1 2664 189 ESTABLISHMENT AND VALIDATION OF EXHAUSTED CD8+ T CELL FEATURE AS A PROGNOSTIC MODEL OF HCC. OBJECTIVES: THE EXHAUSTED CD8+T (TEX) CELLS ARE A UNIQUE CELL POPULATION OF ACTIVATED T CELLS THAT EMERGES IN RESPONSE TO PERSISTENT VIRAL INFECTION OR TUMOR ANTIGENS. TEX CELLS SHOWED THE CHARACTERISTICS OF AGING CELLS, INCLUDING WEAKENED SELF-RENEWAL ABILITY, EFFECTOR FUNCTION INHIBITION, SUSTAINED HIGH EXPRESSION OF INHIBITORY RECEPTORS INCLUDING PD-1, TIGIT, TIM-3, AND LAG-3, AND ALWAYS ACCOMPANIED BY METABOLIC AND EPIGENETIC REPROGRAMMING. TEX CELLS ARE GETTING MORE AND MORE ATTENTION IN RESEARCHING IMMUNE-RELATED DISEASES AND TUMOR IMMUNOTHERAPY. HOWEVER, STUDIES ON TEX-RELATED MODELS FOR TUMOR PROGNOSIS ARE STILL LACKING. WE HOPE TO ESTABLISH A RISK MODEL BASED ON TEX-RELATED GENES FOR HCC PROGNOSIS. METHODS: TEX-RELATED GEO DATASETS FROM DIFFERENT PATHOLOGIC FACTORS (CHRONIC HBV, CHRONIC HCV, AND TELOMERE SHORTENING) WERE ANALYZED RESPECTIVELY TO ACQUIRE DIFFERENTIALLY EXPRESSED GENES (DEGS) BY THE 'LIMMA' PACKAGE OF R. GENES WITH AT LEAST ONE INTERSECTION WERE INCORPORATED INTO TEX-RELATED GENE SET. GO, KEGG, AND GSEA ENRICHMENT ANALYSES WERE PRODUCED. HUB GENES AND THE PPI NETWORK WERE ESTABLISHED AND VISUALIZED BY THE STRING WEBSITE AND CYTOSCAPE SOFTWARE. TRANSCRIPTION FACTORS AND TARGETING SMALL MOLECULES WERE PREDICTED BY THE TRUST AND CLUE WEBSITES. THE TEX-RELATED HCC PROGNOSTIC MODEL WAS BUILT BY COX REGRESSION AND VERIFIED BASED ON DIFFERENT DATASETS. TUMOR IMMUNE DYSFUNCTION AND EXCLUSION (TIDE) AND SUBMAP ALGORITHMS TESTED IMMUNOTHERAPY SENSITIVITY. FINALLY, QRT-PCR AND FLOW CYTOMETRY WAS USED TO CONFIRM THE BIOINFORMATIC RESULTS. RESULTS: HUB GENES SUCH AS AKT1, CDC6, TNF AND THEIR UPSTREAM TRANSCRIPTION FACTOR ILF3, REGULATORY FACTOR X-ASSOCIATED PROTEIN, STAT3, JUN, AND RELA/NFKB1 WERE IDENTIFIED AS POTENTIAL MOTIVATORS FOR TEX. TEX-RELATED GENES SLC16A11, CACYBP, HSF2, AND ATG10 BUILT THE HCC PROGNOSTIC MODEL AND HELPED WITH IMMUNOTHERAPY SENSITIVITY PREDICTION. CONCLUSION: OUR STUDY DEMONSTRATED THAT TEX-RELATED GENES MIGHT PROVIDE ACCURATE PREDICTION FOR HCC PATIENTS IN CLINICAL DECISION-MAKING, PROGNOSTIC ASSESSMENT, AND IMMUNOTHERAPY. IN ADDITION, TARGETING THE HUB GENES OR TRANSCRIPTION FACTORS MAY HELP TO REVERSE T CELL FUNCTION AND ENHANCE THE EFFECT OF TUMOR IMMUNOTHERAPY.	2023	
                                                                                                                                                      
