1  2639 95 EPIGENOMIC ANALYSIS DETECTS WIDESPREAD GENE-BODY DNA HYPOMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. WE HAVE EXTENSIVELY CHARACTERIZED THE DNA METHYLOMES OF 139 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH MUTATED OR UNMUTATED IGHV AND OF SEVERAL MATURE B-CELL SUBPOPULATIONS THROUGH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING AND HIGH-DENSITY MICROARRAYS. THE TWO MOLECULAR SUBTYPES OF CLL HAVE DIFFERING DNA METHYLOMES THAT SEEM TO REPRESENT EPIGENETIC IMPRINTS FROM DISTINCT NORMAL B-CELL SUBPOPULATIONS. DNA HYPOMETHYLATION IN THE GENE BODY, TARGETING MOSTLY ENHANCER SITES, WAS THE MOST FREQUENT DIFFERENCE BETWEEN NAIVE AND MEMORY B CELLS AND BETWEEN THE TWO MOLECULAR SUBTYPES OF CLL AND NORMAL B CELLS. ALTHOUGH DNA METHYLATION AND GENE EXPRESSION WERE POORLY CORRELATED, WE IDENTIFIED GENE-BODY CPG DINUCLEOTIDES WHOSE METHYLATION WAS POSITIVELY OR NEGATIVELY ASSOCIATED WITH EXPRESSION. WE HAVE ALSO RECOGNIZED A DNA METHYLATION SIGNATURE THAT DISTINGUISHES NEW CLINICO-BIOLOGICAL SUBTYPES OF CLL. WE PROPOSE AN EPIGENOMIC SCENARIO IN WHICH DIFFERENTIAL METHYLATION IN THE GENE BODY MAY HAVE FUNCTIONAL AND CLINICAL IMPLICATIONS IN LEUKEMOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  1581 30 DNA METHYLATION PROFILES IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY. BACKGROUND: IN ORDER TO GAIN INSIGHT INTO THE CONTRIBUTION OF DNA METHYLATION TO DISEASE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), USING 450K ILLUMINA ARRAYS, WE DETERMINED THE DNA METHYLATION PROFILES IN PAIRED PRE-TREATMENT/RELAPSE SAMPLES FROM 34 CLL PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY, MOSTLY (N = 31) WITH THE FLUDARABINE-CYCLOPHOSPHAMIDE-RITUXIMAB (FCR) REGIMEN. RESULTS: THE EXTENT OF IDENTIFIED CHANGES IN CLL CELLS VERSUS MEMORY B CELLS FROM HEALTHY DONORS WAS TERMED "EPIGENETIC BURDEN" (EB) WHEREAS THE NUMBER OF CHANGES BETWEEN THE PRE-TREATMENT VERSUS THE RELAPSE SAMPLE WAS TERMED "RELAPSE CHANGES" (RC). SIGNIFICANT (P < 0.05) ASSOCIATIONS WERE IDENTIFIED BETWEEN (I) HIGH EB AND SHORT TIME-TO-FIRST-TREATMENT (TTFT); AND, (II) FEW RCS AND SHORT TIME-TO-RELAPSE. BOTH THE EB AND THE RC CLUSTERED IN SPECIFIC GENOMIC REGIONS AND CHROMATIN STATES, INCLUDING REGULATORY REGIONS CONTAINING BINDING SITES OF TRANSCRIPTION FACTORS IMPLICATED IN B CELL AND CLL BIOLOGY. CONCLUSIONS: OVERALL, WE SHOW THAT DNA METHYLATION IN CLL FOLLOWS DIFFERENT DYNAMICS IN RESPONSE TO CHEMOIMMUNOTHERAPY. THESE EPIGENETIC ALTERATIONS WERE LINKED WITH SPECIFIC CLINICAL AND BIOLOGICAL FEATURES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  2418 31 EPIGENETIC SIGNATURE OF CHRONIC LOW BACK PAIN IN HUMAN T CELLS. OBJECTIVE: DETERMINE IF CHRONIC LOW BACK PAIN (LBP) IS ASSOCIATED WITH DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT WILL REVEAL NOVEL MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS AND EXPLORE THE FEASIBILITY OF EPIGENETIC DIAGNOSTIC MARKERS FOR PAIN-RELATED PATHOPHYSIOLOGY. