1  5061 131 PHF6 FUNCTIONS AS A TUMOR SUPPRESSOR BY RECRUITING METHYLTRANSFERASE SUV39H1 TO NUCLEOLAR REGION AND OFFERS A NOVEL THERAPEUTIC TARGET FOR PHF6-MUNTANT LEUKEMIA. MUTATIONS IN THE PLANT HOMEODOMAIN-LIKE FINGER PROTEIN 6 (PHF6) GENE ARE STRONGLY ASSOCIATED WITH ACUTE MYELOID (AML) AND T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL). IN THIS STUDY, WE DEMONSTRATED THAT PHF6 CAN BIND TO H3K9ME3 AND H3K27ME1 ON THE NUCLEOLAR CHROMATIN AND RECRUIT HISTONE METHYLTRANSFERASE SUV39H1 TO THE RDNA LOCUS. THE DELETION OF PHF6 CAUSED A DECREASE IN THE RECRUITMENT OF SUV39H1 TO RDNA GENE LOCI, RESULTING IN A REDUCTION IN THE LEVEL OF H3K9ME3 AND THE PROMOTION OF RDNA TRANSCRIPTION. THE KNOCKDOWN OF EITHER SUV39H1 OR PHF6 SIGNIFICANTLY ATTENUATED THE EFFECTS OF INCREASE IN H3K9ME3 AND SUPPRESSED THE TRANSCRIPTION OF RDNA INDUCED BY THE OVEREXPRESSION OF THE OTHER INTERACTING PARTNER, THEREBY ESTABLISHING AN INTERDEPENDENT RELATIONSHIP BETWEEN PHF6 AND SUV39H1 IN THEIR CONTROL OF RRNA TRANSCRIPTION. THE PHF6 CLINICAL MUTANTS SIGNIFICANTLY IMPAIRED THE ABILITY TO BIND AND RECRUIT SUV39H1 TO THE RDNA LOCI, RESULTING IN AN INCREASE IN RDNA TRANSCRIPTION ACTIVITY, THE PROLIFERATION OF IN VITRO LEUKEMIA CELLS, AND THE GROWTH OF IN VIVO MOUSE XENOGRAFTS. IMPORTANTLY, SIGNIFICANTLY ELEVATED LEVELS OF PRE-RRNA WERE OBSERVED IN CLINICAL AML PATIENTS WHO POSSESSED A MUTATED VERSION OF PHF6. THE SPECIFIC RDNA TRANSCRIPTION INHIBITOR CX5461 SIGNIFICANTLY REDUCED THE RESISTANCE OF U937 AML CELLS DEFICIENT IN PHF6 TO CYTARABINE, THE DRUG THAT IS MOST COMMONLY USED TO TREAT AML. COLLECTIVELY, WE REVEALED A NOVEL MOLECULAR MECHANISM BY WHICH PHF6 RECRUITS METHYLTRANSFERASE SUV39H1 TO THE NUCLEOLAR REGION IN LEUKEMIA AND PROVIDED A POTENTIAL THERAPEUTIC TARGET FOR PHF6-MUTANT LEUKEMIA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  4514  29 MULTI-OMICS ANALYSIS REVEALS CHANGES IN THE INTESTINAL MICROBIOME, TRANSCRIPTOME, AND METHYLOME IN A RAT MODEL OF CHRONIC NON-BACTERIAL PROSTATITIS: INDICATIONS FOR THE EXISTENCE OF THE GUT-PROSTATE AXIS. CHRONIC NON-BACTERIAL PROSTATITIS (CNP) IS ONE OF THE MOST PREVALENT DISEASES IN HUMAN MALES WORLDWIDE. IN 2005, THE PROSTATE-GUT AXIS WAS FIRST PROPOSED TO INDICATE THE CLOSE RELATIONSHIP BETWEEN THE PROSTATE AND THE INTESTINE. THIS STUDY INVESTIGATED CNP-INDUCED CHANGES OF THE GUT MICROBIOTA, GENE EXPRESSION AND DNA METHYLATION IN A RAT MODEL BY USING MULTI-OMICS ANALYSIS. FIRSTLY, 16S RDNA SEQUENCING PRESENTED AN ALTERED STRUCTURE OF THE MICROBIOTA IN CECUM OF CNP RATS. THEN, TRANSCRIPTOMIC ANALYSIS REVEALED THAT THE EXPRESSION OF 185 GENES IN