1  4240 100 METHYLATION QUANTITATIVE TRAIT LOCUS ANALYSIS OF CHRONIC POSTSURGICAL PAIN UNCOVERS EPIGENETIC MEDIATORS OF GENETIC RISK. BACKGROUND: OVERLAP OF PATHWAYS ENRICHED BY SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA-METHYLATION UNDERLYING CHRONIC POSTSURGICAL PAIN (CPSP), PROMPTED PILOT STUDY OF CPSP-ASSOCIATED METHYLATION QUANTITATIVE TRAIT LOCI (MEQTL). MATERIALS & METHODS: CHILDREN UNDERGOING SPINE-FUSION WERE RECRUITED PROSPECTIVELY. LOGISTIC-REGRESSION FOR GENOME- AND EPIGENOME-WIDE CPSP ASSOCIATION AND DNA-METHYLATION-SINGLE NUCLEOTIDE POLYMORPHISM ASSOCIATION/MEDIATION ANALYSES TO IDENTIFY MEQTLS WERE FOLLOWED BY FUNCTIONAL GENOMICS ANALYSES. RESULTS: CPSP (N = 20/58) AND NON-CPSP GROUPS DIFFERED IN PAIN-MEASURES. OF 2753 MEQTLS, DNA-METHYLATION AT 127 CYTOSINE-GUANINE DINUCLEOTIDES MEDIATED ASSOCIATION OF 470 MEQTLS WITH CPSP (P < 0.05). AT PARK16 LOCUS, CPSP RISK MEQTLS WERE ASSOCIATED WITH DECREASED DNA-METHYLATION AT RAB7L1 AND INCREASED DNA-METHYLATION AT PM20D1. CORRESPONDING RAB7L1/PM20D1 BLOOD EQTLS (GTEX) AND CYTOSINE-GUANINE DINUCLEOTIDE-LOCI ENRICHMENT FOR HISTONE MARKS, TRANSCRIPTION FACTOR BINDING SITES AND ATAC-SEQ PEAKS SUGGEST ALTERED TRANSCRIPTION FACTOR-BINDING. CONCLUSION: CPSP-ASSOCIATED MEQTLS INDICATE EPIGENETIC MECHANISMS MEDIATE GENETIC RISK. CLINICAL TRIAL REGISTRATION: NCT01839461, NCT01731873 (CLINICALTRIALS.GOV).	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  1218  15 CRISPR INTERFERENCE OF A CLONALLY VARIANT GC-RICH NONCODING RNA FAMILY LEADS TO GENERAL REPRESSION OF VAR GENES IN PLASMODIUM FALCIPARUM. THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM USES MUTUALLY EXCLUSIVE EXPRESSION OF THE PFEMP1-ENCODING VAR GENE FAMILY TO EVADE THE HOST IMMUNE SYSTEM. DESPITE PROGRESS IN THE MOLECULAR UNDERSTANDING OF THE DEFAULT SILENCING MECHANISM, THE ACTIVATION MECHANISM OF THE UNIQUELY EXPRESSED VAR MEMBER REMAINS ELUSIVE. A GC-RICH NONCODING RNA (NCRNA) GENE FAMILY HAS COEVOLVED WITH PLASMODIUM SPECIES THAT EXPRESS VAR GENES. HERE, WE SHOW THAT THIS NCRNA FAMILY IS TRANSCRIBED IN A CLONALLY VARIANT MANNER, WITH PREDOMINANT TRANSCRIPTION OF A SINGLE MEMBER OCCURRING WHEN THE NCRNA IS LOCATED ADJACENT TO AND UPSTREAM OF AN ACTIVE VAR GENE. WE DEVELOPED A SPECIFIC CRISPR INTERFERENCE (CRISPRI) STRATEGY THAT ALLOWED FOR THE TRANSCRIPTIONAL REPRESSION OF ALL GC-RICH MEMBERS. A LACK OF GC-RICH NCRNA TRANSCRIPTION LED TO THE DOWNREGULATION OF THE ENTIRE VAR GENE FAMILY IN RING-STAGE PARASITES. STRIKINGLY, IN MATURE BLOOD-STAGE PARASITES, THE GC-RICH NCRNA CRISPRI AFFECTED THE TRANSCRIPTION PATTERNS OF OTHER CLONALLY VARIANT GENE FAMILIES, INCLUDING THE DOWNREGULATION OF ALL PFMC-2TM MEMBERS. WE PROVIDE EVIDENCE FOR THE KEY ROLE OF GC-RICH NCRNA TRANSCRIPTION IN VAR GENE ACTIVATION AND DISCOVERED A MOLECULAR LINK BETWEEN THE TRANSCRIPTIONAL CONTROL OF VARIOUS CLONALLY VARIANT MULTIGENE FAMILIES INVOLVED IN PARASITE VIRULENCE. THIS WORK OPENS NEW AVENUES FOR ELUCIDATING THE MOLECULAR PROCESSES THAT CONTROL IMMUNE EVASION AND PATHOGENESIS IN P. FALCIPARUMIMPORTANCEPLASMODIUM FALCIPARUM IS THE DEADLIEST MALARIA PARASITE SPECIES, ACCOUNTING FOR THE VAST MAJORITY OF DISEASE CASES AND DEATHS. THE VIRULENCE OF THIS PARASITE IS RELIANT UPON THE MUTUALLY EXCLUSIVE EXPRESSION OF CYTOADHERENCE PROTEINS ENCODED BY THE 60-MEMBER VAR GENE FAMILY. ANTIGENIC VARIATION OF THIS MULTIGENE FAMILY SERVES AS AN IMMUNE EVASION MECHANISM, ULTIMATELY LEADING TO CHRONIC INFECTION AND PATHOGENESIS. UNDERSTANDING THE REGULATION MECHANISM OF ANTIGENIC VARIATION IS KEY TO DEVELOPING NEW THERAPEUTIC AND CONTROL STRATEGIES. OUR STUDY UNCOVERS A NOVEL LAYER IN THE EPIGENETIC REGULATION OF TRANSCRIPTION OF THIS FAMILY OF VIRULENCE GENES BY MEANS OF A MULTIGENE-TARGETING CRISPR INTERFERENCE APPROACH.	2020	
              
