1 1425 133 DIFFERENTIAL DNA METHYLATION PROFILES OF CODING AND NON-CODING GENES DEFINE HIPPOCAMPAL SCLEROSIS IN HUMAN TEMPORAL LOBE EPILEPSY. TEMPORAL LOBE EPILEPSY IS ASSOCIATED WITH LARGE-SCALE, WIDE-RANGING CHANGES IN GENE EXPRESSION IN THE HIPPOCAMPUS. EPIGENETIC CHANGES TO DNA ARE ATTRACTIVE MECHANISMS TO EXPLAIN THE SUSTAINED HYPEREXCITABILITY OF CHRONIC EPILEPSY. HERE, THROUGH METHYLATION ANALYSIS OF ALL ANNOTATED C-PHOSPHATE-G ISLANDS AND PROMOTER REGIONS IN THE HUMAN GENOME, WE REPORT A PILOT STUDY OF THE METHYLATION PROFILES OF TEMPORAL LOBE EPILEPSY WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS. FURTHERMORE, BY COMPARATIVE ANALYSIS OF EXPRESSION AND PROMOTER METHYLATION, WE IDENTIFY METHYLATION SENSITIVE NON-CODING RNA IN HUMAN TEMPORAL LOBE EPILEPSY. A TOTAL OF 146 PROTEIN-CODING GENES EXHIBITED ALTERED DNA METHYLATION IN TEMPORAL LOBE EPILEPSY HIPPOCAMPUS (N = 9) WHEN COMPARED TO CONTROL (N = 5), WITH 81.5% OF THE PROMOTERS OF THESE GENES DISPLAYING HYPERMETHYLATION. UNIQUE METHYLATION PROFILES WERE EVIDENT IN TEMPORAL LOBE EPILEPSY WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS, IN ADDITION TO A COMMON METHYLATION PROFILE REGARDLESS OF PATHOLOGY GRADE. GENE ONTOLOGY TERMS ASSOCIATED WITH DEVELOPMENT, NEURON REMODELLING AND NEURON MATURATION WERE OVER-REPRESENTED IN THE METHYLATION PROFILE OF WATSON GRADE 1 SAMPLES (MILD HIPPOCAMPAL SCLEROSIS). IN ADDITION TO GENES ASSOCIATED WITH NEURONAL, NEUROTRANSMITTER/SYNAPTIC TRANSMISSION AND CELL DEATH FUNCTIONS, DIFFERENTIAL HYPERMETHYLATION OF GENES ASSOCIATED WITH TRANSCRIPTIONAL REGULATION WAS EVIDENT IN TEMPORAL LOBE EPILEPSY, BUT OVERALL FEW GENES PREVIOUSLY ASSOCIATED WITH EPILEPSY WERE AMONG THE DIFFERENTIALLY METHYLATED. FINALLY, A PANEL OF 13, METHYLATION-SENSITIVE MICRORNA WERE IDENTIFIED IN TEMPORAL LOBE EPILEPSY INCLUDING MIR27A, MIR-193A-5P (MIR193A) AND MIR-876-3P (MIR876), AND THE DIFFERENTIAL METHYLATION OF LONG NON-CODING RNA DOCUMENTED FOR THE FIRST TIME. THE PRESENT STUDY THEREFORE REPORTS SELECT, GENOME-WIDE DNA METHYLATION CHANGES IN HUMAN TEMPORAL LOBE EPILEPSY THAT MAY CONTRIBUTE TO THE MOLECULAR ARCHITECTURE OF THE EPILEPTIC BRAIN.	2015	
                                                                                                                                                                                                                                                                                                                                                  