INTESTINAL EPITHELIUM WAS SIGNIFICANTLY CHANGED BY CNP. THESE CHANGES CAN PARTICIPATE IN THE IMMUNE SYSTEM, DIGESTIVE SYSTEM, METABOLIC PROCESS, ETC. FINALLY, METHYLC-CAPTURE SEQUENCING (MCC-SEQ) FOUND 73,232 DIFFERENTIALLY METHYLATED SITES (DMSS) IN THE DNA OF INTESTINAL EPITHELIUM BETWEEN CONTROL AND CNP RATS. A COMBINED ANALYSIS OF METHYLOMICS AND TRANSCRIPTOMICS SUGGESTED AN EPIGENETIC MECHANISM FOR CNP-INDUCED DIFFERENTIAL EXPRESSION GENES CORRELATED WITH INTESTINAL BARRIER FUNCTION, IMMUNITY, METABOLISM, ENTERIC INFECTIOUS DISEASE, ETC. MORE IMPORTANTLY, THE TRANSCRIPTOMIC, METHYLOMIC AND GUT MICROBIAL CHANGES WERE HIGHLY CORRELATED WITH MULTIPLE PROCESSES INCLUDING INTESTINAL IMMUNITY, METABOLISM AND EPITHELIAL BARRIER FUNCTION. IN THIS STUDY, DISRUPTED HOMEOSTASIS IN THE GUT MICROBIOTA, GENE EXPRESSION AND DNA METHYLATION WERE REPORTED IN CNP, WHICH SUPPORTS THE EXISTENCE OF THE GUT-PROSTATE AXIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  3648  31 INCREASED RELATIVE ABUNDANCE OF RUMINOCCOCUS IS ASSOCIATED WITH REDUCED CARDIOVASCULAR RISK IN AN OBESE POPULATION. BACKGROUND: OBESITY IS A COMPLEX DISEASE WITH UNDERLYING GENETIC, ENVIRONMENTAL, PSYCHOLOGICAL, PHYSIOLOGICAL, MEDICAL, AND EPIGENETIC FACTORS. OBESITY CAN CAUSE VARIOUS DISORDERS, INCLUDING CARDIOVASCULAR DISEASES (CVDS), THAT ARE AMONG THE MOST PREVALENT CHRONIC CONDITIONS IN QATAR. RECENT STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT ROLES OF THE GUT MICROBIOME IN IMPROVING THE PATHOLOGY OF VARIOUS DISEASES, INCLUDING OBESITY. THUS, IN THIS STUDY, WE AIMED TO INVESTIGATE THE EFFECTS OF DIETARY INTAKE AND GUT MICROBIAL COMPOSITION IN MODULATING THE RISK OF CVD DEVELOPMENT IN OBESE QATARI ADULTS. METHODS: WE ENROLLED 46 ADULT SUBJECTS (18-65 YEARS OF AGE) WHO WERE CLASSIFIED BASED ON THEIR CVD RISK SCORES, CALCULATED USING THE FRAMINGHAM FORMULA, INTO A CVD NO-RISK GROUP (SCORE OF <10%, N = 36) AND CVD RISK GROUP (SCORE OF >/=10%, N = 10). FOR EACH STUDY SUBJECT, WE MEASURED THE GUT MICROBIAL COMPOSITION WITH A 16S RDNA SEQUENCING METHOD THAT TARGETED THE V3-V4 REGION USING ILLUMINA MISEQ, AND THEIR NUTRITIONAL STATUS WAS RECORDED BASED ON 24-H DIETARY RECALL. DIETARY INTAKE, BACTERIAL TAXA SUMMARY, DIVERSITY INDEX, MICROBIAL MARKERS, PATHWAY ANALYSIS, AND NETWORK CORRELATION WERE DETERMINED FOR THE STUDY SUBJECTS. RESULTS: THE CVD RISK GROUP SHOWED A LOWER INTAKE OF VITAMIN D, REDUCED RELATIVE ABUNDANCE OF GENERA RUMINOCOCCUS AND BIFIDOBACTERIUM, NO CHANGE IN BACTERIAL DIVERSITY, AND HIGHER LEVELS OF TAURINE, HYPOTAURINE, AND LIPOIC ACID METABOLISM THAN THE CVD NO-RISK GROUP. BESIDES, THE RELATIVE