3   774  18 CELL TYPE-SPECIFIC MECHANISM OF SETD1A HETEROZYGOSITY IN SCHIZOPHRENIA PATHOGENESIS. SCHIZOPHRENIA (SCZ) IS A CHRONIC, SERIOUS MENTAL DISORDER. ALTHOUGH MORE THAN 200 SCZ-ASSOCIATED GENES HAVE BEEN IDENTIFIED, THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS REMAIN LARGELY UNKNOWN. HERE, WE GENERATED A SETD1A (SET DOMAIN CONTAINING 1A) HAPLOINSUFFICIENCY MOUSE MODEL TO UNDERSTAND HOW THIS SCZ-ASSOCIATED EPIGENETIC FACTOR AFFECTS GENE EXPRESSION IN BRAIN REGIONS HIGHLY RELEVANT TO SCZ. SINGLE-CELL RNA SEQUENCING REVEALED THAT SETD1A HETEROZYGOSITY CAUSES HIGHLY VARIABLE TRANSCRIPTIONAL ADAPTATIONS ACROSS DIFFERENT CELL TYPES IN PREFRONTAL CORTEX (PFC) AND STRIATUM. THE FOXP2(+) NEURONS EXHIBIT THE MOST PROMINENT GENE EXPRESSION CHANGES AMONG THE DIFFERENT NEURON SUBTYPES IN PFC, WHICH CORRELATE WITH CHANGES IN HISTONE H3 LYSINE 4 TRIMETHYLATION. MANY OF THE GENES DYSREGULATED IN SETD1A(+/-) MICE ARE INVOLVED IN NEURON MORPHOGENESIS AND SYNAPTIC FUNCTION. CONSISTENTLY, SETD1A(+/-) MICE EXHIBIT CERTAIN BEHAVIORAL FEATURES OF PATIENTS WITH SCZ. COLLECTIVELY, OUR STUDY ESTABLISHES SETD1A(+/-) MICE AS A MODEL FOR UNDERSTANDING SCZ AND UNCOVERS A COMPLEX BRAIN REGION- AND CELL TYPE-SPECIFIC DYSREGULATION THAT POTENTIALLY UNDERLIES SCZ PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  3755  25 INTEGRATED BIOINFORMATICS ANALYSIS UNCOVERS CHARACTERISTIC GENES AND MOLECULAR SUBTYPING SYSTEM FOR ENDOMETRIOSIS. OBJECTIVE: ENDOMETRIOSIS IS A CHRONIC INFLAMMATORY ESTROGEN-DEPENDENT DISEASE WITH THE GROWTH OF ENDOMETRIAL TISSUES OUTSIDE THE UTERINE CAVITY. NEVERTHELESS, THE ETIOLOGY OF ENDOMETRIOSIS IS STILL UNCLEAR. INTEGRATED BIOINFORMATICS ANALYSIS WAS IMPLEMENTED TO REVEAL THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE. METHODS: A TOTAL OF FOUR GENE EXPRESSION DATASETS (GSE7305, GSE11691, GSE23339, AND GSE25628) WERE RETRIEVED FROM THE GEO, WHICH WERE MERGED INTO A META-DATASET, FOLLOWED BY THE REMOVAL OF BATCH EFFECTS VIA THE SVA PACKAGE. WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA) WAS IMPLEMENTED, AND ENDOMETRIOSIS-RELATED GENES WERE SCREENED UNDER NORMAL AND ENDOMETRIOSIS CONDITIONS. THEREAFTER, CHARACTERISTIC GENES WERE DETERMINED VIA LASSO ANALYSIS. THE DIAGNOSTIC PERFORMANCE WAS ESTIMATED VIA RECEIVER OPERATING CHARACTERISTIC CURVES, AND EPIGENETIC AND POST-TRANSCRIPTIONAL MODIFICATIONS WERE ANALYZED. SMALL MOLECULAR COMPOUNDS WERE PREDICTED. UNSUPERVISED CLUSTERING ANALYSIS WAS CONDUCTED VIA NON-NEGATIVE MATRIX FACTORIZATION ALGORITHM. THE ENRICHED PATHWAYS WERE ANALYZED VIA GENE SET ENRICHMENT ANALYSIS OR GSVA. IMMUNE FEATURES WERE EVALUATED ACCORDING TO IMMUNE-CHECKPOINTS, HLA, RECEPTORS, CHEMOKINES, AND IMMUNE CELLS. RESULTS: IN TOTAL, FOUR CHARACTERISTIC GENES (BGN, AQP1, ELMO1, AND DDR2) WERE DETERMINED FOR ENDOMETRIOSIS, ALL OF WHICH EXHIBITED THE FAVORABLE EFFICACY IN DIAGNOSING ENDOMETRIOSIS. THEIR ABERRANT LEVELS WERE MODULATED BY EPIGENETIC AND POST-TRANSCRIPTIONAL MODIFICATIONS. IN TOTAL, 51 POTENTIAL DRUGS WERE PREDICTED AGAINST ENDOMETRIOSIS. THE CHARACTERISTIC GENES EXHIBITED REMARKABLE ASSOCIATIONS WITH IMMUNOLOGICAL FUNCTION. THREE SUBTYPES WERE CLASSIFIED ACROSS ENDOMETRIOSIS, WITH DIFFERENT MECHANISMS AND IMMUNE FEATURES. CONCLUSION: OUR STUDY REVEALS THE CHARACTERISTIC GENES AND NOVEL MOLECULAR SUBTYPING OF ENDOMETRIOSIS, CONTRIBUTING TO THE EARLY DIAGNOSIS AND INTERVENTION IN ENDOMETRIOSIS.	2022	
                                                                                                                                                                                                                                                                                 