2 1763  37 EARLY TRANSCRIPTIONAL AND EPIGENETIC DIVERGENCE OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTION. DURING A MICROBIAL INFECTION, RESPONDING CD8+ T CELLS GIVE RISE TO EFFECTOR CELLS THAT PROVIDE ACUTE HOST DEFENSE AND MEMORY CELLS THAT PROVIDE SUSTAINED PROTECTION. AN ALTERNATIVE OUTCOME IS EXHAUSTION, A STATE OF T CELL DYSFUNCTION THAT OCCURS IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCER. ALTHOUGH IT IS EVIDENT THAT EXHAUSTED CD8+ T (TEX) CELLS ARE PHENOTYPICALLY AND MOLECULARLY DISTINCT FROM EFFECTOR AND MEMORY CD8+ T CELLS, THE FACTORS REGULATING THE EARLIEST EVENTS IN THE DIFFERENTIATION PROCESS OF TEX CELLS REMAIN INCOMPLETELY UNDERSTOOD. HERE, WE PERFORMED SINGLE-CELL RNA-SEQUENCING AND SINGLE-CELL ATAC-SEQUENCING OF CD8+ T CELLS RESPONDING TO LCMV-ARMSTRONG (LCMV-ARM) OR LCMV-CLONE 13 (LCMV-CL13), WHICH RESULT IN ACUTE OR CHRONIC INFECTIONS, RESPECTIVELY. COMPARED TO CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-ARM (DIV1ARM) CELLS, CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-CL13 (DIV1CL13) EXPRESSED HIGHER LEVELS OF GENES ENCODING TRANSCRIPTION FACTORS PREVIOUSLY ASSOCIATED WITH EXHAUSTION, ALONG WITH HIGHER LEVELS OF EZH2, THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COMPLEX, WHICH MEDIATES EPIGENETIC SILENCING. MODULATION OF EZH2 RESULTED IN ALTERED EXPRESSION OF EXHAUSTION-ASSOCIATED MOLECULES BY CD8+ T CELLS RESPONDING TO LCMV-CL13, THOUGH THE SPECIFIC CELLULAR AND INFECTIOUS CONTEXTS, RATHER THAN SIMPLY THE LEVEL OF EZH2 EXPRESSION, LIKELY DETERMINE THE EVENTUAL OUTCOME. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THE DIFFERENTIATION PATHS OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTIONS MAY DIVERGE EARLIER THAN PREVIOUSLY APPRECIATED.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3 2730  54 EXPLORING THE BIOLOGICAL FUNCTION OF IMMUNE CELL-RELATED GENES IN HUMAN IMMUNODEFICIENCY VIRUS (HIV)-1 INFECTION BASED ON WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA). BACKGROUND: ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) IS A CHRONIC INFECTIOUS DISEASE CHARACTERIZED BY CONSISTENT IMMUNE DYSFUNCTION. THE OBJECTIVE OF THIS STUDY IS TO DETERMINE WHETHER IMMUNE CELL-RELATED GENES CAN BE USED AS BIOMARKERS FOR THE OCCURRENCE OF AIDS AND POTENTIAL MOLECULAR MECHANISMS. METHODS: A WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS WAS PERFORMED USING THE GSE6740 DATASET FROM THE GENE EXPRESSION SYNTHESIS DATABASE TO IDENTIFY THE HUB GENE, WHICH CONTAINED MICROARRAY DATA FROM HIV-1 POSITIVE (HIV-1(+)) AND HIV-1 NEGATIVE (HIV-1(-)) INDIVIDUALS. THE HIV-1(+)-RELATED DIFFERENTIALLY EXPRESSED GENES WERE THEN IDENTIFIED USING THE LIMMA PACKAGE. SUBSEQUENTLY, THE CHARACTERISTIC IMMUNE CELL-RELATED GENES WERE IDENTIFIED AS DIAGNOSTIC BIOMARKERS FOR HIV-1(+) USING THE RANDOM FOREST MODEL (RF), SUPPORT VECTOR MACHINE MODEL, AND GENERALIZED LINEAR MODEL. RESULTS: MEDARKGREEN EXHIBITED THE STRONGEST CORRELATION WITH HIV CLINICAL FEATURES OF ANY OF THESE MODULES. AS THE BEST MODEL FOR DIAGNOSING HIV-1(+/-), RF WAS USED TO SELECT FOUR CRITICAL IMMUNE CELL-RELATED GENES, NAMELY, ARRB1, DPEP2, LTBP3, AND RGCC, AND A NOMOGRAM MODEL WAS CREATED TO PREDICT THE OCCURRENCE OF HIV-1 INFECTION BASED ON FOUR KEY IMMUNE CELL-RELATED GENES. DIAGNOSTIC GENES WERE SHOWN TO BE ENGAGED IN IMMUNE-RELATED PATHWAYS, SUGGESTING THAT