1 1526 168 DNA METHYLATION CHANGES IN GLIAL CELLS OF THE NORMAL-APPEARING WHITE MATTER IN MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS), THE LEADING CAUSE OF NON-TRAUMATIC NEUROLOGICAL DISABILITY IN YOUNG ADULTS, IS A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). DUE TO THE POOR ACCESSIBILITY TO THE TARGET ORGAN, CNS-CONFINED PROCESSES UNDERPINNING THE LATER PROGRESSIVE FORM OF MS REMAIN ELUSIVE THEREBY LIMITING TREATMENT OPTIONS. WE AIMED TO EXAMINE DNA METHYLATION, A STABLE EPIGENETIC MARK OF GENOME ACTIVITY, IN GLIAL CELLS TO CAPTURE RELEVANT MOLECULAR CHANGES UNDERLYING MS NEUROPATHOLOGY. WE PROFILED DNA METHYLATION IN NUCLEI OF NON-NEURONAL CELLS, ISOLATED FROM 38 POST-MORTEM NORMAL-APPEARING WHITE MATTER (NAWM) SPECIMENS OF MS PATIENTS (N = 8) IN COMPARISON TO WHITE MATTER OF CONTROL INDIVIDUALS (N = 14), USING INFINIUM METHYLATIONEPIC BEADCHIP. WE IDENTIFIED 1,226 SIGNIFICANT (GENOME-WIDE ADJUSTED P-VALUE < 0.05) DIFFERENTIALLY METHYLATED POSITIONS (DMPS) BETWEEN MS PATIENTS AND CONTROLS. FUNCTIONAL ANNOTATION OF THE ALTERED DMP-GENES UNCOVERED ALTERATIONS OF PROCESSES RELATED TO CELLULAR MOTILITY, CYTOSKELETON DYNAMICS, METABOLIC PROCESSES, SYNAPTIC SUPPORT, NEUROINFLAMMATION AND SIGNALING, SUCH AS WNT AND TGF-BETA PATHWAYS. A FRACTION OF THE AFFECTED GENES DISPLAYED TRANSCRIPTIONAL DIFFERENCES IN THE BRAIN OF MS PATIENTS, AS REPORTED BY PUBLICALLY AVAILABLE TRANSCRIPTOMIC DATA. CELL TYPE-RESTRICTED ANNOTATION OF DMP-GENES ATTRIBUTED ALTERATIONS OF CYTOSKELETON REARRANGEMENT AND EXTRACELLULAR MATRIX REMODELLING TO ALL GLIAL CELL TYPES, WHILE SOME PROCESSES, INCLUDING ION TRANSPORT, WNT/TGF-BETA SIGNALING AND IMMUNE PROCESSES WERE MORE SPECIFICALLY LINKED TO OLIGODENDROCYTES, ASTROCYTES AND MICROGLIAL CELLS, RESPECTIVELY. OUR FINDINGS STRONGLY SUGGEST THAT NAWM GLIAL CELLS ARE HIGHLY ALTERED, EVEN IN THE ABSENCE OF LESIONAL INSULT, COLLECTIVELY EXHIBITING A MULTICELLULAR REACTION IN RESPONSE TO DIFFUSE INFLAMMATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                      
2 3069  46 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC CHANGES IN CD4+ AND CD14+ CELLS OF MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE AND DEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, WHICH DEVELOPS IN GENETICALLY PREDISPOSED INDIVIDUALS UPON EXPOSURE TO ENVIRONMENTAL INFLUENCES. ENVIRONMENTAL TRIGGERS OF MS, SUCH AS VIRAL INFECTIONS OR SMOKING, WERE DEMONSTRATED TO AFFECT DNA METHYLATION, AND THUS TO INVOLVE THIS IMPORTANT EPIGENETIC MECHANISM IN THE DEVELOPMENT OF PATHOLOGICAL PROCESS. TO IDENTIFY MS-ASSOCIATED DNA METHYLATION HALLMARKS, WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING OF TWO CELL POPULATIONS (CD4+ T-LYMPHOCYTES AND CD14+ MONOCYTES), COLLECTED