5  6651  15 UPDATE ON GENETICS AND EPIGENETICS IN METABOLIC ASSOCIATED FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS BECOMING THE MOST FREQUENT CHRONIC LIVER DISEASE WORLDWIDE. METABOLIC (DYSFUNCTION) ASSOCIATED FATTY LIVER DISEASE (MAFLD) IS SUGGESTED TO REPLACE THE NOMENCLATURE OF NAFLD. FOR INDIVIDUALS WITH METABOLIC DYSFUNCTION, MULTIPLE NAFLD-RELATED FACTORS ALSO CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF MAFLD INCLUDING GENETICS AND EPIGENETICS. THE APPLICATION OF GENOME-WIDE ASSOCIATION STUDY (GWAS) AND EXOME-WIDE ASSOCIATION STUDY (EWAS) UNCOVERS SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) IN MAFLD. IN ADDITION TO THE CLASSIC SNPS IN PNPLA3, TM6SF2, AND GCKR, SOME NEW SNPS HAVE BEEN FOUND RECENTLY TO CONTRIBUTE TO THE PATHOGENESIS OF LIVER STEATOSIS. EPIGENETIC FACTORS INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS REGULATIONS, AND RNA METHYLATION ALSO PLAY A CRITICAL ROLE IN MAFLD. DNA METHYLATION IS THE MOST REPORTED EPIGENETIC MODIFICATION. DEVELOPING A NON-INVASION BIOMARKER TO DISTINGUISH METABOLIC STEATOHEPATITIS (MASH) OR LIVER FIBROSIS IS ONGOING. IN THIS REVIEW, WE SUMMARIZED AND DISCUSSED THE LATEST PROGRESS IN GENETIC AND EPIGENETIC FACTORS OF NAFLD/MAFLD, IN ORDER TO PROVIDE POTENTIAL CLUES FOR MAFLD TREATMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  5096  20 PLASMODIUM FALCIPARUM SET2 DOMAIN IS ALLOSTERICALLY REGULATED BY ITS PHD-LIKE DOMAIN TO METHYLATE AT H3K36. THE ANTIGENIC VARIATION IS AN ESSENTIAL MECHANISM EMPLOYED BY THE MALARIA PARASITE TO ESTABLISH A CHRONIC INFECTION IN HUMANS. THREE MAJOR VIRULENT PROTEINS EMP1, RIFINS, AND STEVOR HAVE BEEN IMPLICATED IN CONTRIBUTING TO THE ANTIGENIC VARIATION PROCESS AND ARE ENCODED BY MULTIGENE FAMILIES IN PLASMODIUM SPP. THE KEY VIRULENCE FACTOR PFEMP1 IS ENCODED BY VAR GENES, AND IT EXHIBITS A MUTUALLY EXCLUSIVE TRANSCRIPTIONAL SWITCHING BETWEEN VAR GENES, ENSURING AN INDIVIDUAL PARASITE ONLY TRANSCRIBES A SINGLE VAR GENE AT A TIME. EXPRESSION OF VAR GENES IS TIGHTLY REGULATED BY TWO HISTONE EPIGENETIC METHYLATION MARKS H3K36ME3 AND H3K9ME3, OF WHICH THE H3K36ME3 MARK IS HIGHLY ENRICHED ON TRANSCRIPTION START SITES (TSSS) OF SUPPRESSED VAR GENES IN P. FALCIPARUM. HOWEVER, THE MECHANISMS OF H3K36ME3 MARK PROPAGATION ON ALL THE 59 VAR GENES OF P. FALCIPARUM ARE NOT KNOWN. HERE, WE HAVE IDENTIFIED A PHD (PLANT HOMEODOMAIN-LIKE DOMAIN) LIKE DOMAIN PRESENT WITHIN THE PFSET2 PROTEIN THAT SPECIFICALLY BINDS TO THE H3K36ME2 MARK, AN INTERMEDIATE PRODUCT OF THE H3K36ME3 MARK FORMATION ON THE NUCLEOSOME. SURPRISINGLY, WE HAVE FOUND THAT PHD - H3K36ME2 INTERACTION LEADS TO STIMULATION OF SET2 DOMAIN ACTIVITY ON THE NUCLEOSOME SUBSTRATES. THE ALLOSTERIC STIMULATION OF THE PFSET2 DOMAIN BY PHD-LIKE DOMAIN PRESENT WITHIN THE SAME PROTEIN SUGGESTS A NOVEL MECHANISM OF H3K36ME3 MARK PROPAGATION ON VAR GENES OF P. FALCIPARUM. THIS STUDY PROPOSES ALLOSTERIC REGULATION OF PFSET2 PROTEIN BY H3K36ME2 MARK AS AN ESSENTIAL MECHANISM OF VAR GENES SUPPRESSION TO ENSURE SUCCESSFUL ANTIGENIC VARIATION BY THE MALARIA PARASITE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  4055  19 MAPPING OF HISTONE MODIFICATIONS IN EPISOMAL HBV CCCDNA UNCOVERS AN UNUSUAL CHROMATIN ORGANIZATION AMENABLE TO EPIGENETIC MANIPULATION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AFFECTS 240 MILLION PEOPLE WORLDWIDE AND IS A MAJOR RISK FACTOR FOR LIVER FAILURE AND HEPATOCELLULAR CARCINOMA. CURRENT ANTIVIRAL THERAPY INHIBITS CYTOPLASMIC HBV GENOMIC REPLICATION, BUT IS NOT CURATIVE BECAUSE IT DOES NOT DIRECTLY AFFECT NUCLEAR HBV CLOSED CIRCULAR DNA (CCCDNA), THE GENOMIC FORM THAT TEMPLATES VIRAL TRANSCRIPTION AND SUSTAINS VIRAL PERSISTENCE. NOVEL APPROACHES THAT DIRECTLY TARGET CCCDNA REGULATION WOULD THEREFORE BE HIGHLY DESIRABLE. CCCDNA IS ASSEMBLED WITH CELLULAR HISTONE PROTEINS INTO CHROMATIN, BUT LITTLE IS KNOWN ABOUT THE REGULATION OF HBV CHROMATIN BY HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). HERE, USING A NEW CCCDNA CHIP-SEQ APPROACH, WE REPORT, TO OUR KNOWLEDGE, THE FIRST GENOME-WIDE MAPS OF PTMS IN CCCDNA-CONTAINING CHROMATIN FROM DE NOVO INFECTED HEPG2 CELLS, PRIMARY HUMAN HEPATOCYTES, AND FROM HBV-INFECTED LIVER TISSUE. WE FIND HIGH LEVELS OF PTMS ASSOCIATED WITH ACTIVE TRANSCRIPTION