IMMUNOLOGICAL MOLECULES, IMMUNE CELLS, AND IMMUNE PATHWAYS ALL HAVE A ROLE IN HIV-1 INFECTION. THE CTD DATABASE WAS EXPLORED FOR PROSPECTIVE MEDICATIONS OR MOLECULAR COMPOUNDS THAT MIGHT BE UTILIZED TO TREAT HIV-1(+) PATIENTS. = MOREOVER, IN HIV-1(+) INDIVIDUALS, THE CERNA NETWORK REVEALED THAT ARRB1, DPEP2, LTBP3, AND RGCC COULD BE REGULATED BY LNCRNAS THROUGH THE CORRESPONDING MIRNAS. ULTIMATELY, RT-PCR RESULTS FROM CLINICAL BLOOD SAMPLES DEMONSTRATED THAT THE FOUR DIAGNOSTIC GENES WERE SIGNIFICANTLY DOWNREGULATED IN HIV-1(+) PATIENTS. CONCLUSION: WE SCREENED FOUR IMMUNE CELL-RELATED GENES, ARRB1, DPEP2, LTBP3, AND RGCC, WHICH MAY BE CONSIDERED AS THE DIAGNOSTIC MARKERS FOR HIV-1/AIDS. OUR FINDINGS REVEAL THAT IMMUNE RELATED GENES AND PATHWAYS INVOLVED IN HIV-1 PATHOGENESIS WERE REGULATED ON BOTH GENETIC AND EPIGENETIC LEVELS BY CONSTRUCTING A CERNA NETWORK ASSOCIATED WITH LNCRNA.	2022	
                                                                     
4 2270  37 EPIGENETIC QUANTIFICATION OF IMMUNOSENESCENT CD8(+) TEMRA CELLS IN HUMAN BLOOD. AGE-RELATED CHANGES IN HUMAN T-CELL POPULATIONS ARE IMPORTANT CONTRIBUTORS TO IMMUNOSENESCENCE. IN PARTICULAR, TERMINALLY DIFFERENTIATED CD8(+) EFFECTOR MEMORY CD45RA(+) TEMRA CELLS AND THEIR SUBSETS HAVE CHARACTERISTICS OF CELLULAR SENESCENCE, ACCUMULATE IN OLDER INDIVIDUALS, AND ARE INCREASED IN AGE-RELATED CHRONIC INFLAMMATORY DISEASES. IN A DETAILED T-CELL PROFILING AMONG INDIVIDUALS OVER 65 YEARS OF AGE, WE FOUND A HIGH INTERINDIVIDUAL VARIATION AMONG CD8(+) TEMRA POPULATIONS. CD8(+) TEMRA PROPORTIONS CORRELATED POSITIVELY WITH CYTOMEGALOVIRUS (CMV) ANTIBODY LEVELS, HOWEVER, NOT WITH THE CHRONOLOGICAL AGE. IN THE ANALYSIS OF OVER 90 INFLAMMATION PROTEINS, WE IDENTIFIED PLASMA TRANCE/RANKL LEVELS TO ASSOCIATE WITH SEVERAL DIFFERENTIATED T-CELL POPULATIONS, INCLUDING CD8(+) TEMRA AND ITS CD28(-) SUBSETS. GIVEN THE STRONG POTENTIAL OF CD8(+) TEMRA CELLS AS A BIOMARKER FOR IMMUNOSENESCENCE, WE USED DEEP-AMPLICON BISULFITE SEQUENCING TO MATCH THEIR FREQUENCIES IN FLOW CYTOMETRY WITH CPG SITE METHYLATION LEVELS AND DEVELOPED A COMPUTATIONAL MODEL TO PREDICT CD8(+) TEMRA CELL PROPORTIONS FROM WHOLE BLOOD GENOMIC DNA. OUR FINDINGS CONFIRM THE ASSOCIATION OF CD8(+) TEMRA AND ITS SUBSETS WITH CMV INFECTION AND PROVIDE A NOVEL TOOL FOR THEIR HIGH THROUGHPUT EPIGENETIC QUANTIFICATION AS A BIOMARKER OF IMMUNOSENESCENCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5 3296  40 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 4866  37 ORTHOGONAL CRISPR SCREENS TO IDENTIFY TRANSCRIPTIONAL AND EPIGENETIC REGULATORS OF HUMAN CD8 T CELL FUNCTION. THE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPIES IS STRONGLY ASSOCIATED WITH TRANSCRIPTIONAL AND EPIGENETIC STATE. THUS, TECHNOLOGIES TO DISCOVER REGULATORS OF T CELL GENE NETWORKS AND THEIR CORRESPONDING PHENOTYPES HAVE GREAT POTENTIAL TO IMPROVE THE EFFICACY OF T CELL THERAPIES. WE DEVELOPED