2 2654  35 EPILEPSY PROGRESSION IS ASSOCIATED WITH CUMULATIVE DNA METHYLATION CHANGES IN INFLAMMATORY GENES. MESIAL TEMPORAL LOBE EPILEPSY WITH HIPPOCAMPAL SCLEROSIS (MTLE-HS) IS THE MOST COMMON FOCAL EPILEPSY IN ADULTS. IT IS CHARACTERIZED BY ALARMING RATES OF PHARMACORESISTANCE. EPILEPTOGENESIS IS ASSOCIATED WITH THE OCCURRENCE OF EPIGENETIC ALTERATIONS, AND THE FEW EPIGENETIC STUDIES CARRIED OUT IN MTLE-HS HAVE MAINLY FOCUSED ON THE HIPPOCAMPUS. IN THIS STUDY, WE OBTAINED THE DNA METHYLATION PROFILES FROM BOTH THE HIPPOCAMPUS AND ANTERIOR TEMPORAL NEOCORTEX OF MTLE-HS PATIENTS SUBJECTED TO RESECTIVE EPILEPSY SURGERY AND AUTOPSIED NON-EPILEPTIC CONTROLS. WE ASSESSED THE PROGRESSIVE NATURE OF DNA METHYLATION CHANGES IN RELATION TO EPILEPSY DURATION. WE IDENTIFIED SIGNIFICANTLY ALTERED HIPPOCAMPAL DNA METHYLATION PATTERNS ENCOMPASSING MULTIPLE PATHWAYS KNOWN TO BE INVOLVED IN EPILEPTOGENESIS. DNA METHYLATION CHANGES WERE EVEN MORE STRIKING IN THE NEOCORTEX, WHEREIN PATHOGENIC PATHWAYS AND GENES WERE COMMON TO BOTH TISSUES. MOST IMPORTANTLY, DNA METHYLATION CHANGES AT MANY GENOMIC SITES VARIED SIGNIFICANTLY WITH EPILEPSY DURATION. SUCH PROGRESSIVE CHANGES WERE ASSOCIATED WITH INFLAMMATION-RELATED GENES IN THE HIPPOCAMPUS. OUR RESULTS SUGGEST THAT THE NEOCORTEX, RELATIVELY SPARED OF EXTENSIVE HISTOPATHOLOGICAL DAMAGE, MAY ALSO BE INVOLVED IN EPILEPSY DEVELOPMENT. THESE RESULTS ALSO OPEN THE POSSIBILITY THAT THE OBSERVED NEOCORTICAL IMPAIRMENT COULD REPRESENT A PRELIMINARY STAGE OF EPILEPTOGENESIS BEFORE THE ESTABLISHMENT OF CHRONIC LESIONS OR A CONSEQUENCE OF PROLONGED SEIZURE EXPOSURE. OUR TWO-TISSUE MULTI-LEVEL CHARACTERIZATION OF THE MTLE-HS DNA METHYLOME SUGGESTS THE OCCURRENCE OF A SELF-PROPAGATING INFLAMMATORY WAVE OF EPIGENETIC DYSREGULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3 1718  40 DYSREGULATED LONG NON-CODING RNAS IN THE TEMPORAL LOBE EPILEPSY MOUSE MODEL. PURPOSE: TO PERFORM COMPREHENSIVE PROFILING OF LONG NON-CODING RNAS (LNCRNAS) IN TEMPORAL LOBE EPILEPSY. METHODS: WE PERFORMED EXTENSIVE PROFILING OF LNCRNAS AND MRNAS IN THE MOUSE PILOCARPINE MODEL IN SPECIFIC BRAIN REGIONS, THE HIPPOCAMPUS AND CORTEX, AND COMPARED THE RESULTS TO THOSE OF THE CONTROL MOUSE. DIFFERENTIALLY EXPRESSED LNCRNAS AND MRNAS WERE IDENTIFIED WITH A MICROARRAY ANALYSIS (ARRAYSTAR MOUSE LNCRNA EXPRESSION MICROARRAY V3.0). THEN, GENE ONTOLOGY (GO) AND PATHWAY ANALYSIS WERE PERFORMED TO INVESTIGATE THE POTENTIAL ROLES OF THE DIFFERENTIALLY EXPRESSED MRNAS IN THE PILOCARPINE MODEL. PROTEIN-PROTEIN INTERACTIONS TRANSCRIBED BY DYSREGULATED MRNAS WITH/WITHOUT CO-DYSREGULATED LNCRNAS WERE ANALYZED USING STRING V10 (HTTP://STRING-DB.ORG/). RESULTS: A TOTAL OF 22 AND 83 LNCRNAS WERE UP- AND DOWN-REGULATED (>/=2.0-FOLD, ALL P < .05), RESPECTIVELY, IN THE HIPPOCAMPUS OF THE EPILEPSY MODEL, WHILE 46 AND 659 LNCRNAS WERE UP- AND DOWN-REGULATED, RESPECTIVELY, IN THE CORTEX OF THE EPILEPSY MODEL. GO AND PATHWAY ANALYSIS REVEALED THAT THE DYSREGULATED MRNAS WERE CLOSELY ASSOCIATED WITH