ENRICHED AT SPECIFIC SITES WITHIN THE HBV GENOME AND, SURPRISINGLY, VERY LOW LEVELS OF PTMS LINKED TO TRANSCRIPTIONAL REPRESSION EVEN AT SILENT HBV PROMOTERS. WE SHOW THAT TRANSCRIPTION AND ACTIVE PTMS IN HBV CHROMATIN ARE REDUCED BY THE ACTIVATION OF AN INNATE IMMUNITY PATHWAY, AND THAT THIS EFFECT CAN BE RECAPITULATED WITH A SMALL MOLECULE EPIGENETIC MODIFYING AGENT, OPENING THE POSSIBILITY THAT CHROMATIN-BASED REGULATION OF CCCDNA TRANSCRIPTION COULD BE A NEW THERAPEUTIC APPROACH TO CHRONIC HBV INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  1468  20 DISTINCT EPIGENETIC PROGRAMS REGULATE CARDIAC MYOCYTE DEVELOPMENT AND DISEASE IN THE HUMAN HEART IN VIVO. EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTOR NETWORKS ESSENTIAL FOR DIFFERENTIATION OF CARDIAC MYOCYTES HAVE BEEN UNCOVERED. HOWEVER, RESHAPING OF THE EPIGENOME OF THESE TERMINALLY DIFFERENTIATED CELLS DURING FETAL DEVELOPMENT, POSTNATAL MATURATION, AND IN DISEASE REMAINS UNKNOWN. HERE, WE INVESTIGATE THE DYNAMICS OF THE CARDIAC MYOCYTE EPIGENOME DURING DEVELOPMENT AND IN CHRONIC HEART FAILURE. WE FIND THAT PRENATAL DEVELOPMENT AND POSTNATAL MATURATION ARE CHARACTERIZED BY A COOPERATION OF ACTIVE CPG METHYLATION AND HISTONE MARKS AT CIS-REGULATORY AND GENIC REGIONS TO SHAPE THE CARDIAC MYOCYTE TRANSCRIPTOME. IN CONTRAST, PATHOLOGICAL GENE EXPRESSION IN TERMINAL HEART FAILURE IS ACCOMPANIED BY CHANGES IN ACTIVE HISTONE MARKS WITHOUT MAJOR ALTERATIONS IN CPG METHYLATION AND REPRESSIVE CHROMATIN MARKS. NOTABLY, CIS-REGULATORY REGIONS IN CARDIAC MYOCYTES ARE SIGNIFICANTLY ENRICHED FOR CARDIOVASCULAR DISEASE-ASSOCIATED VARIANTS. THIS STUDY UNCOVERS DISTINCT LAYERS OF EPIGENETIC REGULATION NOT ONLY DURING PRENATAL DEVELOPMENT AND POSTNATAL MATURATION BUT ALSO IN DISEASED HUMAN CARDIAC MYOCYTES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9    17  14 5' FLANKING REGION OF VAR GENES NUCLEATE HISTONE MODIFICATION PATTERNS LINKED TO PHENOTYPIC INHERITANCE OF VIRULENCE TRAITS IN MALARIA PARASITES. IN THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM ANTIGENIC VARIATION FACILITATES LONG-TERM CHRONIC INFECTION OF THE HOST. THIS IS ACHIEVED BY SEQUENTIAL EXPRESSION OF A SINGLE MEMBER OF THE 60-MEMBER VAR FAMILY. HERE WE SHOW THAT THE 5' FLANKING REGION NUCLEATES EPIGENETIC EVENTS STRONGLY LINKED TO THE MAINTENANCE OF MONO-ALLELIC VAR GENE EXPRESSION PATTERN DURING PARASITE PROLIFERATION. TRI- AND DIMETHYLATION OF HISTONE H3 LYSINE 4 PEAK IN THE 5' UPSTREAM REGION OF TRANSCRIBED VAR AND DURING THE POISED STATE (NON-TRANSCRIBED PHASE OF VAR GENES DURING THE 48 H ASEXUAL LIFE CYCLE), 'BOOKMARKING' THIS MEMBER FOR RE-ACTIVATION AT THE ONSET OF THE NEXT CYCLE. HISTONE H3 LYSINE 9 TRIMETHYLATION ACTS AS AN ANTAGONIST TO LYSINE 4 METHYLATION TO ESTABLISH STABLY SILENT VAR GENE STATES ALONG THE 5' FLANKING AND CODING REGION. FURTHERMORE, WE SHOW THAT COMPETITION EXISTS BETWEEN H3K9 METHYLATION AND H3K9 ACETYLATION IN THE 5' FLANKING REGION AND THAT THESE MARKS CONTRIBUTE EPIGENETICALLY TO REPRESSING OR ACTIVATING VAR GENE EXPRESSION. OUR WORK POINTS TO A PIVOTAL ROLE OF THE HISTONE METHYL MARK WRITING AND READING MACHINERY IN THE PHENOTYPIC INHERITANCE OF VIRULENCE TRAITS IN THE MALARIA PARASITE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10   340  14 ALTERATIONS IN LOCAL CHROMATIN ENVIRONMENT ARE INVOLVED IN SILENCING AND ACTIVATION OF SUBTELOMERIC VAR GENES IN PLASMODIUM FALCIPARUM. PLASMODIUM FALCIPARUM ERYTHROCYTE MEMBRANE PROTEIN 1 (PFEMP1), ENCODED BY THE VAR GENE FAMILY, UNDERGOES ANTIGENIC VARIATION AND PLAYS AN IMPORTANT ROLE IN CHRONIC INFECTION AND SEVERE MALARIA. ONLY A SINGLE VAR GENE IS TRANSCRIBED PER PARASITE, AND EPIGENETIC CONTROL MECHANISMS ARE FUNDAMENTAL IN THIS STRATEGY OF MUTUALLY EXCLUSIVE TRANSCRIPTION. WE SHOW THAT SUBTELOMERIC UPSB VAR GENE PROMOTERS CARRIED ON EPISOMES ARE SILENCED BY DEFAULT, AND THAT PROMOTER ACTIVATION IS SUFFICIENT TO SILENCE ALL