POOLED CRISPR SCREENING APPROACHES WITH COMPACT EPIGENOME EDITORS TO SYSTEMATICALLY PROFILE THE EFFECTS OF ACTIVATION AND REPRESSION OF 120 TRANSCRIPTION FACTORS AND EPIGENETIC MODIFIERS ON HUMAN CD8+ T CELL STATE. THESE SCREENS NOMINATED KNOWN AND NOVEL REGULATORS OF T CELL PHENOTYPES WITH BATF3 EMERGING AS A HIGH CONFIDENCE GENE IN BOTH SCREENS. WE FOUND THAT BATF3 OVEREXPRESSION PROMOTED SPECIFIC FEATURES OF MEMORY T CELLS SUCH AS INCREASED IL7R EXPRESSION AND GLYCOLYTIC CAPACITY, WHILE ATTENUATING GENE PROGRAMS ASSOCIATED WITH CYTOTOXICITY, REGULATORY T CELL FUNCTION, AND T CELL EXHAUSTION. IN THE CONTEXT OF CHRONIC ANTIGEN STIMULATION, BATF3 OVEREXPRESSION COUNTERED PHENOTYPIC AND EPIGENETIC SIGNATURES OF T CELL EXHAUSTION. CAR T CELLS OVEREXPRESSING BATF3 SIGNIFICANTLY OUTPERFORMED CONTROL CAR T CELLS IN BOTH IN VITRO AND IN VIVO TUMOR MODELS. MOREOVER, WE FOUND THAT BATF3 PROGRAMMED A TRANSCRIPTIONAL PROFILE THAT CORRELATED WITH POSITIVE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPY. FINALLY, WE PERFORMED CRISPR KNOCKOUT SCREENS WITH AND WITHOUT BATF3 OVEREXPRESSION TO DEFINE CO-FACTORS AND DOWNSTREAM FACTORS OF BATF3, AS WELL AS OTHER THERAPEUTIC TARGETS. THESE SCREENS POINTED TO A MODEL WHERE BATF3 INTERACTS WITH JUNB AND IRF4 TO REGULATE GENE EXPRESSION AND ILLUMINATED SEVERAL OTHER NOVEL TARGETS FOR FURTHER INVESTIGATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7 2767  53 EXPRESSION, PROGNOSTIC VALUE, AND FUNCTIONAL MECHANISM OF THE KDM5 FAMILY IN PANCREATIC CANCER. BACKGROUND: THE HISTONE LYSINE DEMETHYLASE KDM5 FAMILY IS AN IMPORTANT EPIGENETIC STATE-MODIFYING ENZYME FAMILY. INCREASING EVIDENCE SUPPORTS THAT EPIGENETIC ABNORMALITIES IN THE KDM5 FAMILY ARE RELATED TO MULTIPLE CANCERS IN HUMANS. HOWEVER, THE ROLE OF THE KDM5 FAMILY IN PANCREATIC CANCER IS NOT CLEAR, AND RELATED RESEARCH IS VERY SCARCE. METHODS: R SOFTWARE, KAPLAN-MEIER PLOTTER, CBIOPORTAL, TIMER, LINKEDOMICS, STRING, METASCAPE, TISIDB, AND THE GSCA LITE ONLINE TOOL WERE UTILIZED FOR BIOINFORMATICS ANALYSIS. RESULTS: KDM5A/B/C WAS SIGNIFICANTLY OVEREXPRESSED IN MANY KINDS OF TUMOR TISSUES, INCLUDING PANCREATIC ADENOCARCINOMA (PAAD), WHILE THE EXPRESSION OF KDM5D WAS SIGNIFICANTLY DOWNREGULATED. THE HIGH EXPRESSION OF KDM5A/B/C WAS RELATED TO POOR CLINICAL FEATURES, SUCH AS WORSE TREATMENT EFFICACY, HIGHER TUMOR GRADE, AND MORE ADVANCED CLINICAL STAGE. PATIENTS WITH A FAMILY HISTORY OF BREAST CANCER AND MELANOMA, HISTORY OF DRINKING OR HISTORY CHRONIC PANCREATITIS WERE MORE LIKELY TO HAVE KDM5A/B/C GENE ABNORMALITIES, WHICH WERE RELATED TO A VARIETY OF ADVERSE CLINICAL FEATURES. THE RESULTS OF GENE ONTOLOGY (GO) AND KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSES OF THE KDM5 FAMILY AND ITS 800 CO-EXPRESSED GENES SHOWED THAT MANY GENE TERMS RELATED TO CELL PROLIFERATION, MIGRATION AND MANY CARCINOGENIC PATHWAYS. NOTABLY, WE FOUND THAT THE EXPRESSION LEVEL OF KDM5A/B/C WAS POSITIVELY