A PROCESS ALREADY KNOWN TO BE INVOLVED IN EPILEPTOGENESIS: ACUTE INFLAMMATION, CALCIUM ION REGULATION, EXTRACELLULAR MATRIX REMODELING, AND NEURONAL DIFFERENTIATION. AMONG THE LNCRNAS, WE IDENTIFIED 10 LNCRNAS COMMONLY DYSREGULATED WITH CORRESPONDING MRNAS IN THE CORTEX. THE STRING ANALYSIS SHOWED THAT THE DYSREGULATED MRNAS WERE INTERCONNECTED AROUND TWO CENTERS: THE MTOR PATHWAY-RELATED GENES AND REST PATHWAY-RELATED GENES. CONCLUSION: LNCRNAS WERE DYSREGULATED IN THE PILOCARPINE MOUSE MODEL ACCORDING TO THE BRAIN REGIONS OF THE HIPPOCAMPUS AND CORTEX. THE DYSREGULATED LNCRNAS WITH CO-DYSREGULATED MRNAS MIGHT BE POSSIBLE THERAPEUTIC TARGETS FOR THE EPIGENETIC REGULATION OF CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4 1301  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 1727  46 DYSREGULATION OF LONG NON-CODING RNAS IN MOUSE MODELS OF LOCALIZATION-RELATED EPILEPSY. GENOME-WIDE PROFILING HAS REVEALED THAT EUKARYOTIC GENOMES ARE TRANSCRIBED INTO NUMEROUS NON-CODING RNAS. IN PARTICULAR, LONG NON-CODING RNAS (LNCRNAS) HAVE BEEN IMPLICATED IN VARIOUS HUMAN DISEASES DUE TO THEIR BIOCHEMICAL AND FUNCTIONAL DIVERSITY. EPILEPTIC DISORDERS HAVE BEEN CHARACTERIZED BY DYSREGULATION OF EPIGENETIC REGULATORY MECHANISMS, AND RECENT STUDIES HAVE IDENTIFIED SEVERAL LNCRNAS INVOLVED IN NEURAL DEVELOPMENT AND NETWORK FUNCTION. HOWEVER, COMPREHENSIVE PROFILING OF LNCRNAS IMPLICATED IN CHRONIC EPILEPSY HAS BEEN LACKING. IN THIS STUDY, MICROARRAY ANALYSIS WAS PERFORMED TO OBTAIN THE EXPRESSION PROFILE OF LNCRNAS DYSREGULATED IN PILOCARPINE AND KAINATE MODELS, TWO MODELS OF TEMPORAL LOBE EPILEPSY COMMONLY USED FOR STUDYING EPILEPTIC MECHANISMS. TOTAL OF 4622 LNCRNAS WERE ANALYZED: 384 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN PILOCARPINE MODEL, AND 279 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN KAINATE MODEL COMPARED WITH CONTROL MICE (>/=3.0-FOLD, P < 0.05). AMONG THESE, 54 AND 14 LNCRNAS, RESPECTIVELY, HAD ADJACENT PROTEIN-CODING GENES WHOSE EXPRESSIONS WERE ALSO SIGNIFICANTLY DYSREGULATED (>/=2.0-FOLD, P < 0.05). MAJORITY OF THESE PAIRS OF LNCRNAS AND ADJACENT GENES SHARED THE SAME DIRECTION OF DYSREGULATION. FOR THE SELECTED ADJACENT GENE-LNCRNA PAIRS, SIGNIFICANT GENE ONTOLOGY TERMS WERE EMBRYONIC APPENDAGE MORPHOGENESIS AND NEURON DIFFERENTIATION. THIS WAS THE FIRST STUDY TO COMPREHENSIVELY IDENTIFY DYSREGULATED LNCRNAS IN TWO DIFFERENT MODELS OF CHRONIC EPILEPSY AND WILL LIKELY PROVIDE A NOVEL INSIGHT INTO DEVELOPING LNCRNA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 3077  35 GENOME-WIDE METHYL-SEQ ANALYSIS OF BLOOD-BRAIN TARGETS OF GLUCOCORTICOID EXPOSURE. CHRONIC EXPOSURE TO GLUCOCORTICOIDS (GCS) CAN LEAD TO PSYCHIATRIC COMPLICATIONS THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION (DNAM). WE SOUGHT TO DETERMINE WHETHER EPIGENETIC CHANGES IN A PERIPHERAL TISSUE CAN SERVE AS A SURROGATE FOR THOSE IN A RELATIVELY INACCESSIBLE TISSUE SUCH AS THE BRAIN. DNA EXTRACTED FROM THE HIPPOCAMPUS AND BLOOD OF MICE TREATED WITH GCS OR VEHICLE SOLUTION WAS ASSAYED USING A GENOME-WIDE DNAM PLATFORM (METHYL-SEQ) TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) INDUCED BY GC TREATMENT. WE OBSERVED THAT APPROXIMATELY 70% OF THE DMRS IN BOTH TISSUES LOST METHYLATION FOLLOWING GC TREATMENT. OF THE 3,095 DMRS THAT MAPPED TO THE SAME GENES IN BOTH TISSUES, 1,853 DMRS UNDERWENT DNAM CHANGES IN THE SAME DIRECTION. INTERESTINGLY, ONLY 209 DMRS (<7%) OVERLAPPED IN GENOMIC COORDINATES BETWEEN THE 2 TISSUES, SUGGESTING TISSUE-SPECIFIC DIFFERENCES IN GC-TARGETED LOCI. PATHWAY ANALYSIS SHOWED THAT THE DMR-ASSOCIATED GENES WERE MEMBERS OF PATHWAYS INVOLVED IN METABOLISM, IMMUNE FUNCTION, AND NEURODEVELOPMENT. ALSO, CHANGES IN CELL TYPE COMPOSITION OF BLOOD AND BRAIN WERE EXAMINED BY FLUORESCENCE-ACTIVATED CELL SORTING. SEPARATION OF THE CORTEX INTO NEURONAL AND NON-NEURONAL FRACTIONS AND THE LEUKOCYTES INTO T-CELLS, B-CELLS, AND NEUTROPHILS SHOWED THAT GC-INDUCED METHYLATION CHANGES PRIMARILY OCCURRED IN NEURONS AND T-CELLS, WITH THE BLOOD TISSUE ALSO UNDERGOING A SHIFT IN THE PROPORTION OF CONSTITUENT CELL TYPES WHILE THE PROPORTION OF NEURONS AND GLIA IN THE BRAIN REMAINED STABLE. FROM THE CURRENT PILOT STUDY, WE FOUND THAT DESPITE TISSUE-SPECIFIC EPIGENETIC CHANGES AND CELLULAR HETEROGENEITY, BLOOD CAN SERVE AS A SURROGATE FOR GC-INDUCED CHANGES IN THE BRAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 4879  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  124  35 A SYSTEMS APPROACH DELIVERS A FUNCTIONAL MICRORNA CATALOG AND EXPANDED TARGETS FOR SEIZURE SUPPRESSION IN TEMPORAL LOBE EPILEPSY. TEMPORAL LOBE EPILEPSY IS THE MOST COMMON DRUG-RESISTANT FORM OF EPILEPSY IN ADULTS. THE REORGANIZATION OF NEURAL NETWORKS AND THE GENE EXPRESSION LANDSCAPE UNDERLYING PATHOPHYSIOLOGIC NETWORK BEHAVIOR IN BRAIN STRUCTURES SUCH AS THE HIPPOCAMPUS HAS BEEN SUGGESTED TO BE CONTROLLED, IN PART, BY MICRORNAS. TO SYSTEMATICALLY ASSESS THEIR SIGNIFICANCE, WE SEQUENCED ARGONAUTE-LOADED MICRORNAS TO DEFINE FUNCTIONALLY ENGAGED MICRORNAS IN THE HIPPOCAMPUS OF THREE DIFFERENT ANIMAL MODELS IN TWO SPECIES AND AT SIX TIME POINTS BETWEEN THE INITIAL PRECIPITATING INSULT THROUGH TO THE ESTABLISHMENT OF CHRONIC EPILEPSY. WE THEN SELECTED COMMONLY UP-REGULATED MICRORNAS FOR A FUNCTIONAL IN VIVO THERAPEUTIC SCREEN USING OLIGONUCLEOTIDE INHIBITORS. ARGONAUTE SEQUENCING GENERATED 1.44 BILLION SMALL RNA READS OF WHICH UP TO 82% WERE MICRORNAS, WITH OVER 400 UNIQUE MICRORNAS DETECTED PER MODEL. APPROXIMATELY HALF OF THE