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS OF 850,000 CPG SITES IN WOMEN AND MEN WITH CHRONIC LBP AND PAIN-FREE CONTROLS WAS PERFORMED. T CELLS WERE ISOLATED (DISCOVERY COHORT, N = 32) AND USED TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES, AND GENE ONTOLOGIES AND MOLECULAR PATHWAYS WERE IDENTIFIED. A POLYGENIC DNA METHYLATION SCORE FOR LBP WAS GENERATED IN BOTH WOMEN AND MEN. VALIDATION WAS PERFORMED IN AN INDEPENDENT COHORT (VALIDATION COHORT, N = 63) OF CHRONIC LBP AND HEALTHY CONTROLS. RESULTS: ANALYSIS WITH THE DISCOVERY COHORT REVEALED A TOTAL OF 2,496 AND 419 DIFFERENTIALLY METHYLATED CPGS IN WOMEN AND MEN, RESPECTIVELY. IN WOMEN, MOST OF THESE SITES WERE HYPOMETHYLATED AND ENRICHED IN GENES WITH FUNCTIONS IN THE EXTRACELLULAR MATRIX, IN THE IMMUNE SYSTEM (IE, CYTOKINES), OR IN EPIGENETIC PROCESSES. IN MEN, A UNIQUE CHRONIC LBP DNA METHYLATION SIGNATURE WAS IDENTIFIED CHARACTERIZED BY SIGNIFICANT ENRICHMENT FOR GENES FROM THE MAJOR HISTOCOMPATIBILITY COMPLEX. SEX-SPECIFIC POLYGENIC DNA METHYLATION SCORES WERE GENERATED TO ESTIMATE THE PAIN STATUS OF EACH INDIVIDUAL AND CONFIRMED IN THE VALIDATION COHORT USING PYROSEQUENCING. CONCLUSION: THIS STUDY REVEALS SEX-SPECIFIC DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT DISCRIMINATES CHRONIC LBP PARTICIPANTS FROM HEALTHY CONTROLS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4   972 28 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  3056 28 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  1577 30 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  2771 33 EXTENSIVE PROMOTER DNA HYPERMETHYLATION AND HYPOMETHYLATION IS ASSOCIATED WITH ABERRANT MICRORNA EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA. DYSREGULATED MICRORNA (MIRNA) EXPRESSION CONTRIBUTES TO THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES, INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, AN UNDERSTANDING OF THE MECHANISMS THAT CAUSE ABERRANT MIRNA TRANSCRIPTIONAL CONTROL IS LACKING. IN THIS STUDY, WE COMPREHENSIVELY INVESTIGATED THE ROLE AND EXTENT OF MIRNA EPIGENETIC REGULATION IN CLL. GENOME-WIDE PROFILING CONDUCTED ON 24 CLL AND 10 HEALTHY B CELL SAMPLES REVEALED GLOBAL DNA METHYLATION PATTERNS UPSTREAM OF MIRNA SEQUENCES THAT DISTINGUISHED MALIGNANT FROM HEALTHY CELLS AND IDENTIFIED PUTATIVE MIRNA PROMOTERS. INTEGRATION OF DNA METHYLATION AND MIRNA PROMOTER DATA LED TO THE IDENTIFICATION OF 128 RECURRENT MIRNA TARGETS FOR ABERRANT PROMOTER DNA METHYLATION. DNA HYPOMETHYLATION ACCOUNTED FOR MORE THAN 60% OF ALL ABERRANT PROMOTER-ASSOCIATED DNA METHYLATION IN CLL, AND PROMOTER DNA HYPOMETHYLATION WAS RESTRICTED TO WELL-DEFINED REGIONS. INDIVIDUAL HYPER- AND HYPOMETHYLATED PROMOTERS ALLOWED DISCRIMINATION OF CLL SAMPLES FROM HEALTHY CONTROLS. PROMOTER DNA METHYLATION PATTERNS WERE CONFIRMED IN AN INDEPENDENT PATIENT COHORT, WITH 11 MIRNAS CONSISTENTLY SHOWING AN INVERSE CORRELATION BETWEEN DNA METHYLATION STATUS AND EXPRESSION LEVEL. TOGETHER, OUR FINDINGS CHARACTERIZE THE ROLE OF EPIGENETIC CHANGES IN THE REGULATION OF MIRNA TRANSCRIPTION AND CREATE A REPOSITORY OF DISEASE-SPECIFIC PROMOTER REGIONS THAT MAY PROVIDE ADDITIONAL INSIGHTS INTO THE PATHOGENESIS OF CLL.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  1571 30 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	