FROM THE SAME TREATMENT-NAIVE RELAPSING-REMITTING MS PATIENTS AND HEALTHY SUBJECTS, USING ILLUMINA 450 K METHYLATION ARRAYS. WE REVEALED SIGNIFICANT CHANGES IN DNA METHYLATION FOR BOTH CELL POPULATIONS IN MS. IN CD4+ CELLS OF MS PATIENTS THE MAJORITY OF DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE SHOWN TO BE HYPOMETHYLATED, WHILE IN CD14+ CELLS - HYPERMETHYLATED. DIFFERENTIAL METHYLATION OF HLA-DRB1 GENE IN CD4+ AND CD14+ CELLS WAS ASSOCIATED WITH CARRIAGE OF DRB1*15 ALLELE INDEPENDENTLY FROM THE DISEASE STATUS. BESIDES, ABOUT 20% OF IDENTIFIED DMPS WERE SHARED BETWEEN TWO CELL POPULATIONS AND HAD THE SAME DIRECTION OF METHYLATION CHANGES; THEY MAY BE INVOLVED IN BASIC EPIGENETIC PROCESSES OCCURING IN MS. THESE FINDINGS SUGGEST THAT THE EPIGENETIC MECHANISM OF DNA METHYLATION IN IMMUNE CELLS CONTRIBUTES TO MS; FURTHER STUDIES ARE NOW REQUIRED TO VALIDATE THESE RESULTS AND UNDERSTAND THEIR FUNCTIONAL SIGNIFICANCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3 1611  41 DNA METHYLATION: A NEW PLAYER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A NEUROLOGICAL AND CHRONIC INFLAMMATORY DISEASE THAT IS MEDIATED BY DEMYELINATION AND AXONAL DEGENERATION IN THE CENTRAL NERVOUS SYSTEM (CNS). STUDIES HAVE SHOWN THAT IMMUNE SYSTEM COMPONENTS SUCH AS CD4+, CD8+, CD44+ T CELLS, B LYMPHATIC CELLS, AND INFLAMMATORY CYTOKINES PLAY A CRITICAL ROLE IN INFLAMMATORY PROCESSES AND MYELIN DAMAGE ASSOCIATED WITH MS. NEVERTHELESS, THE PATHOGENESIS OF MS REMAINS POORLY DEFINED. DNA METHYLATION, A SIGNIFICANT EPIGENETIC MODIFICATION, IS REPORTED TO BE EXTENSIVELY INVOLVED IN MS PATHOGENESIS THROUGH THE REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON DNA METHYLATION INVOLVED IN MS PATHOGENESIS. EVIDENCE SHOWED THE HYPERMETHYLATION OF HUMAN LEUKOCYTE ANTIGEN-DRB1 (HLA-DRB1) IN CD4+ T CELLS, THE GENOME-WIDE DNA METHYLATION IN CD8+ T CELLS, THE HYPERMETHYLATION OF INTERLEUKIN-4 (IL-4)/FORKHEAD WINGED HELIX TRANSCRIPTION FACTOR 3 (FOXP3), AND THE DEMETHYLATION OF INTERFERON-GAMMA (IFN-GAMMA)/IL-17A IN CD44+ ENCEPHALITOGENIC T CELLS. STUDIES ALSO SHOWED THE HYPERMETHYLATION OF SH2-CONTAINING PROTEIN TYROSINE PHOSPHATASE-1 (SHP-1) IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND METHYLATED CHANGES OF GENES REGULATING OLIGODENDROCYTE AND NEURONAL FUNCTION IN NORMAL-APPEARING WHITE MATTER. CLARIFYING THE MECHANISM OF ABERRANT METHYLATION ON MS MAY EXPLAIN PART OF THE PATHOLOGY AND WILL LEAD TO THE DEVELOPMENT OF A NEW THERAPEUTIC TARGET FOR THE TREATMENT OF MS IN THE FUTURE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  810  39 CHANGES IN DNA METHYLATION IN APOE AND ACKR3 GENES IN MULTIPLE SCLEROSIS PATIENTS AND THE RELATIONSHIP WITH THEIR HEAVY METAL BLOOD LEVELS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE WITH DEMYELINATED LESIONS IN THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION AS AN EPIGENETIC CHANGE INFLUENCED BY ENVIRONMENTAL FACTORS, INCLUDING HEAVY METALS HAS BEEN IMPLEMENTED IN MS DISEASE. WE INVESTIGATED THE CORRELATION OF DNA METHYLATION CHANGES IN APOE AND ACKR3 GENES IN MS PATIENTS AND THE POSSIBLE ASSOCIATION WITH BLOOD CONCENTRATION OF ARSENIC (AS), CADMIUM (CD) AND LEAD (PB) AS MAJOR HEAVY METAL POLLUTANTS. THIS STUDY INCLUDED 69 RELAPSING-REMITTING MULTIPLE SCLEROSIS (RR-MS) PATIENTS AND 69 AGE/GENDER-MATCHED HEALTHY SUBJECTS. THE HRM REAL-TIME PCR METHOD WAS USED TO INVESTIGATE THE CHANGES IN DNA METHYLATION AND HEAVY METAL CONCENTRATIONS WERE MEASURED BY ELECTROTHERMAL ATOMIC ABSORPTION SPECTROMETRY. OUR RESULTS SHOWED THAT THE METHYLATION PATTERN IN THE ACKR3 GENE OF THE PATIENT GROUP WAS MORE HYPOMETHYLATED, WHILE IN THE CASE OF THE APOE GENE, THIS PATTERN WAS MORE TOWARDS HYPERMETHYLATION COMPARED TO HEALTHY SUBJECTS. MOREOVER, THE BLOOD LEVELS OF AS AND CD METALS, BUT NOT PB, WERE SIGNIFICANTLY HIGHER IN THE PATIENT GROUP COMPARE TO THE CONTROL GROUP (P </= 0.05). THE DATA INDICATE THAT THE INCREASE IN EXPRESSION OF ACKR3 GENE BY HYPOMETHYLATION AND THE DECREASE IN EXPRESSION OF APOE GENE VIA HYPERMETHYLATION ARE POSSIBLY INVOLVED IN THE ONSET AND PROGRESSION OF INFLAMMATORY PROCESSES IN MS PATIENTS. THE LEVEL OF AS CAN ALSO LEAD TO HYPOMETHYLATION BY DISRUPTING THE METHYLATION PATTERNS OF THE ACKR3 GENE, RESULTING IN INCREASED EXPRESSION IN MS PATIENTS. FINALLY, WE HAVE SHOWN THAT EPIGENETIC CHANGES CAN BE AN IMPORTANT FACTOR IN INCREASING AND DECREASING THE EXPRESSION OF GENES INVOLVED IN THE ONSET AND/OR PROGRESSION OF INFLAMMATORY PROCESSES IN MS. FURTHERMORE, EXPOSURE TO HEAVY METALS, ESPECIALLY AS, BY CHANGING THE NATURAL PATTERNS OF DNA METHYLATION CAN BE EFFECTIVE IN THIS DISEASE.	2021	
                                                                                                                                                                                                                                                                                                 
5 1600  36 DNA METHYLATION SIGNATURES OF ALZHEIMER'S DISEASE NEUROPATHOLOGY IN THE CORTEX ARE PRIMARILY DRIVEN BY VARIATION IN NON-NEURONAL CELL-TYPES. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE CHARACTERIZED BY THE PROGRESSIVE ACCUMULATION OF AMYLOID-BETA AND NEUROFIBRILLARY TANGLES OF TAU IN THE NEOCORTEX. WE PROFILED DNA METHYLATION IN TWO REGIONS OF THE CORTEX FROM 631 DONORS, PERFORMING AN EPIGENOME-WIDE ASSOCIATION STUDY OF MULTIPLE MEASURES OF AD NEUROPATHOLOGY. WE META-ANALYZED OUR RESULTS WITH THOSE FROM PREVIOUS STUDIES OF DNA METHYLATION IN AD CORTEX (TOTAL N = 2013 DONORS), IDENTIFYING 334 CORTICAL DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH AD PATHOLOGY INCLUDING METHYLOMIC VARIATION AT LOCI NOT PREVIOUSLY IMPLICATED IN DEMENTIA. WE SUBSEQUENTLY PROFILED DNA METHYLATION IN NEUN+ (NEURONAL-ENRICHED), SOX10+ (OLIGODENDROCYTE-ENRICHED) AND NEUN-/SOX10- (MICROGLIA- AND ASTROCYTE-ENRICHED) NUCLEI, FINDING THAT THE MAJORITY OF DMPS IDENTIFIED IN 'BULK' CORTEX TISSUE REFLECT DNA METHYLATION DIFFERENCES OCCURRING IN NON-NEURONAL CELLS. OUR STUDY HIGHLIGHTS THE POWER OF UTILIZING MULTIPLE MEASURES OF NEUROPATHOLOGY TO IDENTIFY EPIGENETIC SIGNATURES OF AD AND THE IMPORTANCE OF CHARACTERIZING DISEASE-ASSOCIATED VARIATION IN PURIFIED CELL-TYPES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6 1508  39 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014	

7 2909  33 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8 3076  37 GENOME-WIDE EPIGENOMIC ANALYSES IN PATIENTS WITH NOCICEPTIVE AND NEUROPATHIC CHRONIC PAIN SUBTYPES REVEALS ALTERATIONS IN METHYLATION OF GENES INVOLVED IN THE NEURO-MUSCULOSKELETAL SYSTEM. NOCICEPTIVE PAIN INVOLVES THE ACTIVATION OF NOCICEPTORS WITHOUT DAMAGE TO THE NERVOUS SYSTEM, WHEREAS NEUROPATHIC PAIN IS RELATED TO AN ALTERATION IN THE CENTRAL OR PERIPHERAL NERVOUS SYSTEM. CHRONIC PAIN ITSELF AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN MAY BE EPIGENETICALLY CONTROLLED. IN THIS CROSS-SECTIONAL STUDY, A GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED USING THE BLOOD DNA REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TECHNIQUE. THREE PROSPECTIVE COHORTS INCLUDING 20 HEALTHY CONTROLS (CTL), 18 PATIENTS WITH CHRONIC NOCICEPTIVE PAIN (NOCI), AND 19 PATIENTS WITH CHRONIC NEUROPATHIC PAIN (NEURO) WERE COMPARED AT BOTH THE SINGLE CPG AND DIFFERENTIALLY METHYLATED REGION (DMR) LEVELS. GENES WITH DMRS WERE SEEN IN THE NOCI AND NEURO GROUPS BELONGED TO THE NEURO-MUSCULOSKELETAL SYSTEM AND DIFFERED BETWEEN NOCI AND NEURO PATIENTS. OUR RESULTS DEMONSTRATE THAT THE EPIGENETIC DISTURBANCES ACCOMPANYING NOCICEPTIVE PAIN ARE VERY DIFFERENT FROM THOSE ACCOMPANYING NEUROPATHIC PAIN. IN THE FORMER, AMONG OTHERS, THE EPIGENETIC DISTURBANCE OBSERVED WOULD AFFECT THE FUNCTION OF THE OPIOID ANALGESIC SYSTEM, WHEREAS IN THE LATTER IT WOULD AFFECT THAT OF THE GABAERGIC REWARD SYSTEM. THIS STUDY PRESENTS BIOLOGICAL FINDINGS THAT HELP TO CHARACTERIZE NOCI- AND NEURO-AFFECTED PATHWAYS AND OPENS THE POSSIBILITY OF DEVELOPING EPIGENETIC DIAGNOSTIC ASSAYS. PERSPECTIVE: OUR RESULTS HELP TO EXPLAIN THE VARIOUS BIOLOGICAL PATHWAYS MODIFICATIONS UNDERLYING THE DIFFERENT CLINICAL MANIFESTATIONS OF NOCICEPTIVE AND NEUROPATHIC PAINS. FURTHERMORE, THE NEW TARGETS IDENTIFIED IN OUR STUDY MIGHT HELP TO DISCOVER MORE SPECIFIC TREATMENTS FOR NOCICEPTIVE OR NEUROPATHIC PAINS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 3077  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 1584  29 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11 2139  63 EPIGENETIC INSIGHTS INTO MULTIPLE SCLEROSIS DISEASE PROGRESSION. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS TODAY A LEADING CAUSE OF UNPREDICTABLE LIFELONG DISABILITY IN YOUNG ADULTS. THE TREATMENT OF PATIENTS IN PROGRESSIVE STAGES REMAINS HIGHLY CHALLENGING, ALLUDING TO OUR LIMITED UNDERSTANDING OF THE UNDERLYING PATHOLOGICAL PROCESSES. IN THIS REVIEW, WE PROVIDE INSIGHTS INTO THE MECHANISMS UNDERPINNING MS PROGRESSION FROM A PERSPECTIVE OF EPIGENETICS, THAT REFERS TO STABLE AND MITOTICALLY HERITABLE, YET REVERSIBLE, CHANGES IN THE GENOME ACTIVITY AND GENE EXPRESSION. WE FIRST RECAPITULATE FINDINGS FROM EPIGENETIC STUDIES EXAMINING THE BRAIN TISSUE OF PROGRESSIVE MS PATIENTS, WHICH SUPPORT A CONTRIBUTION OF DNA AND HISTONE MODIFICATIONS IN IMPAIRED OLIGODENDROCYTE DIFFERENTIATION, DEFECTIVE MYELINATION/REMYELINATION AND SUSTAINED NEURO-AXONAL VULNERABILITY. WE NEXT EXPLORE POSSIBILITIES FOR IDENTIFYING FACTORS AFFECTING PROGRESSION USING EASILY ACCESSIBLE TISSUES SUCH AS BLOOD BY COMPARING EPIGENETIC SIGNATURES IN PERIPHERAL IMMUNE CELLS AND BRAIN TISSUE. DESPITE MINOR OVERLAP AT INDIVIDUAL METHYLATION SITES, NEARLY 30% OF ALTERED GENES REPORTED IN PERIPHERAL IMMUNE CELLS OF PROGRESSIVE MS PATIENTS WERE FOUND IN BRAIN TISSUE, JOINTLY CONVERGING ON ALTERATIONS OF NEURONAL FUNCTIONS. WE FURTHER SPECULATE ABOUT THE MECHANISMS UNDERLYING SHARED EPIGENETIC PATTERNS BETWEEN BLOOD AND BRAIN, WHICH LIKELY IMPLY THE INFLUENCE OF INTERNAL (GENETIC CONTROL) AND/OR EXTERNAL (E.G. SMOKING AND AGEING) FACTORS IMPRINTING A COMMON SIGNATURE IN BOTH COMPARTMENTS. OVERALL, WE PROPOSE THAT EPIGENETICS MIGHT SHED LIGHT ON CLINICALLY RELEVANT MECHANISMS INVOLVED IN DISEASE PROGRESSION AND OPEN NEW AVENUES FOR THE TREATMENT OF PROGRESSIVE MS PATIENTS IN THE FUTURE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12 4590  44 NANOPORE SEQUENCING IDENTIFIES DIFFERENTIALLY METHYLATED GENES IN THE CENTRAL NERVOUS SYSTEM IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE-MEDIATED DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) THAT MIGHT BE TRIGGERED BY ABERRANT EPIGENETIC CHANGES IN THE GENOME. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MECHANISM THAT PARTICIPATES IN MS PATHOGENESIS. HOWEVER, THE OVERALL METHYLATION LEVEL IN THE CNS OF MS PATIENTS REMAINS ELUSIVE. WE USED DIRECT LONG-READ NANOPORE DNA SEQUENCING AND CHARACTERIZED THE DIFFERENTIALLY METHYLATED GENES IN THE BRAIN FROM MICE WITH EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), AN ANIMAL MODEL OF MS. WE IDENTIFIED 163 HYPOMETHYLATED PROMOTERS AND 327 HYPERMETHYLATED PROMOTERS. THESE GENOMIC ALTERATIONS WERE LINKED TO VARIOUS BIOLOGICAL PROCESSES INCLUDING METABOLISM, IMMUNE RESPONSES, NEURAL ACTIVITIES, AND MITOCHONDRIAL DYNAMICS, ALL OF WHICH ARE VITAL FOR EAE DEVELOPMENT. OUR RESULTS INDICATE A GREAT POTENTIAL OF NANOPORE SEQUENCING IN IDENTIFYING GENOMIC DNA METHYLATION IN EAE AND PROVIDE IMPORTANT GUIDANCE FOR FUTURE STUDIES INVESTIGATING THE MS/EAE PATHOLOGY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 5894  36 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	
                                                                                                                                                                                                                                                                                                                                                    
14  276  33 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15 1567  30 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16 2625  41 EPIGENOME-WIDE ASSOCIATION STUDY AND MULTI-TISSUE REPLICATION OF INDIVIDUALS WITH ALCOHOL USE DISORDER: EVIDENCE FOR ABNORMAL GLUCOCORTICOID SIGNALING PATHWAY GENE REGULATION. ALCOHOL USE DISORDER (AUD) IS A CHRONIC DEBILITATING DISORDER WITH LIMITED TREATMENT OPTIONS AND POORLY DEFINED PATHOPHYSIOLOGY. THERE ARE SUBSTANTIAL GENETIC AND EPIGENETIC COMPONENTS; HOWEVER, THE UNDERLYING MECHANISMS CONTRIBUTING TO AUD REMAIN LARGELY UNKNOWN. WE CONDUCTED THE LARGEST DNA METHYLATION EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ANALYSES CURRENTLY AVAILABLE FOR AUD (TOTAL N = 625) AND EMPLOYED A TOP HIT REPLICATION (N = 4798) USING A CROSS-TISSUE/CROSS-PHENOTYPIC APPROACH WITH THE GOAL OF IDENTIFYING NOVEL EPIGENETIC TARGETS RELEVANT TO AUD. RESULTS SHOW THAT A NETWORK OF DIFFERENTIALLY METHYLATED REGIONS IN GLUCOCORTICOID SIGNALING AND INFLAMMATION-RELATED GENES WERE ASSOCIATED WITH ALCOHOL USE BEHAVIORS. A TOP PROBE CONSISTENTLY ASSOCIATED ACROSS ALL COHORTS WAS LOCATED IN THE LONG NON-CODING RNA GROWTH ARREST SPECIFIC FIVE GENE (GAS5) (P < 10(-24)). GAS5 HAS BEEN IMPLICATED IN REGULATING TRANSCRIPTIONAL ACTIVITY OF THE GLUCOCORTICOID RECEPTOR AND HAS MULTIPLE FUNCTIONS RELATED TO APOPTOSIS, IMMUNE FUNCTION AND VARIOUS CANCERS. ENDOPHENOTYPIC ANALYSES USING PERIPHERAL CORTISOL LEVELS AND NEUROIMAGING PARADIGMS SHOWED THAT METHYLOMIC VARIATION IN GAS5 NETWORK-RELATED PROBES WERE ASSOCIATED WITH STRESS PHENOTYPES. POSTMORTEM BRAIN ANALYSES DOCUMENTED INCREASED GAS5 EXPRESSION IN THE AMYGDALA OF INDIVIDUALS WITH AUD. OUR DATA SUGGEST THAT ALCOHOL USE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN THE GLUCOCORTICOID SYSTEM THAT MIGHT INFLUENCE STRESS AND INFLAMMATORY