ABUNDANCE OF GENUS RUMINOCOCCUS WAS POSITIVELY CORRELATED WITH THE INTAKE OF PROTEIN, MONOUNSATURATED FAT, VITAMIN A, AND VITAMIN D. CONCLUSION: TAKEN TOGETHER, OUR RESULTS SUGGEST THAT THE GENUS RUMINOCOCCUS COULD BE USED AS A MICROBIAL MARKER, AND ITS REDUCED RELATIVE ABUNDANCE COULD MEDIATE THE RISK OF CVDS IN THE OBESE QATARI POPULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  6196  28 THE IMPACT OF THE TH17:TREG AXIS ON THE IGA-BIOME ACROSS THE GLYCEMIC SPECTRUM. SECRETORY IGA (SIGA) IS RELEASED INTO MUCOSAL SURFACES WHERE ITS FUNCTION EXTENDS BEYOND THAT OF HOST DEFENSE TO INCLUDE THE SHAPING OF RESIDENT MICROBIAL COMMUNITIES BY MEDIATING EXCLUSION/INCLUSION OF RESPECTIVE MICROBES AND REGULATING BACTERIAL GENE EXPRESSION. IN THIS CAPACITY, SIGA ACTS AS THE FULCRUM ON WHICH HOST IMMUNITY AND THE HEALTH OF THE MICROBIOTA ARE BALANCED. WE RECENTLY COMPLETED AN ANALYSIS OF THE GUT AND SALIVARY IGA-BIOMES (16S RDNA SEQUENCING OF SIGA-COATED/UNCOATED BACTERIA) IN MEXICAN-AMERICAN ADULTS THAT IDENTIFIED IGA-BIOME DIFFERENCES ACROSS THE GLYCEMIC SPECTRUM. AS TH17:TREG RATIO IMBALANCES ARE ASSOCIATED WITH GUT MICROBIOME DYSBIOSIS AND CHRONIC INFLAMMATORY CONDITIONS SUCH AS TYPE 2 DIABETES, THE PRESENT STUDY EXTENDS OUR PRIOR WORK BY EXAMINING THE IMPACT OF TH17:TREG RATIOS (PRO-INFLAMMATORY:ANTI-INFLAMMATORY T-CELL RATIOS) AND THE SIGA RESPONSE (TH17:TREG-SIGA AXIS) IN SHAPING MICROBIAL COMMUNITIES. EXAMINING THE IMPACT OF TH17:TREG RATIOS (DETERMINED BY EPIGENETIC QPCR LYMPHOCYTE SUBSET QUANTIFICATION) ON THE IGA-BIOME ACROSS DIABETES PHENOTYPES IDENTIFIED A PROPORTIONAL RELATIONSHIP BETWEEN TH17:TREG RATIOS AND ALPHA DIVERSITY IN THE STOOL IGA-BIOME OF THOSE WITH DYSGLYCEMIA, SIGNIFICANT CHANGES IN COMMUNITY COMPOSITION OF THE STOOL AND SALIVARY MICROBIOMES ACROSS GLYCEMIC PROFILES, AND GENERA PREFERENTIALLY ABUNDANT BY T-CELL INFLAMMATORY PHENOTYPE. THIS IS THE FIRST STUDY TO ASSOCIATE EPIGENETICALLY QUANTIFIED TH17:TREG RATIOS WITH BOTH THE LARGER AND SIGA-FRACTIONATED MICROBIOME, ASSESS THESE ASSOCIATIONS IN THE CONTEXT OF A CHRONIC INFLAMMATORY DISEASE, AND OFFERS A NOVEL FRAME THROUGH WHICH TO EVALUATE MUCOSAL MICROBIOMES IN THE CONTEXT OF HOST RESPONSES AND INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5   502  31 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849.	2019	
             