9  1343 32 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10   812 33 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020	
                                                                                                      
11  3501 30 IDENTIFICATION OF POTENTIAL BIOMARKERS FOR SYSTEMIC LUPUS ERYTHEMATOSUS BY INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA. INTRODUCTION: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS AND CHRONIC AUTOIMMUNE DISEASE. ABERRANT DNA METHYLATION OCCURS DURING VARIOUS PROCESSES OF SLE DEVELOPMENT REGULATING THE MRNA EXPRESSION OF INTERRELATED GENES. THIS STUDY AIMS TO SCREEN POTENTIAL DNA METHYLATION MARKERS FOR SLE. METHODS: GENE EXPRESSION AND METHYLATION DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN SLE PATIENTS AND HEALTHY CONTROLS WERE SCREENED USING THE LIMMA R PACKAGE, AND DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND REGIONS (DMRS) WERE IDENTIFIED USING DMPFINDER AND BUMPHUNTER (MINFI). ADDITIONALLY, THE DNA METHYLATION MARKERS TO DISTINGUISH SLE PATIENTS FROM HEALTHY CONTROLS WERE EXPLORED THROUGH RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES AND LOGISTIC REGRESSION ANALYSES. FINALLY, WE VALIDATED THE RESULTS OF THE BIOINFORMATIC ANALYSIS BY PYROSEQUENCING. RESULTS: IN TOTAL, 91 DEGS, 90,092 DMPS, 15 DMRS, AND 13 DMR-ASSOCIATED GENES WERE IDENTIFIED. THROUGH THE INTEGRATIVE ANALYSIS OF DEG- AND DMR-ASSOCIATED GENES, WE IDENTIFIED FIVE TYPE I INTERFERON (IFN)-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE. GO ENRICHMENT ANALYSIS SHOWED THAT THE FIVE SLE-ASSOCIATED EPIGENETIC-DRIVEN GENES WERE MAINLY ENRICHED IN THE TYPE I IFN SIGNALING PATHWAY INVOLVED IN IMMUNE RESPONSE AND DEFENSE RESPONSE TO VIRUS. MOREOVER, WE IDENTIFIED TWO SLE-SPECIFIC DNA METHYLATION MARKERS, THREE SLE WITHOUT LUPUS NEPHRITIS (SLE-LN(-))-SPECIFIC DNA METHYLATION MARKERS, AND TWO SLE WITH LUPUS NEPHRITIS (SLE-LN(+))-SPECIFIC DNA METHYLATION MARKERS BY STEPWISE LOGISTIC REGRESSION. CONCLUSIONS: OVERALL, OUR STUDY DEMONSTRATES POTENTIAL DNA METHYLATION MARKERS OF SLE, SLE-LN(-), AND SLE-LN(+), WHICH MAY HELP THE DIAGNOSIS, BOOST THE DEVELOPMENT OF NEW EPIGENETIC THERAPY, AND CONTRIBUTE TO INDIVIDUALIZED TREATMENT. KEY POINTS * THIS STUDY IDENTIFIED FIVE TYPE I IFN-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE, WHICH SUPPORT THE IMPORTANCE OF THE TYPE I IFN PATHWAY IN THE PATHOGENESIS OF SLE * WE IDENTIFIED NOVEL DNA METHYLATION BIOMARKERS IN SLE, SLE-LN-, AND SLE-LN+ BY A COMPREHENSIVE ANALYSIS OF BIOINFORMATICS METHODS AND EXECUTED EXPERIMENTAL VALIDATION, AND BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT THEY HAVE EXCELLENT POTENTIAL * THESE RESULTS MAY PROVIDE NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS OF SLE, AND IDENTIFY RELIABLE BIOMARKERS FOR SLE, SLE-LN-, AND SLE-LN+, WHICH MAY CONTRIBUTE TO DIAGNOSIS AND INDIVIDUALIZED TREATMENT.	