DETECTED MICRORNAS WERE DYSREGULATED IN EACH EPILEPSY MODEL. WE PRIORITIZED COMMONLY UP-REGULATED MICRORNAS THAT WERE FULLY CONSERVED IN HUMANS AND DESIGNED CUSTOM ANTISENSE OLIGONUCLEOTIDES FOR THESE CANDIDATE TARGETS. ANTISEIZURE PHENOTYPES WERE OBSERVED UPON KNOCKDOWN OF MIR-10A-5P, MIR-21A-5P, AND MIR-142A-5P AND ELECTROPHYSIOLOGICAL ANALYSES INDICATED BROAD SAFETY OF THIS APPROACH. COMBINED INHIBITION OF THESE THREE MICRORNAS REDUCED SPONTANEOUS SEIZURES IN EPILEPTIC MICE. PROTEOMIC DATA, RNA SEQUENCING, AND PATHWAY ANALYSIS ON PREDICTED AND VALIDATED TARGETS OF THESE MICRORNAS IMPLICATED DEREPRESSED TGF-BETA SIGNALING AS A SHARED SEIZURE-MODIFYING MECHANISM. CORRESPONDINGLY, INHIBITION OF TGF-BETA SIGNALING OCCLUDED THE ANTISEIZURE EFFECTS OF THE ANTAGOMIRS. TOGETHER, THESE RESULTS IDENTIFY SHARED, DYSREGULATED, AND FUNCTIONALLY ACTIVE MICRORNAS DURING THE PATHOGENESIS OF EPILEPSY WHICH REPRESENT THERAPEUTIC ANTISEIZURE TARGETS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 1528  35 DNA METHYLATION CHANGES IN REGIONAL LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES. A NUMBER OF PULMONARY DISEASES OCCUR WITH UPPER LOBE PREDOMINANCE, INCLUDING CYSTIC FIBROSIS AND SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IN THE HEALTHY LUNG, SEVERAL PHYSIOLOGIC AND METABOLIC FACTORS EXHIBIT DISPARITY WHEN COMPARING THE UPPER LOBE OF THE LUNG TO LOWER LOBE, INCLUDING DIFFERENCES IN OXYGENATION, VENTILATION, LYMPHATIC FLOW, PH, AND BLOOD FLOW. IN THIS STUDY, WE ASKED WHETHER THESE REGIONAL DIFFERENCES IN THE LUNG ARE ASSOCIATED WITH DNA METHYLATION CHANGES IN LUNG MACROPHAGES THAT COULD POTENTIALLY LEAD TO ALTERED CELL RESPONSIVENESS UPON SUBSEQUENT ENVIRONMENTAL CHALLENGE. ALL ANALYSES WERE PERFORMED USING PRIMARY LUNG MACROPHAGES COLLECTED VIA BRONCHOALVEOLAR LAVAGE FROM HEALTHY HUMAN SUBJECTS WITH NORMAL PULMONARY FUNCTION. EPIGENOME-WIDE DNA METHYLATION WAS EXAMINED VIA INFINIUM METHYLATIONEPIC (850K) ARRAY AND VALIDATED BY TARGETED NEXT-GENERATION BISULFITE SEQUENCING. WE OBSERVED 95 CPG LOCI WITH SIGNIFICANT DIFFERENTIAL METHYLATION IN LUNG MACROPHAGES, COMPARING UPPER LOBE TO LOWER LOBE (ALL FALSE DISCOVERY RATE < 0.05). SEVERAL OF THESE GENES, INCLUDING CLIP4, HSH2D, NR4A1, SNX10, AND TYK2, HAVE BEEN IMPLICATED AS PARTICIPANTS IN INFLAMMATORY/IMMUNE-RELATED BIOLOGICAL PROCESSES. FUNCTIONALLY, WE IDENTIFIED PHENOTYPIC DIFFERENCES IN OXYGEN USE, COMPARING UPPER VERSUS LOWER LUNG MACROPHAGES. OUR RESULTS SUPPORT A HYPOTHESIS THAT EPIGENETIC CHANGES, SPECIFICALLY DNA METHYLATION, AT A MULTITUDE OF GENE LOCI IN LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES REGIONALLY IN LUNG.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  344  40 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	
                                                                                                                                                                                                                                                                                                                                                                          