6  3557  22 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  6383  39 THE ROLE OF PHF6 IN HEMATOPOIESIS AND HEMATOLOGIC MALIGNANCIES. EPIGENETIC REGULATION OF GENE EXPRESSION REPRESENTS AN IMPORTANT MECHANISM IN THE MAINTENANCE OF STEM CELL FUNCTION. ALTERATIONS IN EPIGENETIC REGULATION CONTRIBUTE TO THE PATHOGENESIS OF HEMATOLOGICAL MALIGNANCIES. PLANT HOMEODOMAIN FINGER PROTEIN 6 (PHF6) IS A MEMBER OF THE PLANT HOMEODOMAIN (PHD)-LIKE ZINC FINGER FAMILY OF PROTEINS THAT IS INVOLVED IN TRANSCRIPTIONAL REGULATION THROUGH THE MODIFICATION OF THE CHROMATIN STATE. GERMLINE MUTATION OF PHF6 IS THE CAUSATIVE GENETIC ALTERATION OF THE X-LINKED MENTAL RETARDATION BORJESON-FORSSMAN-LEHMANN SYNDROME (BFLS). SOMATIC MUTATIONS IN PHF6 ARE IDENTIFIED IN HUMAN LEUKEMIA, SUCH AS ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL, ~ 38%), PEDIATRIC T-ALL (~ 16%), ACUTE MYELOID LEUKEMIA (AML, ~ 3%), CHRONIC MYELOID LEUKEMIA (CML, ~ 2.5%), MIXED PHENOTYPE ACUTE LEUKEMIA (MPAL, ~ 20%), AND HIGH-GRADE B-CELL LYMPHOMA (HGBCL, ~ 3%). MORE RECENT STUDIES IMPLY AN ONCOGENIC EFFECT OF PHF6 IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) AND SOLID TUMORS. THESE DATA DEMONSTRATE THAT PHF6 COULD ACT AS A DOUBLE-EDGED SWORD, EITHER A TUMOR SUPPRESSOR OR AN ONCOGENE, IN A LINEAGE-DEPENDENT MANNER. HOWEVER, THE UNDERLYING MECHANISMS OF PHF6 IN NORMAL HEMATOPOIESIS AND LEUKEMOGENESIS REMAIN LARGELY UNKNOWN. IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF PHF6, EMPHASIZING THE ROLE OF PHF6 IN HEMATOLOGICAL MALIGNANCIES. EPIGENETIC REGULATION OF PHF6 IN B-ALL. PHF6 MAINTAINS A CHROMATIN STRUCTURE THAT IS PERMISSIVE TO B-CELL IDENTITY GENES, BUT NOT T-CELL-SPECIFIC GENES (LEFT). LOSS OF PHF6 LEADS TO ABERRANT EXPRESSION OF B-CELL- AND T-CELL-SPECIFIC GENES RESULTING FROM LINEAGE PROMISCUITY AND BINDING OF T-CELL TRANSCRIPTION FACTORS (RIGHT).	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  4271  29 MICROBIAL DYSBIOSIS-INDUCED OBESITY: ROLE OF GUT MICROBIOTA IN HOMOEOSTASIS OF ENERGY METABOLISM. THE GLOBAL OBESITY EPIDEMIC HAS NECESSITATED THE SEARCH FOR BETTER INTERVENTION STRATEGIES INCLUDING THE EXPLOITATION OF THE HEALTH BENEFITS OF SOME GUT MICROBIOTA AND THEIR METABOLIC PRODUCTS. THEREFORE, WE EXAMINED THE GUT MICROBIAL COMPOSITION AND MECHANISMS OF INTERACTION WITH THE HOST IN RELATION TO HOMOEOSTATIC ENERGY METABOLISM AND PATHOPHYSIOLOGY OF DYSBIOSIS-INDUCED METABOLIC INFLAMMATION AND OBESITY. WE ALSO DISCUSSED THE EUBIOTIC, HEALTH-PROMOTING EFFECTS OF PROBIOTICS AND PREBIOTICS AS WELL AS EPIGENETIC MODIFICATIONS ASSOCIATED WITH GUT MICROBIAL DYSBIOSIS AND RISK OF OBESITY. HIGH-FAT/CARBOHYDRATE DIET PROGRAMMES THE GUT MICROBIOTA TO ONE PREDOMINATED BY FIRMICUTES (CLOSTRIDIUM), PREVOTELLA AND METHANOBREVIBACTER BUT DEFICIENT IN BENEFICIAL GENERA/SPECIES SUCH AS BACTEROIDES, BIFIDOBACTERIUM, LACTOBACILLUS AND AKKERMANSIA. ALTERED GUT MICROBIOTA IS