIODONTAL PATHOGENS AND HOST'S IMMUNE RESPONSE. EPIGENETIC MAY CONTRIBUTE TO DISEASE DEVELOPMENT AND OUTCOME BY INFLUENCING THE EXPRESSION OF GENES INVOLVED IN THE IMMUNE RESPONSE. IT HAS BEEN SHOWN THAT TOLL-LIKE RECEPTORS (TLR) PLAY AN IMPORTANT ROLE IN THE RESPONSE TO PERIODONTOPATHIC BACTERIA. THE AIM OF STUDY WAS TO EVALUATE THE METHYLATION STATUS AND THE EXPRESSION OF TLR2 GENE IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH AND WITHOUT PERIODONTITIS. DNA WAS ANALYZED USING THE METHYL PROFILER DNA METHYLATION QPCR ASSAY. DNA METHYLATION AND TRANSCRIPT LEVELS WERE EVALUATED BY REAL-TIME POLYMERASE CHAIN REACTION. THE PERIODONTITIS GROUP SHOWED A HYPERMETHYLATED PROFILE AND A LOW EXPRESSION OF GENE. POSITIVE CORRELATION BETWEEN THE TLR2 METHYLATION FREQUENCY AND PROBING DEPTH WAS OBSERVED. THIS STUDY GIVES THE FIRST EVIDENCE OF METHYLATION FREQUENCY IN INFLAMED PERIODONTAL TISSUES AND OF THE POSSIBLE PARTICIPATION OF METHYLATION IN THE DEVELOPMENT OF PERIODONTITIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  1500  45 DNA METHYLATION ANALYSIS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABERRANT CROSS-TALK BETWEEN KERATINOCYTES AND IMMUNE CELLS SUCH AS CD4+ T CELLS, RESULTING IN KERATINOCYTE HYPERPROLIFERATION IN THE EPIDERMIS. DNA METHYLATION, ONE OF SEVERAL EPIGENETIC MECHANISMS, PLAYS AN IMPORTANT ROLE IN GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. SEVERAL STUDIES HAVE SUGGESTED THE INVOLVEMENT OF EPIGENETIC REGULATION IN SKIN LESIONS FROM PATIENTS WITH PSORIASIS. IN THIS STUDY, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION STATUS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS COMPARED WITH HEALTHY SUBJECTS USING METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). THE RESULTS OF MEDIP-SEQ SHOWED THAT THE GLOBAL METHYLATION VALUES OF CD4+ T CELLS ARE HIGHER IN PATIENTS WITH PSORIASIS THAN IN HEALTHY CONTROLS, PARTICULARLY IN THE PROMOTER REGIONS. AMONG THE MOST HYPERMETHYLATED GENES IN THE PROMOTER REGIONS, WE SELECTED THE GENES WHOSE EXPRESSION IS SIGNIFICANTLY REDUCED IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. STUDIES USING THE METHYLATION INHIBITOR 5-AZACYTIDINE IN VITRO METHYLATION ASSAYS HAVE SHOWN THAT THE DIFFERENTIAL EXPRESSION LEVELS WERE ASSOCIATED WITH THE METHYLATION STATUS OF EACH GENE. BISULFITE SEQUENCING OF THE TRANSCRIPTION START REGION OF PHOSPHATIDIC ACID PHOSPHATASE TYPE 2 DOMAIN CONTAINING 3 (PPAPDC3), ONE OF THE SELECTED GENES, SHOWED HYPERMETHYLATION IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. THESE RESULTS SUGGESTED THAT THE METHYLATION STATUS, WHICH IS IDENTIFIED BY MEDIP-SEQ OF THE GENES, WAS CORRELATED WITH THE MRNA EXPRESSION LEVEL OF THE GENES. COLLECTIVELY, THE DNA METHYLATION STATUS IN CD4+ T CELLS MIGHT BE ASSOCIATED WITH THE PATHOGENESIS OF PSORIASIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  1301  27 DEEP SEQUENCING REVEALS INCREASED DNA METHYLATION IN CHRONIC RAT EPILEPSY. EPILEPSY IS A FREQUENT NEUROLOGICAL DISORDER, ALTHOUGH ONSET AND PROGRESSION OF SEIZURES REMAIN DIFFICULT TO PREDICT IN AFFECTED PATIENTS, IRRESPECTIVE OF THEIR