2023	
                                                                                                                                                                                
12  1185 30 COORDINATED CHANGES IN AHRR METHYLATION IN LYMPHOBLASTS AND PULMONARY MACROPHAGES FROM SMOKERS. SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, DIABETES, DEPRESSION, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THESE PROCESSES, WE EXAMINED THE RELATIONSHIP OF SMOKING TO GENOME WIDE METHYLATION AND GENE EXPRESSION USING BIOMATERIAL FROM TWO INDEPENDENT SAMPLES, LYMPHOBLAST DNA AND RNA (N = 119) AND LUNG ALVEOLAR MACROPHAGE DNA (N = 19). WE FOUND THAT IN BOTH SAMPLES CURRENT SMOKING STATUS WAS ASSOCIATED WITH SIGNIFICANT CHANGES IN DNA METHYLATION, IN PARTICULAR AT THE ARYL HYDROCARBON RECEPTOR REPRESSOR (AHRR), A KNOWN TUMOR SUPPRESSOR. BOTH BASELINE DNA METHYLATION AND SMOKER ASSOCIATED DNA METHYLATION SIGNATURES AT AHRR WERE HIGHLY CORRELATED (R = 0.94 AND 0.45, RESPECTIVELY). DNA METHYLATION AT THE MOST DIFFERENTIALLY METHYLATED AHRR CPG RESIDUE IN BOTH SAMPLES, CG0557592, WAS SIGNIFICANTLY ASSOCIATED WITH AHRR GENE EXPRESSION. PATHWAY ANALYSIS OF LYMPHOBLAST DATA (GENES WITH MOST SIGNIFICANT METHYLATION CHANGES) DEMONSTRATED ENRICHMENT IN PROTEIN KINASE C PATHWAYS AND IN TGF BETA SIGNALING PATHWAYS. FOR ALVEOLAR MACROPHAGES, PATHWAY ANALYSIS DEMONSTRATED ALTERATIONS IN INFLAMMATION-RELATED PROCESSES. WE CONCLUDE THAT SMOKING IS ASSOCIATED WITH FUNCTIONALLY SIGNIFICANT GENOME WIDE CHANGES IN DNA METHYLATION IN BOTH LYMPHOBLASTS AND PULMONARY MACROPHAGES AND THAT FURTHER INTEGRATED INVESTIGATIONS OF THESE EPIGENETIC EFFECTS OF SMOKING ON CARCINOGENESIS AND OTHER RELATED CO-MORBIDITIES ARE INDICATED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  1068 33 CLL INTRACLONAL FRACTIONS EXHIBIT ESTABLISHED AND RECENTLY ACQUIRED PATTERNS OF DNA METHYLATION. INTRACLONAL SUBPOPULATIONS OF CIRCULATING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS WITH DIFFERENT PROLIFERATIVE HISTORIES AND RECIPROCAL SURFACE EXPRESSION OF CXCR4 AND CD5 HAVE BEEN OBSERVED IN THE PERIPHERAL BLOOD OF CLL PATIENTS AND NAMED PROLIFERATIVE (PF), INTERMEDIATE (IF), AND RESTING (RF) CELLULAR FRACTIONS. HERE, WE FOUND THAT THESE INTRACLONAL CIRCULATING FRACTIONS SHARE PERSISTENT DNA METHYLATION SIGNATURES LARGELY ASSOCIATED WITH THE MUTATION STATUS OF THE IMMUNOGLOBULIN HEAVY CHAIN LOCUS (IGHV) AND THEIR ORIGINS FROM DISTINCT STAGES OF DIFFERENTIATION OF ANTIGEN-EXPERIENCED B CELLS. INCREASED LEUKEMIC BIRTH RATE, HOWEVER, SHOWED A VERY LIMITED IMPACT ON DNA METHYLATION OF CIRCULATING CLL FRACTIONS INDEPENDENT