CORRELATED WITH THE EXPRESSION OF MULTIPLE KEY DRIVER GENES SUCH AS KRAS, BRCA1, AND BRCA2 ETC. IN ADDITION, PPI NETWORK ANALYSIS SHOWED KDM5 FAMILY PROTEINS HAVE STRONG INTERACTIONS WITH HISTONE DEACETYLASE FAMILY 1 (HDAC1), WHICH COULD MODIFY THE LYSINES OF HISTONE H3, AND CO-ACT ON MANY PATHWAYS, INCLUDING THE "LONGEVITY-REGULATING PATHWAY" AND "NOTCH SIGNALING PATHWAY". MOREOVER, THE UPREGULATION OF KDM5A/B/C EXPRESSION WAS ASSOCIATED WITH AN INCREASE IN THE INFILTRATION OF B CELLS, CD8(+) T CELLS AND OTHER INFILTRATING IMMUNE LYMPHOCYTES AND THE EXPRESSION LEVELS OF IMMUNE MOLECULES SUCH AS NT5E AND CD274. INTERESTINGLY, THE OVEREXPRESSION OF KDM5A/C WAS ALSO CORELATED WITH REDUCED SENSITIVITY OF PANCREATIC CANCER CELLS TO MANY KINDS OF PANCREATIC CANCER-TARGETING OR CHEMOTHERAPEUTIC DRUGS, INCLUDING AXITINIB AND GEMCITABINE. CONCLUSION: KDM5 FAMILY MEMBERS MAY BE PROGNOSTIC MARKERS AND NEW THERAPEUTIC TARGETS FOR PATIENTS WITH PANCREATIC CANCER.	2022	

8 3764  35 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 3959  31 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10 6826  42 [GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS INDICATES INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE DISEASE IMMUNOPATHOGENESIS]. THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS), A CHRONIC DISEASE OF THE CNS, INCLUDES AUTOIMMUNE AND NEURODEGENERATIVE COMPONENTS. IN MOST CASES, PATIENTS DEVELOP RELAPSING-REMITTING MS (RRMS), WHILE 10-15% OF PATIENTS DEVELOP PRIMARY PROGRESSIVE MS (PPMS), WHICH DIFFERS FROM RRMS IN THE MECHANISMS OF THE PATHOLOGICAL PROCESS, SOME DEMOGRAPHIC, AND SOME CLINICAL CHARACTERISTICS. THESE DIFFERENCES MAY BE EXPLAINED BY THE EPIGENETIC REGULATION OF GENE EXPRESSION IN PPMS INCLUDING DNA METHYLATION AS ONE OF THE KEY EPIGENETIC PROCESSES. THE FEATURES OF DNA METHYLATION IN VARIOUS CELL POPULATIONS IN PPMS PATIENTS REMAIN UNDERSTUDIED. THE GOAL OF THIS STUDY IS TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES (DMSS) OF THE GENOME OF CD4+ T LYMPHOCYTES, WHICH CHARACTERIZE PPMS. THE STUDY INCLUDED EIGHT TREATMENT-NAIVE PPMS PATIENTS AND EIGHT HEALTHY CONTROLS. GENOME-WIDE ANALYSIS OF DNA METHYLATION OF CD4+ T LYMPHOCYTES WAS PERFORMED USING HIGH-DENSITY DNA MICROARRAYS. WE HAVE IDENTIFIED 108 DMSS, WHICH DISTINGUISH PPMS PATIENTS FROM HEALTHY CONTROLS. IN PPMS PATIENTS 81% OF THE DMSS ARE HYPERMETHYLATED. MORE THAN A HALF OF THE IDENTIFIED DMSS ARE LOCATED IN KNOWN GENES IN CPG ISLANDS AND ADJACENT REGIONS, WHICH INDICATES A HIGH FUNCTIONAL SIGNIFICANCE OF THESE DMSS IN PPMS DEVELOPMENT. ANALYSIS OF THE OVERREPRESENTATION OF DMS-CONTAINING GENES IN THE MAIN BIOLOGICAL PROCESSES DEMONSTRATES THEIR INVOLVEMENT IN THE REGULATION OF CELL ADHESION TO THE EXTRACELLULAR MATRIX AND THE DEVELOPMENT OF THE IMMUNE RESPONSE, I.E., ANTIGEN PROCESSING AND PRESENTATION, AND DEVELOPMENT OF THE IMMUNE SYSTEM. GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PPMS PATIENTS INDICATES THE INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE IMMUNOPATHOGENESIS OF THE DISEASE. THESE RESULTS MAY HELP BETTER UNDERSTAND THE PATHOGENESIS OF THIS SEVERE FORM OF MS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                              