OTHER FAMILY MEMBERS. HOWEVER, THEY ARE ACTIVE BY DEFAULT WHEN PLACED DOWNSTREAM OF A SECOND ACTIVE VAR PROMOTER, UNDERSCORING THE SIGNIFICANCE OF LOCAL CHROMATIN ENVIRONMENT AND NUCLEAR COMPARTMENTALIZATION IN VAR PROMOTER REGULATION. NATIVE CHROMATIN COVERING THE SPE2-REPEAT ARRAY IN UPSB PROMOTERS IS RESISTANT TO NUCLEASE DIGESTION, AND INSERTION OF THESE REGULATORY ELEMENTS INTO A HETEROLOGOUS PROMOTER CAUSES LOCAL ALTERATIONS IN NUCLEOSOMAL ORGANIZATION AND PROMOTER REPRESSION. OUR FINDINGS SUGGEST A COMMON LOGIC UNDERLYING THE TRANSCRIPTIONAL CONTROL OF ALL VAR GENES, AND HAVE IMPORTANT IMPLICATIONS FOR OUR UNDERSTANDING OF THE EPIGENETIC PROCESSES INVOLVED IN THE REGULATION OF THIS MAJOR VIRULENCE GENE FAMILY.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11   408  23 ANALYSIS OF GENE EXPRESSION AND METHYLATION DATASETS IDENTIFIED ADAMTS9, FKBP5, AND PFKBF3 AS BIOMARKERS FOR OSTEOARTHRITIS. BACKGROUND: OSTEOARTHRITIS (OA) IS A KIND OF CHRONIC OSTEOARTHROPATHY AND DEGENERATIVE JOINT DISEASE. EPIGENETIC REGULATION IN THE GENE EXPRESSION DYNAMICS HAS BECOME INCREASINGLY IMPORTANT IN OA. WE PERFORMED A COMBINED ANALYSIS OF TWO TYPES OF MICROARRAY DATASETS (GENE EXPRESSION AND DNA METHYLATION) TO IDENTIFY METHYLATION-BASED KEY BIOMARKERS TO PROVIDE A BETTER UNDERSTANDING OF MOLECULAR BIOLOGICAL MECHANISMS OF OA. METHODS: WE OBTAINED TWO EXPRESSION PROFILING DATASETS (GSE55235, GSE55457) AND ONE DNA METHYLATION PROFILING DATA SET (GSE63695) FROM THE GENE EXPRESSION OMNIBUS. FIRST, DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN PATIENTS WITH OA AND CONTROLS WERE IDENTIFIED USING THE LIMMA PACKAGE IN R(V3.4.4). THEN, FUNCTION ENRICHMENT ANALYSIS OF DEGS WAS PERFORMED USING A DAVID DATABASE. FOR DNA METHYLATION DATASETS, CHAMP METHYLATION ANALYSIS PACKAGE WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION GENES (DMGS). FINALLY, A COMPREHENSIVE ANALYSIS OF DEGS AND DMGS WAS CONDUCTED TO IDENTIFY GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION SIMULTANEOUSLY. RESULTS: WE IDENTIFIED 112 DEGS AND 2,896 DMGS IN PATIENTS WITH OA COMPARED WITH CONTROLS. FUNCTIONAL ANALYSIS OF DEGS OBTAINED THAT INFLAMMATORY RESPONSES, IMMUNE RESPONSES, AND POSITIVE REGULATION OF APOPTOSIS, TUMOR NECROSIS FACTOR (TNF) SIGNALING PATHWAY, AND OSTEOCLAST DIFFERENTIATION MAY BE INVOLVED IN THE PATHOGENESIS OF OA. CROSS-ANALYSIS REVEALED 26 GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION IN OA. AMONG THEM, ADAMTS9, FKBP5, AND PFKBF3 WERE IDENTIFIED AS VALUABLE METHYLATION-BASED BIOMARKERS FOR OA. CONCLUSION: IN SUMMARY, OUR STUDY IDENTIFIED DIFFERENT MOLECULAR FEATURES BETWEEN PATIENTS WITH OA AND CONTROLS. THIS MAY PROVIDE NEW CLUES FOR CLARIFYING THE PATHOGENETIC MECHANISMS OF OA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                         
12  1590  24 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  3420  26 HUMAN LUNG DNA METHYLATION QUANTITATIVE TRAIT LOCI COLOCALIZE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE GENOME-WIDE ASSOCIATION LOCI. RATIONALE: AS THE THIRD LEADING CAUSE OF DEATH IN THE UNITED STATES, THE IMPACT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) MAKES IDENTIFICATION OF ITS MOLECULAR MECHANISMS OF GREAT IMPORTANCE. GENOME-WIDE ASSOCIATION STUDIES (GWASS) HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS ASSOCIATED WITH COPD. HOWEVER, GENETIC VARIATION ONLY EXPLAINS A SMALL FRACTION OF THE SUSCEPTIBILITY TO COPD, AND SUB-GENOME-WIDE SIGNIFICANT LOCI MAY PLAY A ROLE IN PATHOGENESIS. OBJECTIVES: REGULATORY ANNOTATION WITH EPIGENETIC EVIDENCE MAY GIVE PRIORITY FOR FURTHER INVESTIGATION, PARTICULARLY FOR GWAS ASSOCIATIONS IN NONCODING REGIONS. WE PERFORMED INTEGRATIVE GENOMICS ANALYSES USING DNA METHYLATION PROFILING AND GENOME-WIDE SNP GENOTYPING FROM LUNG TISSUE SAMPLES FROM 90 SUBJECTS WITH COPD AND 36 CONTROL SUBJECTS. METHODS: WE PERFORMED METHYLATION QUANTITATIVE TRAIT LOCI (MQTL) ANALYSES, TESTING FOR SNPS ASSOCIATED WITH PERCENT DNA METHYLATION AND ASSESSED THE COLOCALIZATION OF THESE RESULTS WITH PREVIOUS COPD GWAS FINDINGS USING BAYESIAN METHODS IN THE R PACKAGE COLOC TO HIGHLIGHT POTENTIAL REGULATORY FEATURES OF THE LOCI. MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED 942,068 UNIQUE SNPS AND 33,996 UNIQUE CPG SITES AMONG THE SIGNIFICANT (5% FALSE DISCOVERY RATE) CIS-MQTL RESULTS. THE GENOME-WIDE SIGNIFICANT AND SUBTHRESHOLD (P < 10(-4)) GWAS SNPS WERE ENRICHED IN THE SIGNIFICANT MQTL SNPS (HYPERGEOMETRIC TEST P < 0.00001). WE OBSERVED ENRICHMENT FOR SITES LOCATED IN CPG SHORES AND SHELVES, BUT NOT CPG ISLANDS. USING BAYESIAN COLOCALIZATION, WE IDENTIFIED LOCI IN REGIONS NEAR KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, AND IL27. CONCLUSIONS: COLOCALIZATION OF MQTL AND GWAS LOCI PROVIDES REGULATORY CHARACTERIZATION OF SIGNIFICANT AND SUBTHRESHOLD GWAS FINDINGS, SUPPORTING A ROLE FOR GENETIC CONTROL OF METHYLATION IN COPD PATHOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                         
14  4750  32 NOVEL REGIONAL AGE-ASSOCIATED DNA METHYLATION CHANGES WITHIN HUMAN COMMON DISEASE-ASSOCIATED LOCI. BACKGROUND: ADVANCING AGE PROGRESSIVELY IMPACTS ON RISK AND SEVERITY OF CHRONIC DISEASE. IT ALSO MODIFIES THE EPIGENOME, WITH CHANGES IN DNA METHYLATION, DUE TO BOTH RANDOM DRIFT AND VARIATION WITHIN SPECIFIC FUNCTIONAL LOCI. RESULTS: IN A DISCOVERY SET OF 2238 PERIPHERAL-BLOOD GENOME-WIDE DNA METHYLOMES AGED 19-82 YEARS, WE IDENTIFY 71 AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS WITHIN THE LINKAGE DISEQUILIBRIUM BLOCKS OF THE SINGLE NUCLEOTIDE POLYMORPHISMS FROM THE NIH GENOME-WIDE ASSOCIATION STUDY CATALOGUE. THIS INCLUDED 52 NOVEL REGIONS, 29 WITHIN LOCI NOT COVERED BY 450 K OR 27 K ILLUMINA ARRAY, AND WITH ENRICHMENT FOR DNASE-I HYPERSENSITIVITY SITES ACROSS THE FULL RANGE OF TISSUES. THESE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS ALSO SHOW MARKED ENRICHMENT FOR ENHANCERS AND POISED PROMOTERS ACROSS MULTIPLE CELL TYPES. IN A REPLICATION SET OF 2084 DNA METHYLOMES, 95.7 % OF THE AGE-ASSOCIATED DIFFERENTIALLY METHYLATED REGIONS SHOWED THE SAME DIRECTION OF AGEING EFFECT, WITH 80.3 % AND 53.5 % REPLICATED TO P < 0.05 AND P < 1.85 X 10(-8), RESPECTIVELY. CONCLUSION: BY ANALYSING THE FUNCTIONALLY ENRICHED DISEASE AND TRAIT-ASSOCIATED REGIONS OF THE HUMAN GENOME, WE IDENTIFY NOVEL EPIGENETIC AGEING CHANGES, WHICH COULD BE USEFUL BIOMARKERS OR PROVIDE MECHANISTIC INSIGHTS INTO AGE-RELATED COMMON DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  5238  28 PROFILING OF H3K27AC REVEALS THE INFLUENCE OF ASTHMA ON THE EPIGENOME OF THE AIRWAY EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC AIRWAY DISEASE DRIVEN BY COMPLEX GENETIC-ENVIRONMENTAL INTERACTIONS. THE ROLE OF EPIGENETIC MODIFICATIONS IN BRONCHIAL EPITHELIAL CELLS (BECS) IN ASTHMA IS POORLY UNDERSTOOD. METHODS: WE PILOTED GENOME-WIDE PROFILING OF THE ENHANCER-ASSOCIATED HISTONE MODIFICATION H3K27AC IN BECS FROM PEOPLE WITH ASTHMA (N = 4) AND HEALTHY CONTROLS (N = 3). RESULTS: WE IDENTIFIED N = 4,321 (FDR < 0.05) REGIONS EXHIBITING DIFFERENTIAL H3K27AC ENRICHMENT BETWEEN ASTHMA AND HEALTH, CLUSTERING AT GENES ASSOCIATED PREDOMINATELY WITH EPITHELIAL PROCESSES (EMT). WE IDENTIFIED INITIAL EVIDENCE OF ASTHMA-ASSOCIATED SUPER-ENHANCERS ENCOMPASSING GENES ENCODING TRANSCRIPTION FACTORS (TP63) AND ENZYMES REGULATING LIPID METABOLISM (PTGS1). WE INTEGRATED PUBLISHED DATASETS TO IDENTIFY EPITHELIUM-SPECIFIC TRANSCRIPTION FACTORS ASSOCIATED WITH H3K27AC IN ASTHMA (TP73) AND IDENTIFY INITIAL RELATIONSHIPS BETWEEN ASTHMA-ASSOCIATED CHANGES IN H3K27AC AND TRANSCRIPTIONAL PROFILES. FINALLY, WE INVESTIGATED THE POTENTIAL OF CRISPR-BASED APPROACHES TO FUNCTIONALLY EVALUATE H3K27AC-ASTHMA LANDSCAPE IN VITRO BY IDENTIFYING GUIDE-RNAS CAPABLE OF TARGETING ACETYLATION TO ASTHMA DERS AND INDUCING GENE EXPRESSION (TLR3). CONCLUSION: OUR SMALL PILOT STUDY VALIDATES GENOME-WIDE APPROACHES FOR DECIPHERING EPIGENETIC MECHANISMS UNDERLYING ASTHMA PATHOGENESIS IN THE AIRWAYS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  5745  27 SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION ARE ASSOCIATED WITH CARDIO-METABOLIC TRAITS. BACKGROUND: TOBACCO SMOKING IS A WELL-KNOWN MODIFIABLE RISK FACTOR FOR MANY CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASE (CVD). ONE OF THE PROPOSED UNDERLYING MECHANISM LINKING SMOKING TO DISEASE IS VIA EPIGENETIC MODIFICATIONS, WHICH COULD AFFECT THE EXPRESSION OF DISEASE-ASSOCIATED GENES. HERE, WE CONDUCTED A THREE-WAY ASSOCIATION STUDY TO IDENTIFY THE RELATIONSHIP BETWEEN SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION AND THEIR ASSOCIATIONS WITH CARDIO-METABOLIC TRAITS. RESULTS: WE SELECTED 2549 CPG SITES AND 443 GENE EXPRESSION PROBES ASSOCIATED WITH CURRENT VERSUS NEVER SMOKERS, FROM THE LARGEST EPIGENOME-WIDE ASSOCIATION STUDY AND TRANSCRIPTOME-WIDE ASSOCIATION STUDY TO DATE. WE EXAMINED THREE-WAY ASSOCIATIONS, INCLUDING CPG VERSUS GENE EXPRESSION, CARDIO-METABOLIC TRAIT VERSUS CPG, AND CARDIO-METABOLIC TRAIT VERSUS GENE EXPRESSION, IN THE ROTTERDAM STUDY. SUBSEQUENTLY, WE REPLICATED OUR FINDINGS IN THE COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG (KORA) STUDY. AFTER CORRECTION FOR MULTIPLE TESTING, WE IDENTIFIED BOTH CIS- AND TRANS-EXPRESSION QUANTITATIVE TRAIT METHYLATION (EQTM) ASSOCIATIONS IN BLOOD. SPECIFICALLY, WE FOUND 1224 SMOKING-RELATED CPGS ASSOCIATED WITH AT LEAST ONE OF THE 443 GENE EXPRESSION PROBES, AND 200 SMOKING-RELATED GENE EXPRESSION PROBES TO BE ASSOCIATED WITH AT LEAST ONE OF THE 2549 CPGS. OUT OF THESE, 109 CPGS AND 27 GENES WERE ASSOCIATED WITH AT LEAST ONE CARDIO-METABOLIC TRAIT IN THE ROTTERDAM STUDY. WE WERE ABLE TO REPLICATE THE ASSOCIATIONS WITH CARDIO-METABOLIC TRAITS OF 26 CPGS AND 19 GENES IN THE KORA STUDY. FURTHERMORE, WE IDENTIFIED A THREE-WAY ASSOCIATION OF TRIGLYCERIDES WITH TWO CPGS AND TWO GENES (GZMA; CLDND1), AND BMI WITH SIX CPGS AND TWO GENES (PID1; LRRN3). FINALLY, OUR RESULTS REVEALED THE MEDIATION EFFECT OF CG03636183 (F2RL3), CG06096336 (PSMD1), CG13708645 (KDM2B), AND CG17287155 (AHRR) WITHIN THE ASSOCIATION BETWEEN SMOKING AND LRRN3 EXPRESSION. CONCLUSIONS: OUR STUDY INDICATES THAT SMOKING-RELATED CHANGES IN DNA METHYLATION AND GENE EXPRESSION ARE ASSOCIATED WITH CARDIO-METABOLIC RISK FACTORS. THESE FINDINGS MAY PROVIDE ADDITIONAL INSIGHTS INTO THE MOLECULAR MECHANISMS LINKING SMOKING TO THE DEVELOPMENT OF CVD.	2020	

17   118  15 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18    57  26 A GENOME-WIDE ASSOCIATION STUDY OF QUANTITATIVE COMPUTED TOMOGRAPHIC EMPHYSEMA IN KOREAN POPULATIONS. EMPHYSEMA IS AN IMPORTANT FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). GENETIC FACTORS LIKELY AFFECT EMPHYSEMA PATHOGENESIS, BUT THIS QUESTION HAS PREDOMINANTLY BEEN STUDIED IN THOSE OF EUROPEAN ANCESTRY. IN THIS STUDY, WE SOUGHT TO DETERMINE GENETIC COMPONENTS OF EMPHYSEMA SEVERITY AND CHARACTERIZE THE POTENTIAL FUNCTION OF THE ASSOCIATED LOCI IN KOREAN POPULATION. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) ON QUANTITATIVE EMPHYSEMA IN SUBJECTS WITH OR WITHOUT COPD FROM TWO KOREAN COPD COHORTS. WE INVESTIGATED THE FUNCTIONAL CONSEQUENCES OF THE LOCI USING EPIGENETIC ANNOTATION AND GENE EXPRESSION DATA. WE ALSO COMPARED OUR GWAS RESULTS WITH AN EPIGENOME-WIDE ASSOCIATION STUDY AND PREVIOUS DIFFERENTIAL GENE EXPRESSION ANALYSIS. IN TOTAL, 548 SUBJECTS (476 [86.9%] MALE) INCLUDING 514 COPD PATIENTS WERE EVALUATED. WE IDENTIFIED ONE GENOME-WIDE SIGNIFICANT SNP (P < 5.0 X 10(-8)), RS117084279, NEAR PIBF1. WE IDENTIFIED AN ADDITIONAL 57 SNPS (P < 5.0 X 10(-6)) ASSOCIATED WITH EMPHYSEMA IN ALL SUBJECTS, AND 106 SNPS (P < 5.0 X 10(-6)) IN COPD PATIENTS. OF THESE CANDIDATE SNPS, 2 (RS12459249, RS11667314) NEAR CYP2A6 WERE EXPRESSION QUANTITATIVE TRAIT