REACTIVITY AND SUBSEQUENTLY RISK FOR AUD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17 1518  38 DNA METHYLATION AS AN EPIGENETIC MECHANISM IN THE DEVELOPMENT OF MULTIPLE SCLEROSIS. THE EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION ARE A GROUP OF THE KEY CELLULAR AND MOLECULAR PATHWAYS THAT LEAD TO INHERITED ALTERATIONS IN GENES' ACTIVITY WITHOUT CHANGING THEIR CODING SEQUENCE. DNA METHYLATION AT THE C5 POSITION OF CYTOSINE IN CPG DINUCLEOTIDES IS AMONGST THE CENTRAL EPIGENETIC MECHANISMS. CURRENTLY, THE NUMBER OF STUDIES THAT ARE DEVOTED TO THE IDENTIFICATION OF METHYLATION PATTERNS SPECIFIC TO MULTIPLE SCLEROSIS (MS), A SEVERE CHRONIC AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS ON A RAPID RISE. HOWEVER, THE ISSUE OF THE CONTRIBUTION OF DNA METHYLATION TO THE DEVELOPMENT OF THE DIFFERENT CLINICAL PHENOTYPES OF THIS HIGHLY HETEROGENEOUS DISEASE HAS ONLY BEGUN TO ATTRACT THE ATTENTION OF RESEARCHERS. THIS REVIEW SUMMARIZES THE DATA ON THE MOLECULAR MECHANISMS UNDERLYING DNA METHYLATION AND THE MS RISK FACTORS THAT CAN AFFECT THE DNA METHYLATION PROFILE AND, THEREBY, MODULATE THE EXPRESSION OF THE GENES INVOLVED IN THE DISEASE'S PATHOGENESIS. THE FOCUS OF OUR ATTENTION IS CENTERED ON THE ANALYSIS OF THE PUBLISHED DATA ON THE DIFFERENTIAL METHYLATION OF DNA FROM VARIOUS BIOLOGICAL SAMPLES OF MS PATIENTS OBTAINED USING BOTH THE CANDIDATE GENE APPROACH AND HIGH-THROUGHPUT METHODS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 2483  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19 6684  23 VALIDATION OF AN LC-MS BASED APPROACH FOR PROFILING HISTONES IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE IN VITRO EVALUATION OF HISTONES AND THEIR PTMS HAS DRAWN SUBSTANTIAL INTEREST IN THE DEVELOPMENT OF EPIGENETIC THERAPIES. THE DIFFERENTIAL EXPRESSION OF HISTONE ISOFORMS MAY SERVE AS A POTENTIAL MARKER IN THE CLASSIFICATION OF DISEASES AFFECTED BY CHROMATIN ABNORMALITIES. IN THIS STUDY, PROTEIN PROFILING BY LC AND MS WAS USED TO EXPLORE DIFFERENCES IN HISTONE COMPOSITION IN PRIMARY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. EXTENSIVE METHOD VALIDATIONS WERE PERFORMED TO DETERMINE THE EXPERIMENTAL VARIANCES THAT WOULD IMPACT HISTONE RELATIVE ABUNDANCE. THE RESULTING DATA DEMONSTRATED THAT THE PROPOSED METHODOLOGY WAS SUITABLE FOR THE ANALYSIS OF HISTONE PROFILES. IN 4 NORMAL INDIVIDUALS AND 40 CLL PATIENTS, A SIGNIFICANT DECREASE IN THE RELATIVE ABUNDANCE OF HISTONE H2A VARIANTS (H2AFL AND H2AFA/M*) WAS OBSERVED IN PRIMARY CLL CELLS AS COMPARED TO NORMAL B CELLS. PROTEIN IDENTITIES WERE DETERMINED USING HIGH MASS ACCURACY MS AND SHOTGUN PROTEOMICS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  665  42 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