OF IGHV MUTATION STATUS. ADDITIONALLY, DNA METHYLATION HETEROGENEITY INCREASED AS LEUKEMIC CELLS ADVANCED FROM PF TO RF IN THE PERIPHERAL BLOOD. THIS FREQUENTLY CO-OCCURRED WITH HETEROCHROMATIN HYPOMETHYLATION AND HYPERMETHYLATION OF POLYCOMB-REPRESSED REGIONS IN THE PF, SUGGESTING ACCUMULATION OF LONGEVITY-ASSOCIATED EPIGENETIC FEATURES IN RECENTLY BORN CELLS. ON THE OTHER HAND, TRANSCRIPTIONAL DIFFERENCES BETWEEN PAIRED INTRACLONAL FRACTIONS CONFIRMED THEIR PROLIFERATIVE EXPERIENCE AND FURTHER SUPPORTED A LINEAR ADVANCEMENT FROM PF TO RF IN THE PERIPHERAL BLOOD. SEVERAL OF THESE DIFFERENTIALLY EXPRESSED GENES SHOWED UNIQUE ASSOCIATIONS WITH CLINICAL OUTCOME NOT EVIDENT IN THE BULK CLONE, SUPPORTING THE PATHOLOGICAL AND THERAPEUTIC RELEVANCE OF STUDYING INTRACLONAL CLL FRACTIONS. WE CONCLUDE THAT INDEPENDENT METHYLATION AND TRANSCRIPTIONAL LANDSCAPES REFLECT BOTH PREEXISTING CELL-OF-ORIGIN FINGERPRINTS AND MORE RECENTLY ACQUIRED HALLMARKS ASSOCIATED WITH THE LIFE CYCLE OF CIRCULATING CLL CELLS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  2400 32 EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IN WOMEN WITH PCOS IMPACT GENES CONTROLLING REPRODUCTIVE FUNCTION. CONTEXT: POLYCYSTIC OVARY SYNDROME (PCOS) IS A CHRONIC DISEASE AFFECTING REPRODUCTIVE FUNCTION AND WHOLE-BODY METABOLISM. ALTHOUGH THE ETIOLOGY IS UNCLEAR, EMERGING EVIDENCE INDICATES THAT THE EPIGENETICS MAY BE A CONTRIBUTING FACTOR. OBJECTIVE: TO DETERMINE THE ROLE OF GLOBAL AND GENOME-WIDE EPIGENETIC MODIFICATIONS IN SPECIFIC IMMUNE CELLS IN PCOS COMPARED WITH CONTROLS AND WHETHER THESE COULD BE RELATED TO CLINICAL FEATURES OF PCOS. DESIGN: CROSS-SECTIONAL STUDY. PARTICIPANTS: WOMEN WITH (N = 17) OR WITHOUT PCOS (N = 17). SETTING: RECRUITED FROM THE GENERAL COMMUNITY. MAIN OUTCOME MEASURES: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS WERE ANALYZED USING MULTICOLOR FLOW CYTOMETRY METHODS TO DETERMINE GLOBAL DNA METHYLATION LEVELS IN A CELL-SPECIFIC FASHION. TRANSCRIPTOMIC AND GENOME-WIDE DNA METHYLATION ANALYSES WERE PERFORMED ON T HELPER CELLS USING RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING. RESULTS: WOMEN WITH PCOS HAD LOWER GLOBAL DNA METHYLATION IN MONOCYTES (P = 0.006) AND IN T HELPER (P = 0.004), T CYTOTOXIC (P = 0.004), AND B CELLS (P = 0.03). SPECIFIC GENOME-WIDE DNA METHYLATION ANALYSIS OF T HELPER CELLS FROM WOMEN WITH PCOS IDENTIFIED 5581 DIFFERENTIALLY METHYLATED CPG SITES. FUNCTIONAL GENE ONTOLOGY ENRICHMENT ANALYSIS SHOWED THAT GENES LOCATED AT THE PROXIMITY OF DIFFERENTIALLY METHYLATED CPG SITES BELONG TO PATHWAYS RELATED TO REPRODUCTIVE FUNCTION AND IMMUNE CELL FUNCTION. HOWEVER, THESE GENES WERE NOT ALTERED AT THE TRANSCRIPTOMIC LEVEL. CONCLUSIONS: IT WAS SHOWN THAT PCOS IS ASSOCIATED WITH GLOBAL AND GENE-SPECIFIC DNA METHYLATION REMODELING IN A CELL TYPE-SPECIFIC MANNER. FURTHER INVESTIGATION IS WARRANTED TO DETERMINE WHETHER EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IS IMPORTANT IN DETERMINING THE DIFFERENT PHENOTYPES OF PCOS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15   785 30 CELL-TYPE SPECIFIC EWAS IDENTIFIES GENES INVOLVED IN HIV PATHOGENESIS AND ONCOGENESIS AMONG PEOPLE WITH HIV INFECTION. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) OF HETEROGENOUS BLOOD CELLS HAVE IDENTIFIED CPG SITES ASSOCIATED WITH CHRONIC HIV INFECTION, WHICH OFFER LIMITED KNOWLEDGE OF CELL-TYPE SPECIFIC METHYLATION PATTERNS ASSOCIATED WITH HIV INFECTION. APPLYING A COMPUTATIONAL DECONVOLUTION METHOD VALIDATED BY CAPTURE BISULFITE DNA METHYLATION SEQUENCING, WE CONDUCTED A CELL TYPE-BASED EWAS AND IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES SPECIFIC FOR CHRONIC HIV INFECTION AMONG FIVE IMMUNE CELL TYPES IN BLOOD: CD4+ T-CELLS, CD8+ T-CELLS, B CELLS, NATURAL KILLER (NK) CELLS, AND MONOCYTES IN TWO INDEPENDENT COHORTS (N (TOTAL) =1,134). DIFFERENTIALLY METHYLATED CPG SITES FOR HIV-INFECTION WERE HIGHLY CONCORDANT BETWEEN THE TWO COHORTS. CELL-TYPE LEVEL META-EWAS REVEALED DISTINCT PATTERNS OF HIV-ASSOCIATED DIFFERENTIAL CPG METHYLATION, WHERE 67% OF CPG SITES WERE UNIQUE TO INDIVIDUAL CELL TYPES (FALSE DISCOVERY RATE, FDR <0.05). CD4+ T-CELLS HAD THE LARGEST NUMBER OF HIV-ASSOCIATED CPG SITES (N=1,472) COMPARED TO ANY OTHER CELL TYPE. GENES HARBORING STATISTICALLY SIGNIFICANT CPG SITES ARE INVOLVED IN IMMUNITY AND HIV PATHOGENESIS (E.G. CX3CR1 IN CD4+ T-CELLS, CCR7 IN B CELLS, IL12R IN NK CELLS, LCK IN MONOCYTES). MORE IMPORTANTLY, HIV-ASSOCIATED CPG SITES WERE OVERREPRESENTED FOR HALLMARK GENES INVOLVED IN CANCER PATHOLOGY ( FDR <0.05) (E.G. BCL FAMILY, PRDM16, PDCD1LGD, ESR1, DNMT3A, NOTCH2 ). HIV-ASSOCIATED CPG SITES WERE ENRICHED AMONG GENES INVOLVED IN HIV PATHOGENESIS AND ONCOGENESIS SUCH AS KRAS-SIGNALING, INTERFERON-ALPHA AND -GAMMA, TNF-ALPHA, INFLAMMATORY, AND APOPTOTIC PATHWAYS. OUR FINDINGS ARE NOVEL, UNCOVERING CELL-TYPE SPECIFIC MODIFICATIONS IN THE HOST EPIGENOME FOR PEOPLE WITH HIV THAT CONTRIBUTE TO THE GROWING BODY OF EVIDENCE REGARDING PATHOGEN-INDUCED EPIGENETIC ONCOGENICITY, SPECIFICALLY ON HIV AND ITS COMORBIDITY WITH CANCERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  1473 40 DISTINCT PATTERNS OF GLOBAL PROMOTER METHYLATION IN EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA. GENOMIC AND EPIGENOMIC STUDIES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARE RESHAPING OUR UNDERSTANDING OF THE DISEASE AND HAVE PROVIDED NEW PERSPECTIVES FOR A MORE INDIVIDUALIZED DIAGNOSIS AND NEW POTENTIAL THERAPEUTIC TARGETS. IN THIS STUDY, THE GLOBAL PROMOTER METHYLATION PROFILE WAS DETERMINED IN HIGHLY PURIFIED B-CELLS FROM 37 (BINET STAGE A) CLL PATIENTS, USING HIGH-RESOLUTION METHYLATION MICROARRAYS (27,578 CPG). OVERALL, THE METHYLATION PATTERN CORRELATED WITH THE MAJOR BIOLOGICAL (ZAP-70 AND CD38), AND MOLECULAR (IGHV MUTATION) MARKERS, DISTINGUISHING CLL CASES ACCORDING TO IGHV MUTATIONAL STATUS. CELL ADHESION MOLECULES WERE ENRICHED IN THE