11 3948  43 LNCRNA-CD160 DECREASES THE IMMUNITY OF CD8(+) T CELLS THROUGH EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS INFECTION. THE TRANSFER AND DEVELOPMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ASSOCIATED WITH THE T CELL IMMUNE RESPONSE, THEREFORE INVESTIGATING THE KEY REGULATORS OF CELL IMMUNE RESPONSE IS NEEDED TO IMPROVE CHRONIC HBV TREATMENT. BLOOD SAMPLES FROM PATIENTS WITH CHRONIC HBV INFECTION WERE USED TO CONFIRM THE CORRELATION BETWEEN HBV INFECTION STAGE AND CD160 RECEPTOR EXPRESSION LEVELS IN CD8(+) T CELLS, THE CD8(+) T CELLS ARE USED TO RESEARCH THE MECHANISM OF T CELL IMMUNE RESPONSE MODULATION, MOREOVER, C3H/HEN MICE WITH REDUCED CD160 EXPRESSION LEVELS WERE USED TO INVESTIGATE THE ASSOCIATION BETWEEN LONG NON-CODING (LNC)RNA-CD160 AND HBV INFECTION. LONG NON-CODING (LNC)RNA-CD160 AND HISTONE-MODIFICATION ENZYME GENE HISTONE DEACETYLASE 11 (HDAC11) EXPRESSION LEVELS WERE NEGATIVELY ASSOCIATED WITH CD160 EXPRESSION. LNCRNA-CD160 CAN INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA THROUGH HDAC11 RECRUITMENT AND BIND TO HDAC11 TO FORM A COMPLEX ON THE PROMOTERS OF IFN-GAMMA AND TNF-ALPHA. THE HDAC11, IFN-GAMMA AND TNF-ALPHA FORM A COMPLEX AND ENHANCE THE METHYLATION OF H3K9ME1, CHROMATIN CHANGES INTO THE HETEROCHROMATIN AND THE TRANSCRIPTION OF IFN-GAMMA AND TNF-ALPHA IS BLOCKED; MOREOVER, THE HDAC11/IFN-GAMMA/TNF-ALPHA COMPLEX CAN ALSO INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA IN CD160(-) CD8(+) T CELLS AND SUPPRESSES THE FUNCTION OF CD8(+) T CELLS. FURTHERMORE, SMALL INTERFERING RNA TARGETING LNCRNA-CD160 CAN BLOCK HBV INFECTION PROGRESSION. LNCRNA-CD160 ACTS AS AN IMMUNE SUPPRESSIVE FACTOR AND IS EXPRESSED AT A HIGH LEVEL IN PERIPHERAL BLOOD CD8(+) T CELLS OF HBV INFECTED PATIENTS. FURTHERMORE, HIGH EXPRESSION LEVELS OF LNCRNA-CD160 CAN CONTRIBUTE TO THE INHIBITION OF IFN-GAMMA AND TNF-ALPHA SECRETION IN CD8(+) T CELLS AND DECREASE THE IMMUNE RESPONSE OF CD8(+) T CELLS. THEREFORE, LNCRNA-CD160 MAY BECOME A NEW TARGET FOR IMMUNOTHERAPY OF CHRONIC HBV INFECTION IN THE FUTURE AND MAY PROVIDE A NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF HBV INFECTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                        