EPILEPTOGENIC CONDITION. PREVIOUS STUDIES IN ANIMAL MODELS AS WELL AS HUMAN EPILEPTIC BRAIN TISSUE REVEALED A REMARKABLY DIVERSE PATTERN OF GENE EXPRESSION IMPLICATING EPIGENETIC CHANGES TO CONTRIBUTE TO DISEASE PROGRESSION. HERE WE MAPPED FOR THE FIRST TIME GLOBAL DNA METHYLATION PATTERNS IN CHRONIC EPILEPTIC RATS AND CONTROLS. USING METHYL-CPG CAPTURE ASSOCIATED WITH MASSIVE PARALLEL SEQUENCING (METHYL-SEQ) WE REPORT THE GENOMIC METHYLATION SIGNATURE OF THE CHRONIC EPILEPTIC STATE. WE OBSERVED A PREDOMINANT INCREASE, RATHER THAN LOSS OF DNA METHYLATION IN CHRONIC RAT EPILEPSY. ABERRANT METHYLATION PATTERNS WERE INVERSELY CORRELATED WITH GENE EXPRESSION CHANGES USING MRNA SEQUENCING FROM SAME ANIMALS AND TISSUE SPECIMENS. ADMINISTRATION OF A KETOGENIC, HIGH-FAT, LOW-CARBOHYDRATE DIET ATTENUATED SEIZURE PROGRESSION AND AMELIORATED DNA METHYLATION MEDIATED CHANGES IN GENE EXPRESSION. THIS IS THE FIRST REPORT OF UNSUPERVISED CLUSTERING OF AN EPIGENETIC MARK BEING USED IN EPILEPSY RESEARCH TO SEPARATE EPILEPTIC FROM NON-EPILEPTIC ANIMALS AS WELL AS FROM ANIMALS RECEIVING ANTI-CONVULSIVE DIETARY TREATMENT. WE FURTHER DISCUSS THE POTENTIAL IMPACT OF EPIGENETIC CHANGES AS A PATHOGENIC MECHANISM OF EPILEPTOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  1525  46 DNA METHYLATION CHANGES IN GENES INVOLVED IN INFLAMMATION AND DEPRESSION IN FIBROMYALGIA: A PILOT STUDY. OBJECTIVES: THE PRESENT PILOT STUDY AIMS TO INVESTIGATE DNA METHYLATION CHANGES OF GENES RELATED TO FIBROMYALGIA (FM) DEVELOPMENT AND ITS MAIN COMORBID SYMPTOMS, INCLUDING SLEEP IMPAIRMENT, INFLAMMATION, DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. EPIGENETIC MODIFICATIONS MIGHT TRIGGER OR PERPETUATE COMPLEX INTERPLAY BETWEEN PAIN TRANSDUCTION/TRANSMISSION, CENTRAL PAIN PROCESSING AND EXPERIENCED STRESSORS IN VULNERABLE INDIVIDUALS. METHODS: WE CONDUCTED DNA METHYLATION ANALYSIS BY TARGETED BISULFITE NGS SEQUENCING TESTING DIFFERENTIAL METHYLATION IN 112 GENOMIC REGIONS FROM LEUKOCYTES OF EIGHT WOMEN WITH FM AND THEIR EIGHT HEALTHY SISTERS AS CONTROLS. RESULTS: TESTS FOR DIFFERENTIALLY METHYLATED REGIONS AND CYTOSINES BROUGHT FOCUS ON THE GRM2 GENE, ENCODING THE METABOTROPIC GLUTAMATE RECEPTOR2. THE SLIGHTLY INCREASED DNA METHYLATION OBSERVED IN THE GRM2 REGION OF FM PATIENTS MAY CONFIRM THE INVOLVEMENT OF THE GLUTAMATE PATHWAY IN THIS PATHOLOGICAL CONDITION. LOGISTIC REGRESSION HIGHLIGHTED THE SIMULTANEOUS ASSOCIATION OF METHYLATION LEVELS OF DEPRESSION AND INFLAMMATION-RELATED GENES WITH FM. CONCLUSIONS: ALTOGETHER, THE RESULTS EVIDENCE THE GLUTAMATE PATHWAY INVOLVEMENT IN FM AND SUPPORT THE IDEA THAT A COMBINATION OF METHYLATED AND UNMETHYLATED GENES COULD REPRESENT A RISK FACTOR TO FM OR ITS CONSEQUENCE, MORE THAN SINGLE GENES. FURTHER STUDIES ON THE IDENTIFIED BIOMARKERS COULD CONTRIBUTE TO UNRAVEL THE CAUSATIVE UNDERLYING FM MECHANISMS, GIVING RELIABLE DIRECTIONS TO RESEARCH, IMPROVING THE DIAGNOSIS AND EFFECTIVE THERAPIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  1599  40 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  4879  24 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