SIGNATURE OF UNMUTATED (UM) VERSUS MUTATED (M-) CLL. MOREOVER, IN M-CLL CPG HYPER-METHYLATION IN THREE GENES, INCLUDING SPG20, WAS SIGNIFICANTLY ANTI-CORRELATED WITH THE CORRESPONDING GENE EXPRESSION LEVEL. FINALLY, THE CORRELATION BETWEEN THE METHYLATION PATTERN AND CLINICAL PARAMETERS WAS INVESTIGATED. NOTABLY, OUT OF 42 METHYL-PROBES THAT WERE SIGNIFICANTLY ASSOCIATED WITH PROGRESSION FREE SURVIVAL (PFS), HYPER-METHYLATION OF SPG20 WAS ALSO POSITIVELY ASSOCIATED WITH PFS. THESE DATA SUPPORT THE NOTION THAT EPIGENETIC CHANGES HAVE CLINICAL IMPACT IN CLL AND MAY CONTRIBUTE TO THE IDENTIFICATION OF NOVEL CANDIDATE DISEASE-ASSOCIATED GENES POTENTIALLY USEFUL TO PREDICT THE CLINICAL OUTCOME OF EARLY STAGE CLL PATIENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  2643 27 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  3309 30 HIGHER GENE EXPRESSION VARIABILITY IN THE MORE AGGRESSIVE SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PRESENTS TWO SUBTYPES WHICH HAVE DRASTICALLY DIFFERENT CLINICAL OUTCOMES, IGVH MUTATED (M-CLL) AND IGVH UNMUTATED (U-CLL). SO FAR, THESE TWO SUBTYPES ARE NOT ASSOCIATED TO CLEAR DIFFERENCES IN GENE EXPRESSION PROFILES. INTERESTINGLY, RECENT RESULTS HAVE HIGHLIGHTED IMPORTANT ROLES FOR HETEROGENEITY, BOTH AT THE GENETIC AND AT THE EPIGENETIC LEVEL IN CLL PROGRESSION. METHODS: WE ANALYZED GENE EXPRESSION DATA OF TWO LARGE COHORTS OF CLL PATIENTS AND QUANTIFIED EXPRESSION VARIABILITY ACROSS INDIVIDUALS TO INVESTIGATE DIFFERENCES BETWEEN THE TWO SUBTYPES USING DIFFERENT MEASURES AND STATISTICAL TESTS. FUNCTIONAL SIGNIFICANCE WAS EXPLORED BY PATHWAY ENRICHMENT AND NETWORK ANALYSES. FURTHERMORE, WE IMPLEMENTED A RANDOM FOREST APPROACH BASED ON EXPRESSION VARIABILITY TO CLASSIFY PATIENTS INTO DISEASE SUBTYPES. RESULTS: WE FOUND THAT U-CLL, THE MORE AGGRESSIVE TYPE OF THE DISEASE, SHOWS SIGNIFICANTLY INCREASED VARIABILITY OF GENE EXPRESSION ACROSS PATIENTS AND THAT, OVERALL, GENES THAT SHOW HIGHER VARIABILITY IN THE AGGRESSIVE SUBTYPE ARE RELATED TO CELL CYCLE, DEVELOPMENT AND INTER-CELLULAR COMMUNICATION. THESE FUNCTIONS INDICATE A POTENTIAL RELATION BETWEEN GENE EXPRESSION VARIABILITY AND THE FASTER PROGRESSION OF THIS CLL SUBTYPE. FINALLY, A CLASSIFIER BASED ON GENE EXPRESSION VARIABILITY WAS ABLE TO CORRECTLY PREDICT THE DISEASE SUBTYPE OF CLL PATIENTS. CONCLUSIONS: THERE ARE STRONG RELATIONS BETWEEN GENE EXPRESSION VARIABILITY AND DISEASE SUBTYPE LINKING SIGNIFICANTLY INCREASED EXPRESSION VARIABILITY TO PHENOTYPES SUCH AS AGGRESSIVENESS AND RESISTANCE TO THERAPY IN CLL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  3068 28 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES DIFFERENTIAL METHYLATION IN UNINVOLVED PSORIATIC EPIDERMIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH BOTH LOCAL AND SYSTEMIC COMPONENTS. GENOME-WIDE APPROACHES HAVE IDENTIFIED MORE THAN 60 PSORIASIS-SUSCEPTIBILITY LOCI, BUT GENES ARE ESTIMATED TO EXPLAIN ONLY ONE-THIRD OF THE