12 5464  31 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13 1584  26 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 2395  37 EPIGENETIC REPROGRAMMING IN MIST1(-/-) MICE PREDICTS THE MOLECULAR RESPONSE TO CERULEIN-INDUCED PANCREATITIS. GENE EXPRESSION IS AFFECTED BY MODIFICATIONS TO HISTONE CORE PROTEINS WITHIN CHROMATIN. CHANGES IN THESE MODIFICATIONS, OR EPIGENETIC REPROGRAMMING, CAN DICTATE CELL FATE AND PROMOTE SUSCEPTIBILITY TO DISEASE. THE GOAL OF THIS STUDY WAS TO DETERMINE THE EXTENT OF EPIGENETIC REPROGRAMMING IN RESPONSE TO CHRONIC STRESS THAT OCCURS FOLLOWING ABLATION OF MIST1 (MIST1(-/-) ), WHICH IS REPRESSED IN PANCREATIC DISEASE. CHROMATIN IMMUNOPRECIPITATION FOR TRIMETHYLATION OF LYSINE RESIDUE 4 ON HISTONE 3 (H3K4ME3) IN PURIFIED ACINAR CELLS FROM WILD TYPE AND MIST1(-/-) MICE WAS FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) OR CHIP-QPCR. H3K4ME3-ENRICHED GENES WERE ASSESSED FOR EXPRESSION BY QRT-PCR IN PANCREATIC TISSUE BEFORE AND AFTER INDUCTION OF CERULEIN-INDUCED PANCREATITIS. WHILE MOST OF H3K4ME3-ENRICHMENT IS RESTRICTED TO TRANSCRIPTIONAL START SITES, >25% OF ENRICHMENT SITES ARE FOUND WITHIN, DOWNSTREAM OR BETWEEN ANNOTATED GENES. LESS THAN 10% OF THESE SITES WERE ALTERED IN MIST1(-/-) ACINI, WITH MOST CHANGES IN H3K4ME3 ENRICHMENT NOT REFLECTING ALTERED GENE EXPRESSION. INGENUITY PATHWAY ANALYSIS OF GENES DIFFERENTIALLY-ENRICHED FOR H3K4ME3 REVEALED AN ASSOCIATION WITH PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA IN MIST1(-/-) TISSUE. MOST OF THESE GENES WERE NOT DIFFERENTIALLY EXPRESSED BUT SEVERAL WERE READILY INDUCED BY ACUTE EXPERIMENTAL PANCREATITIS, WITH SIGNIFICANTLY INCREASED EXPRESSION IN MIST1(-/-) TISSUE RELATIVE TO WILD TYPE MICE. WE SUGGEST THAT THE CHRONIC CELL STRESS OBSERVED IN THE ABSENCE OF MIST1 RESULTS IN EPIGENETIC REPROGRAMMING OF GENES INVOLVED IN PROMOTING PANCREATITIS TO A POISED STATE, THEREBY INCREASING THE SENSITIVITY TO EVENTS THAT PROMOTE DISEASE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 3468  35 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA.	2012	
                                                                                                                                                                                                                                            
16 6468  29 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17 2637  39 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	
                                                                                                                                                                           
18  217  34 ACUTE EXERCISE INCREASES THE EXPRESSION OF KIR2DS4 BY PROMOTER DEMETHYLATION IN NK CELLS. POSITIVE EFFECTS OF EXERCISE ON CANCER PREVENTION AND PROGRESSION HAVE BEEN PROPOSED TO BE MEDIATED BY STIMULATING NATURAL KILLER (NK) CELLS. BECAUSE NK CELL RECEPTORS ARE REGULATED BY EPIGENETIC MODIFICATIONS, WE INVESTIGATED WHETHER ACUTE AEROBIC EXERCISE AND TRAINING CHANGE PROMOTER DNA METHYLATION AND GENE EXPRESSION OF THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1 GENE. SIXTEEN HEALTHY WOMEN (50-60 YEARS) PERFORMED A GRADED EXERCISE TEST (GXT) AND WERE RANDOMIZED INTO EITHER A PASSIVE CONTROL GROUP OR AN INTERVENTION GROUP PERFORMING A FOUR-WEEK ENDURANCE EXERCISE INTERVENTION. BLOOD