ASSOCIATED WITH DECREASED EXPRESSION OF SCFA THAT MAINTAIN INTESTINAL EPITHELIAL BARRIER INTEGRITY, REDUCE BACTERIAL TRANSLOCATION AND INFLAMMATION AND INCREASE EXPRESSION OF HUNGER-SUPPRESSING HORMONES. REDUCED AMOUNTS OF BENEFICIAL MICRO-ORGANISMS ALSO INHIBIT FASTING-INDUCED ADIPOCYTE FACTOR EXPRESSION LEADING TO DYSLIPIDAEMIA. A LOW-GRADE CHRONIC INFLAMMATION (METABOLIC ENDOTOXAEMIA) ENSUES WHICH CULMINATES IN OBESITY AND ITS CO-MORBIDITIES. THE SYNERGY OF HIGH-FAT DIET AND DYSBIOTIC GUT MICROBIOTA INITIATES A RECIPE THAT EPIGENETICALLY PROGRAMMES THE HOST FOR INCREASED ADIPOSITY AND POOR GLYCAEMIC CONTROL. INTERESTINGLY, THESE OBESOGENIC MECHANISTIC PATHWAYS THAT ARE TRANSMITTABLE FROM ONE GENERATION TO ANOTHER CAN BE MODULATED THROUGH THE ADMINISTRATION OF PROBIOTICS, PREBIOTICS AND SYNBIOTICS. THOUGH THE INFLUENCE OF GUT MICROBIOTA ON THE RISK OF OBESITY AND SEVERAL INTERVENTION STRATEGIES HAVE BEEN EXTENSIVELY DEMONSTRATED IN ANIMAL MODELS, APPLICATION IN HUMANS STILL REQUIRES FURTHER ROBUST INVESTIGATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  3450  29 HYPERMETHYLATION OF THE TSPOAP1-AS1 PROMOTER MAY BE ASSOCIATED WITH OBESITY IN OVERWEIGHT/OBESE KOREAN SUBJECTS. OBESITY IS A MAJOR CHRONIC DISEASE ASSOCIATED WITH THE RISK OF SERIOUS CARDIOVASCULAR OR ENDOCRINAL DISEASES, SUCH AS HYPERTENSION, DIABETES, ATHEROSCLEROSIS AND STROKE. CONSIDERABLE INTEREST HAS BEEN DIRECTED TOWARDS THE POTENTIAL EFFECTS OF EPIGENETIC VARIATIONS IN OBESITY. IN THIS STUDY, WE EVALUATED DNA METHYLATION LEVEL AT THE PROMOTER REGION OF THE GENE ENCODING TSPO-ASSOCIATED PROTEIN 1 ANTISENSE RNA 1 (TSPOAP1-AS1) IN 80 OVERWEIGHT/OBESE SUBJECTS (BODY MASS INDEX (BMI) > 25) AND 104 NON-OBESE SUBJECTS WHO PARTICIPATED IN THE SOPI-STROKE STUDY IN KOREA. DNA METHYLATION WAS MEASURED USING BISULFITE AMPLICON SEQUENCING (BSAS). A GENERAL LINEAR MODEL OR RELATIVE CORRELATION WAS USED TO DETERMINE THE EFFECTS OF DNA METHYLATION ON OBESITY AND OBESE PHENOTYPES. NOTABLY, THE MEAN LEVEL OF DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN THE OVERWEIGHT/OBESE GROUP THAN IN THE NON-OBESE GROUP (18.62% VS. 17.18%). FURTHER ANALYSES REVEALED SIGNIFICANT POSITIVE CORRELATIONS OF THE BMI, THE SERUM TOTAL CHOLESTEROL AND LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS WITH THE DNA METHYLATION LEVEL (P = 0.0493, P = 0.003, AND P = 0.0094, RESPECTIVELY). THE STUDY FINDINGS SUGGEST AN ASSOCIATION BETWEEN DNA METHYLATION AT THE TSPOAP1-AS1 PROMOTER AND OVERWEIGHT/OBESITY. ACCORDINGLY, METHYLATION IN THIS PROMOTER REGION MIGHT BE A POTENTIAL PREDICTOR OF OBESITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10  