LOCI IN LUNG TISSUE AND A SNP (RS11214944) NEAR NNMT WAS AN EXPRESSION QUANTITATIVE TRAIT LOCUS IN WHOLE BLOOD. OF NOTE, RS11214944 WAS IN LINKAGE DISEQUILIBRIUM WITH VARIANTS IN ENHANCER HISTONE MARKS IN LUNG TISSUE. SEVERAL GENES NEAR ADDITIONAL SNPS WERE IDENTIFIED IN OUR PREVIOUS EWAS STUDY WITH NOMINAL LEVEL OF SIGNIFICANCE. WE IDENTIFIED A NOVEL SNP ASSOCIATED WITH QUANTITATIVE EMPHYSEMA ON CT. INCLUDING THE NOVEL SNP, SEVERAL CANDIDATE SNPS IN OUR STUDY MAY PROVIDE CLUES TO THE GENETIC ETIOLOGY OF EMPHYSEMA IN ASIAN POPULATIONS. FURTHER RESEARCH AND VALIDATION OF THE LOCI WILL HELP DETERMINE THE GENETIC FACTORS FOR THE DEVELOPMENT OF EMPHYSEMA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                              
19  1279  21 DE NOVO MUTATIONS IDENTIFIED BY WHOLE-GENOME SEQUENCING IMPLICATE CHROMATIN MODIFICATIONS IN OBSESSIVE-COMPULSIVE DISORDER. OBSESSIVE-COMPULSIVE DISORDER (OCD) IS A CHRONIC ANXIETY DISORDER WITH A SUBSTANTIAL GENETIC BASIS AND A BROADLY UNDISCOVERED ETIOLOGY. RECENT STUDIES OF DE NOVO MUTATION (DNM) EXOME-SEQUENCING STUDIES FOR OCD HAVE REINFORCED THE HYPOTHESIS THAT RARE VARIATION CONTRIBUTES TO THE RISK. WE PERFORMED, TO OUR KNOWLEDGE, THE FIRST WHOLE-GENOME SEQUENCING ON 53 PARENT-OFFSPRING FAMILIES WITH OFFSPRING AFFECTED WITH OCD TO INVESTIGATE ALL RARE DE NOVO VARIANTS AND INSERTIONS/DELETIONS. WE OBSERVED HIGHER MUTATION RATES IN PROMOTER-ANCHORED CHROMATIN LOOPS (EMPIRICAL P = 0.0015) AND REGIONS WITH HIGH FREQUENCIES OF HISTONE MARKS (EMPIRICAL P = 0.0001). MUTATIONS AFFECTING CODING REGIONS WERE SIGNIFICANTLY ENRICHED WITHIN COEXPRESSION MODULES OF GENES INVOLVED IN CHROMATIN MODIFICATION DURING HUMAN BRAIN DEVELOPMENT. FOUR GENES-SETD5, KDM3B, ASXL3, AND FBL-HAD STRONG AGGREGATED EVIDENCE AND FUNCTIONALLY CONVERGED ON TRANSCRIPTION'S EPIGENETIC REGULATION, SUGGESTING AN IMPORTANT OCD RISK MECHANISM. OUR DATA CHARACTERIZED DIFFERENT GENOME-WIDE DNMS AND HIGHLIGHTED THE CONTRIBUTION OF CHROMATIN MODIFICATION IN THE ETIOLOGY OF OCD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  1555  36 DNA METHYLATION MAPPING IDENTIFIES GENE REGULATORY EFFECTS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. OBJECTIVES: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE CONDITION WITH HETEROGENEOUS PRESENTATION AND COMPLEX AETIOLOGY WHERE DNA METHYLATION CHANGES ARE EMERGING AS A CONTRIBUTING FACTOR. IN ORDER TO DISCOVER NOVEL EPIGENETIC ASSOCIATIONS AND INVESTIGATE THEIR RELATIONSHIP TO GENETIC RISK FOR SLE, WE ANALYSED DNA METHYLATION PROFILES IN A LARGE COLLECTION OF PATIENTS WITH SLE AND HEALTHY INDIVIDUALS. METHODS: DNA EXTRACTED FROM BLOOD FROM 548 PATIENTS WITH SLE AND 587 HEALTHY CONTROLS WERE ANALYSED ON THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP, WHICH TARGETS 485 000 CPG SITES ACROSS THE GENOME. SINGLE NUCLEOTIDE POLYMORPHISM (SNP) GENOTYPE DATA FOR 196 524 SNPS ON THE ILLUMINA IMMUNOCHIP FROM THE SAME INDIVIDUALS WERE UTILISED FOR METHYLATION QUANTITATIVE TRAIT LOCI (CIS-MEQTLS) ANALYSES. RESULTS: WE IDENTIFIED AND REPLICATED DIFFERENTIALLY METHYLATED CPGS (DMCS) IN SLE AT 7245 CPG SITES IN THE GENOME. THE LARGEST METHYLATION DIFFERENCES WERE OBSERVED AT TYPE I INTERFERON-REGULATED GENES WHICH EXHIBITED DECREASED METHYLATION IN SLE. WE MAPPED CIS-MEQTLS AND IDENTIFIED GENETIC REGULATION OF METHYLATION LEVELS AT 466 OF THE DMCS IN SLE. THE MEQTLS FOR DMCS IN SLE WERE ENRICHED FOR GENETIC ASSOCIATION TO SLE, AND INCLUDED SEVEN SLE GENOME-WIDE ASSOCIATION STUDY (GWAS) LOCI: PTPRC (CD45), MHC-CLASS III, UHRF1BP1, IRF5, IRF7, IKZF3 AND UBE2L3. IN ADDITION, WE OBSERVED ASSOCIATION BETWEEN GENOTYPE AND VARIANCE OF METHYLATION AT 20 DMCS IN SLE, INCLUDING AT THE HLA-DQB2 LOCUS. CONCLUSIONS: OUR RESULTS SUGGEST THAT SEVERAL OF THE GENETIC RISK VARIANTS FOR SLE MAY EXERT THEIR INFLUENCE ON THE PHENOTYPE THROUGH ALTERATION OF DNA METHYLATION LEVELS AT REGULATORY REGIONS OF TARGET GENES.	2018