SAMPLES (PRE-, POST-GXT AND POST-TRAINING) WERE USED FOR ISOLATION OF DNA/RNA OF NK CELLS TO ASSESS DNA PROMOTER METHYLATION BY TARGETED DEEP-AMPLICON SEQUENCING AND GENE EXPRESSION BY QRT-PCR. POTENTIAL CHANGES IN NK CELL SUBSETS WERE DETERMINED BY FLOW CYTOMETRY. ACUTE AND CHRONIC EXERCISE DID NOT PROVOKE SIGNIFICANT ALTERATIONS OF NK CELL PROPORTIONS. PROMOTER METHYLATION DECREASED AND GENE EXPRESSION INCREASED FOR KIR2DS4 AFTER ACUTE EXERCISE. A HIGH GENE EXPRESSION CORRELATED WITH A LOW METHYLATION OF CPGS THAT WERE ALTERED BY ACUTE EXERCISE. CHRONIC EXERCISE RESULTED IN A MINOR DECREASE OF DNA METHYLATION AND DID NOT ALTER GENE EXPRESSION. ACUTE EXERCISE PROVOKES EPIGENETIC MODIFICATIONS, AFFECTING THE BALANCE BETWEEN THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1, WITH POTENTIAL BENEFITS ON NK CELL FUNCTION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  546  32 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20 2331  42 EPIGENETIC REGULATION OF INFLAMMATION BY MICRORNAS IN POST-INFECTIOUS BRONCHIOLITIS OBLITERANS. OBJECTIVES: POST-INFECTIOUS BRONCHIOLITIS OBLITERANS (PIBO) IS A RARE, CHRONIC DISEASE INITIATED BY SEVERE INFECTION AND FOLLOWED BY PERPETUATING INFLAMMATION AND OBLITERATION OF THE SMALL AIRWAYS. MICRORNAS (MIRNAS) HAVE BEEN PROPOSED TO PLAY A CENTRAL ROLE AS EPIGENETIC REGULATORS, WHICH CONTROL RESOLUTION AND PREVENT THE UNCONTROLLED PROGRESS OF INFLAMMATION. THE AIM OF THIS STUDY WAS TO DEFINE BIOMARKERS ON THE LEVEL OF POST-TRANSCRIPTIONAL GENE REGULATION IN ORDER TO CHARACTERISE PIBO. METHODS: A TOTAL OF 39 PATIENTS WITH WELL-DEFINED PIBO AND 31 CONTROLS FROM TWO CENTRES, BARCELONA, SPAIN, AND FRANKFURT, GERMANY, WERE ANALYSED BY NEXT-GENERATION SEQUENCING (NGS). THE EVALUATION OF THE BIOLOGICAL TARGETS OF THE MIRNAS WAS PERFORMED BY PATHWAY ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION NETWORK ANALYSIS RESPECTIVELY. RESULTS: PATIENTS WITH PIBO HAD SIGNIFICANTLY LOWER LUNG FUNCTION VALUES AND INCREASED AIRWAY INFLAMMATION IN INDUCED SPUTUM AS INDICATED BY TOTAL CELL COUNTS, NEUTROPHILS, IL-1BETA, IL-6, IL-8 AND TGF-BETA COMPARED TO CONTROLS.NEXT-GENERATION SEQUENCING ANALYSIS REVEALED A TOTAL OF 22 DYSREGULATED MIRNAS, WHICH PASSED SIGNIFICANCE THRESHOLD FOR PADJ </= 0.001 WITH 17 BEING UPREGULATED AND 5 BEING DOWNREGULATED. OF THESE DYSREGULATED MIRNAS, MIR-335-5P, MIR-186-5P, MIR-30B-5P AND MIR-30C-5P WERE FURTHER VALIDATED USING QRT-PCR. INTERESTINGLY, THESE MIRNAS ARE FUNCTIONALLY IMPLICATED IN CYTOKINE-CYTOKINE RECEPTOR INTERACTION, TGF-BETA SIGNALLING AND FOXO SIGNALLING PATHWAY AND SIGNIFICANTLY CORRELATED WITH LUNG FUNCTION VALUES (FEV1). CONCLUSION: OUR RESULTS DEMONSTRATE AN ABERRANT MIRNA EXPRESSION PROFILE IN PIBO, WHICH IMPACTS PATHWAYS RESPONSIBLE FOR THE REGULATION OF INFLAMMATION AND FIBROSIS. THE DEFINED MIRNAS ARE USEFUL BIOMARKERS AND SHOULD BE ASSESSED AS POTENTIAL TARGET IN THE FIELD OF MIRNA THERAPEUTICS.	2022