11 5345  34 RAPID CHANGES IN EXPRESSION OF CLASS I AND IV HISTONE DEACETYLASES DURING EPILEPTOGENESIS IN MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. A PROMINENT ROLE OF EPIGENETIC MECHANISMS IN MANIFESTATION OF EPILEPSY HAS BEEN PROPOSED. THUS ALTERED HISTONE H3 AND H4 ACETYLATION HAS BEEN DEMONSTRATED IN EXPERIMENTAL MODELS OF TEMPORAL LOBE EPILEPSY (TLE). WE NOW INVESTIGATED CHANGES IN THE EXPRESSION OF THE CLASS I AND CLASS IV HISTONE DEACETYLASES (HDAC) IN TWO COMPLEMENTARY MOUSE TLE MODELS. UNILATERAL INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS LASTING 6 TO 24H, DEVELOPMENT OF SPONTANEOUS LIMBIC SEIZURES (2 TO 3 DAYS AFTER KA INJECTION) AND CHRONIC EPILEPSY, AS REVEALED BY TELEMETRIC RECORDINGS OF THE EEGS. MICE WERE KILLED AT DIFFERENT INTERVALS AFTER KA INJECTION AND EXPRESSION OF HDAC MRNAS WAS INVESTIGATED BY IN SITU HYBRIDIZATION. WE OBSERVED MARKED DECREASES IN THE EXPRESSION OF HDACS 1, 2 AND 11 (BY UP TO 75%) IN THE GRANULE CELL AND PYRAMIDAL CELL LAYERS OF THE HIPPOCAMPUS DURING THE ACUTE STATUS EPILEPTICUS (2 TO 6H AFTER KA INJECTION). THIS WAS FOLLOWED BY INCREASED EXPRESSION OF ALL CLASS I HDAC MRNAS IN ALL PRINCIPAL CELL LAYERS OF THE HIPPOCAMPUS AFTER 12 TO 48 H. IN THE CHRONIC PHASE, 14 AND 28 DAYS AFTER KA, ONLY MODEST INCREASES IN THE EXPRESSION OF HDAC1 MRNA WERE OBSERVED IN GRANULE AND PYRAMIDAL CELLS. IMMUNOHISTOCHEMISTRY USING AN ANTIBODY DETECTING HDAC2 REVEALED RESULTS CONSISTENT WITH THE MRNA DATA AND INDICATES ALSO EXPRESSION IN GLIAL CELLS ON THE INJECTION SIDE. SIMILAR CHANGES AS SEEN IN THE KA MODEL WERE OBSERVED AFTER A PILOCARPINE-INDUCED STATUS EPILEPTICUS EXCEPT THAT DECREASES IN HDACS 2, 3 AND 8 WERE ALSO SEEN AT THE CHRONIC 28 DAY INTERVAL. THE PROMINENT DECREASES IN HDAC EXPRESSION DURING STATUS EPILEPTICUS ARE CONSISTENT WITH THE PREVIOUSLY DEMONSTRATED INCREASED EXPRESSION OF NUMEROUS PROTEINS AND WITH THE AUGMENTED ACETYLATION OF HISTONE H4. IT IS SUGGESTED THAT RESPECTIVE PUTATIVE GENE PRODUCTS COULD FACILITATE PROCONVULSIVE AS WELL AS ANTICONVULSIVE MECHANISMS. THE INCREASED EXPRESSION OF ALL CLASS I HDACS DURING THE "SILENT PHASE", ON THE OTHER HAND, MAY BE RELATED TO DECREASED HISTONE ACETYLATION, WHICH COULD CAUSE A DECREASE IN EXPRESSION OF CERTAIN PROTEINS, A MECHANISM THAT COULD ALSO PROMOTE EPILEPTOGENESIS. THUS, ADDRESSING HDAC EXPRESSION MAY HAVE A THERAPEUTIC POTENTIAL IN INTERFERING WITH A STATUS EPILEPTICUS AND WITH THE MANIFESTATION OF TLE.	2015	