HERITABILITY IN PSORIASIS, SUGGESTING ADDITIONAL, YET UNIDENTIFIED, SOURCES OF HERITABILITY. EPIGENETIC MODIFICATIONS HAVE BEEN LINKED TO PSORIASIS AND ALTERED DNA METHYLATION PATTERNS IN PSORIATIC VERSUS HEALTHY SKIN HAVE BEEN REPORTED IN WHOLE-SKIN BIOPSIES. IN THIS STUDY, FOCUSING ON EPIGENETIC MODIFICATIONS IN THE PSORIATIC UNINVOLVED SKIN, WE COMPARED THE LESIONAL AND NON-LESIONAL EPIDERMIS FROM PSORIASIS PATIENTS WITH EPIDERMIS FROM HEALTHY CONTROLS. WE PERFORMED AN EXHAUSTIVE GENOME-WIDE DNA METHYLATION PROFILING USING REDUCED REPRESENTATION BISULFITE SEQUENCING, WHICH INTERROGATES THE METHYLATION STATUS OF APPROXIMATELY 3-4 MILLION CPG SITES. MORE THAN 2,000 STRONGLY DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED AND A STRIKING OVERREPRESENTATION OF THE WNT AND CADHERIN PATHWAYS AMONG THE DIFFERENTIALLY METHYLATED SITES WAS FOUND. IN PARTICULAR, WE OBSERVE A STRONG DIFFERENTIAL METHYLATION IN SEVERAL PSORIASIS CANDIDATE GENES. A SUBSTANTIAL NUMBER OF DIFFERENTIALLY METHYLATED SITES PRESENT IN THE UNINVOLVED VERSUS HEALTHY EPIDERMIS SUGGESTS THE PRESENCE OF A PRE-PSORIATIC STATE IN THE CLINICALLY HEALTHY SKIN TYPE. OUR EXPLORATORY STUDY REPRESENTS A STARTING POINT FOR IDENTIFYING BIOMARKERS FOR PSORIASIS-PRONE SKIN BEFORE DISEASE ONSET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  1132 32 COMPREHENSIVE DNA METHYLATION ANALYSIS USING A METHYL-CPG-BINDING DOMAIN CAPTURE-BASED METHOD IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. THE ROLE OF LONG NONCODING RNAS (LNCRNAS) IN CANCER IS COMING TO THE FOREFRONT DUE TO GROWING INTEREST IN UNDERSTANDING THEIR MECHANISTIC FUNCTIONS DURING CANCER DEVELOPMENT AND PROGRESSION. DESPITE THIS, THE GLOBAL EPIGENETIC REGULATION OF LNCRNAS AND REPETITIVE SEQUENCES IN CANCER HAS NOT BEEN WELL INVESTIGATED, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THIS STUDY FOCUSES ON A UNIQUE APPROACH: THE IMMUNOPRECIPITATION-BASED CAPTURE OF DOUBLE-STRANDED, METHYLATED DNA FRAGMENTS USING METHYL-BINDING DOMAIN (MBD) PROTEINS, FOLLOWED BY NEXT-GENERATION SEQUENCING (MBD-SEQ). CLL PATIENT SAMPLES BELONGING TO TWO PROGNOSTIC SUBGROUPS (5 IGVH MUTATED SAMPLES + 5 IGVH UNMUTATED SAMPLES) WERE USED IN THIS STUDY. ANALYSIS REVEALED 5,800 HYPERMETHYLATED AND 12,570 HYPOMETHYLATED CLL-SPECIFIC DIFFERENTIALLY METHYLATED GENES (CLLDMGS) COMPARED TO NORMAL HEALTHY CONTROLS. IMPORTANTLY, THESE RESULTS IDENTIFIED SEVERAL CLL-SPECIFIC, DIFFERENTIALLY METHYLATED LNCRNAS, REPETITIVE ELEMENTS, AND PROTEIN-CODING GENES WITH POTENTIAL PROGNOSTIC VALUE. THIS WORK OUTLINES A DETAILED PROTOCOL FOR AN MBD-SEQ AND BIOINFORMATICS PIPELINE DEVELOPED FOR THE COMPREHENSIVE ANALYSIS OF GLOBAL METHYLATION PROFILES IN HIGHLY CPG-RICH REGIONS USING CLL PATIENT SAMPLES. FINALLY, A PROTEIN-CODING GENE AND AN LNCRNA WERE VALIDATED USING PYROSEQUENCING, WHICH IS A HIGHLY QUANTITATIVE METHOD TO ANALYZE CPG METHYLATION LEVELS TO FURTHER CORROBORATE THE FINDINGS FROM THE MBD-SEQ PROTOCOL.	2017