4349  20 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  5395  27 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  4394  37 MODIFICATION OF EPIGENETIC PATTERNS IN LOW BIRTH WEIGHT CHILDREN: IMPORTANCE OF HYPOMETHYLATION OF THE ACE GENE PROMOTER. THERE IS A GROWING BODY OF EVIDENCE THAT EPIGENETIC ALTERATIONS ARE INVOLVED IN THE PATHOLOGICAL MECHANISMS OF MANY CHRONIC DISORDERS LINKED TO FETAL PROGRAMMING. ANGIOTENSIN-CONVERTING ENZYME (ACE) APPEARS AS ONE CANDIDATE GENE THAT BRINGS NEW INSIGHTS INTO THE EPIGENETIC CONTROL AND LATER DEVELOPMENT OF DISEASES. IN THIS VIEW, WE HAVE POSTULATED THAT EPIGENETIC MODIFICATIONS IN THE ACE GENE MIGHT SHOW DIFFERENT INTERACTIONS BETWEEN BIRTH WEIGHT (BW), BLOOD PRESSURE LEVELS, PLASMA ACE ACTIVITY AND ACE I/D POLYMORPHISM. TO EXPLORE THIS HYPOTHESIS, WE PERFORMED A CROSS-SECTIONAL STUDY TO EVALUATE THE DNA METHYLATION OF 3 CPG SITES USING PYROSEQUENCING WITHIN THE ACE GENE PROMOTER OF PERIPHERAL BLOOD LEUKOCYTES FROM 45 LBW CHILDREN COMPARED WITH 70 NBW CHILDREN. OUR RESULTS HAVE REVEALED THAT LBW CHILDREN HAVE LOWER METHYLATION LEVELS (P<0.001) IN PARALLEL WITH A HIGHER ACE ACTIVITY (P = 0.001). ADJUSTING FOR PREMATURITY, GENDER, AGE, BODY MASS INDEX, AND FAMILY HISTORY OF CARDIOVASCULAR DISEASE DID NOT ALTER THESE FINDINGS. WE HAVE ALSO PERFORMED ANALYSES OF INDIVIDUAL CPG SITES. THE FREQUENCY OF DNA METHYLATION WAS SIGNIFICANTLY DIFFERENT AT TWO CPG SITES (SITE 1: NUCLEOTIDE POSITION +555; AND SITE 3: NUCLEOTIDE POSITION +563). IN ADDITION, WE HAVE FOUND A SIGNIFICANT INVERSE CORRELATION BETWEEN DEGREE OF DNA METHYLATION AND BOTH ACE ACTIVITY (P<0.001) AND SYSTOLIC BLOOD PRESSURE LEVELS (P<0.001). WE ALSO OBSERVED THAT THE METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN LBW CHILDREN WHO ARE CARRIERS OF THE DD GENOTYPE COMPARED TO NBW CHILDREN WITH DD GENOTYPE (P<0.024). IN CONCLUSION, WE ARE ABLE TO DEMONSTRATE THAT THE HYPOMETHYLATION IN THE 3 CPG SITES OF ACE GENE PROMOTER IS ASSOCIATED WITH LBW IN 6 TO 12 YEAR-OLD CHILDREN. THE MAGNITUDE OF THESE EPIGENETIC CHANGES APPEARS TO BE CLINICALLY IMPORTANT, WHICH IS SUPPORTED BY THE OBSERVATION THAT DISCRETE CHANGES IN DNA METHYLATION CAN AFFECT SYSTOLIC BLOOD PRESSURE AND ACE PROTEIN ACTIVITY LEVELS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  1780  27 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  4269  19 MICROBIAL DYSBIOSIS AND LACK OF SCFA PRODUCTION IN A SPANISH COHORT OF PATIENTS WITH MULTIPLE SCLEROSIS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, DEMYELINATING, AND IMMUNE-MEDIATED DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE INCIDENCE OF MS HAS INCREASED IN THE PAST SEVERAL DECADES, SUGGESTING CHANGES IN THE ENVIRONMENTAL RISK FACTORS. MUCH EFFORT HAS BEEN MADE IN THE DESCRIPTION OF THE GUT MICROBIOTA IN MS; HOWEVER, LITTLE IS KNOWN ABOUT THE DYSBIOSIS ON ITS FUNCTION. THE MICROBIOTA PRODUCES THOUSANDS OF BIOLOGICALLY ACTIVE SUBSTANCES AMONG WHICH ARE NOTABLE THE SHORT-CHAIN FATTY ACID (SCFA) EXCRETION. OBJECTIVES: ANALYZE THE INTERACTION BETWEEN MICROBIOTA, SCFAS, DIET, AND MS. METHODS: 16S, NUTRITIONAL QUESTIONNAIRES, AND SCFAS QUANTIFICATION HAVE BEEN RECOVERED FROM MS PATIENTS AND CONTROLS. RESULTS: OUR RESULTS REVEALED AN INCREMENT IN THE PHYLUM PROTEOBACTERIA, ESPECIALLY THE FAMILY ENTEROBACTERIACEAE, A LACK IN TOTAL SCFA EXCRETION, AND AN ALTERED PROFILE OF SCFAS IN A SPANISH COHORT OF MS PATIENTS. THESE ALTERATIONS ARE MORE EVIDENT IN PATIENTS WITH HIGHER DISABILITY. CONCLUSIONS: THE ABUNDANCE OF PROTEOBACTERIA AND ACETATE AND THE LOW EXCRETION OF TOTAL SCFAS, ESPECIALLY BUTYRATE, ARE COMMON CHARACTERISTICS OF MS PATIENTS, AND BESIDES, BOTH ARE ASSOCIATED WITH A WORSE PROGNOSIS OF THE DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  4252  28 METHYLOME CHANGES ASSOCIATED WITH FUNCTIONAL MOVEMENT/CONVERSION DISORDER: INFLUENCE OF BIOLOGICAL SEX AND CHILDHOOD ABUSE EXPOSURE. EPIGENETIC CHANGES, SUCH AS DNA METHYLATION (DNAM), MAY REPRESENT AN IMPORTANT MECHANISM IMPLICATED IN THE ETIOPATHOGENESIS OF FUNCTIONAL MOVEMENT/CONVERSION DISORDER (FMD). HERE, WE AIMED TO IDENTIFY METHYLOMIC VARIATIONS IN A CASE-CONTROL COHORT OF FMD AND TO UNCOVER SPECIFIC EPIGENETIC SIGNATURES ASSOCIATED WITH FEMALE SEX AND CHILDHOOD ABUSE, TWO KEY RISK FACTORS FOR FMD AND OTHER FUNCTIONAL NEUROLOGICAL DISORDERS. GENOME-WIDE DNAM ANALYSIS WAS PERFORMED FROM PERIPHERAL BLOOD IN 57 PATIENTS WITH FMD AND 47 HEALTHY CONTROLS WITH AND WITHOUT CHILDHOOD ABUSE. USING PRINCIPAL COMPONENT ANALYSIS, WE EXAMINED THE ASSOCIATION OF PRINCIPAL COMPONENTS WITH FMD STATUS IN ABUSED AND NON-ABUSED INDIVIDUALS, IN THE ENTIRE STUDY SAMPLE AND IN FEMALE SUBJECTS ONLY. NEXT, WE USED ENRICHMENT PATHWAY ANALYSIS TO INVESTIGATE THE BIOLOGICAL SIGNIFICANCE OF DNAM CHANGES AND EXPLORED DIFFERENCES IN METHYLATION LEVELS OF GENES ANNOTATED TO THE TOP ENRICHED BIOLOGICAL PATHWAYS SHARED ACROSS COMPARISONS. WE FOUND THAT FMD WAS ASSOCIATED WITH DNAM VARIATION ACROSS THE GENOME AND IDENTIFIED A COMMON EPIGENETIC 'SIGNATURE' ENRICHED FOR BIOLOGICAL PATHWAYS IMPLICATED IN CHRONIC STRESS AND CHRONIC PAIN. HOWEVER, METHYLATION LEVELS OF GENES INCLUDED IN THE TOP TWO SHARED PATHWAYS HARDLY OVERLAPPED, SUGGESTING THAT TRANSCRIPTIONAL PROFILES MAY