12 3076  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13 2297  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 2625  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  665  38 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	
                                                                                                                                                                                                                                                                                                                                                       
16  990  31 CHRONIC SOCIAL STRESS INDUCES DNA METHYLATION CHANGES AT AN EVOLUTIONARY CONSERVED INTERGENIC REGION IN CHROMOSOME X. CHRONIC STRESS RESULTING FROM PROLONGED EXPOSURE TO NEGATIVE LIFE EVENTS INCREASES THE RISK OF MOOD AND ANXIETY DISORDERS. ALTHOUGH CHRONIC STRESS CAN CHANGE GENE EXPRESSION RELEVANT FOR BEHAVIOR, MOLECULAR REGULATORS OF THIS CHANGE HAVE NOT BEEN FULLY DETERMINED. ONE PROCESS THAT COULD PLAY A ROLE IS DNA METHYLATION, AN EPIGENETIC PROCESS WHEREBY A METHYL GROUP IS ADDED ONTO NUCLEOTIDES, PREDOMINANTLY CYTOSINE IN THE CPG CONTEXT, AND WHICH CAN BE INDUCED BY CHRONIC STRESS. IT IS UNKNOWN TO WHAT EXTENT CHRONIC SOCIAL DEFEAT, A MODEL OF HUMAN SOCIAL STRESS, INFLUENCES DNA METHYLATION PATTERNS ACROSS THE GENOME. OUR STUDY ADDRESSED THIS QUESTION BY USING A TARGETED-CAPTURE APPROACH CALLED METHYL-SEQ TO INVESTIGATE DNA METHYLATION PATTERNS OF THE DENTATE GYRUS AT PUTATIVE REGULATORY REGIONS ACROSS THE MOUSE GENOME FROM MICE EXPOSED TO 14 DAYS OF SOCIAL DEFEAT. FINDINGS WERE REPLICATED IN INDEPENDENT COHORTS BY BISULFITE-PYROSEQUENCING. TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE IDENTIFIED. ONE DMR WAS LOCATED AT INTRON 9 OF DROSHA, AND IT SHOWED REDUCED METHYLATION IN STRESSED MICE. THIS OBSERVATION REPLICATED IN ONE OF TWO INDEPENDENT COHORTS. A SECOND DMR WAS IDENTIFIED AT AN INTERGENIC REGION OF CHROMOSOME X, AND METHYLATION IN THIS REGION WAS INCREASED IN STRESSED MICE. THIS METHYLATION DIFFERENCE REPLICATED IN TWO INDEPENDENT COHORTS AND IN MAJOR DEPRESSIVE DISORDER (MDD) POSTMORTEM BRAINS. THESE RESULTS HIGHLIGHT A REGION NOT PREVIOUSLY KNOWN TO BE DIFFERENTIALLY METHYLATED BY CHRONIC SOCIAL DEFEAT STRESS AND WHICH MAY BE INVOLVED IN MDD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 1508  38 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	
                                                                                        
18 6684  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 2909  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 1345  30 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019