DIFFER AS A FUNCTION OF CHILDHOOD ABUSE EXPOSURE AND SEX AMONG SUBJECTS WITH FMD. THIS STUDY IS UNIQUE IN PROVIDING GENOME-WIDE EVIDENCE OF DNAM CHANGES IN FMD AND IN INDICATING A POTENTIAL MECHANISM LINKING CHILDHOOD ABUSE EXPOSURE AND FEMALE SEX TO DIFFERENCES IN FMD PATHOPHYSIOLOGY. FUTURE STUDIES ARE NEEDED TO REPLICATE OUR FINDINGS IN INDEPENDENT COHORTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  2643  29 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17   561  29 BARIATRIC SURGERY-INDUCED WEIGHT LOSS AND ASSOCIATED GENOME-WIDE DNA-METHYLATION ALTERATIONS IN OBESE INDIVIDUALS. BACKGROUND: OBESITY IS A MULTIFACTORIAL AND CHRONIC CONDITION OF GROWING UNIVERSAL CONCERN. IT HAS RECENTLY BEEN REPORTED THAT BARIATRIC SURGERY IS A MORE SUCCESSFUL TREATMENT FOR SEVERE OBESITY THAN OTHER NONINVASIVE INTERVENTIONS, RESULTING IN RAPID SIGNIFICANT WEIGHT LOSS AND ASSOCIATED CHRONIC DISEASE REMISSION. THE IDENTIFICATION OF DISTINCT EPIGENETIC PATTERNS IN PATIENTS WHO ARE OBESE OR HAVE METABOLIC IMBALANCES HAS SUGGESTED A POTENTIAL ROLE FOR EPIGENETIC ALTERATIONS IN CAUSAL OR MEDIATING PATHWAYS IN THE DEVELOPMENT OF OBESITY-RELATED PATHOLOGIES. SPECIFIC CHANGES IN THE EPIGENOME (DNA METHYLOME), ASSOCIATED WITH METABOLIC DISORDERS, CAN BE DETECTED IN THE BLOOD. WE INVESTIGATED WHETHER SUCH EPIGENETIC CHANGES ARE REVERSIBLE AFTER WEIGHT LOSS USING GENOME-WIDE DNA METHYLOME ANALYSIS OF BLOOD SAMPLES FROM INDIVIDUALS WITH SEVERE OBESITY (MEAN BMI ~ 45) UNDERGOING BARIATRIC SURGERY. RESULTS: OUR ANALYSIS REVEALED 41 SIGNIFICANT (BONFERRONI P < 0.05) AND 1169 (FALSE DISCOVERY RATE P < 0.05) SUGGESTIVE DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH WEIGHT LOSS DUE TO BARIATRIC SURGERY. AMONG THE 41 SIGNIFICANT DMPS, 5 CPGS WERE REPLICATED IN AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS (THE HEAVIER TWIN UNDERWENT DIET-INDUCED WEIGHT LOSS). THE EFFECT SIZES OF THESE 5 CPGS WERE CONSISTENT ACROSS DISCOVERY AND REPLICATION SETS (P < 0.05). WE ALSO IDENTIFIED 192 DIFFERENTIALLY METHYLATED REGIONS (DMRS) AMONG WHICH SMAD6 AND PFKFB3 GENES WERE THE TOP HYPERMETHYLATED AND HYPOMETHYLATED REGIONS, RESPECTIVELY. PATHWAY ENRICHMENT ANALYSIS OF THE DMR-ASSOCIATED GENES SHOWED THAT FUNCTIONAL PATHWAYS RELATED TO IMMUNE FUNCTION AND TYPE 1 DIABETES WERE SIGNIFICANT. WEIGHT LOSS DUE TO BARIATRIC SURGERY ALSO SIGNIFICANTLY DECELERATED EPIGENETIC AGE 12 MONTHS AFTER THE INTERVENTION (MEAN = - 4.29; P = 0.02). CONCLUSIONS: WE IDENTIFIED WEIGHT LOSS-ASSOCIATED DNA-METHYLATION ALTERATIONS TARGETING IMMUNE AND INFLAMMATORY GENE PATHWAYS IN BLOOD SAMPLES FROM BARIATRIC-SURGERY PATIENTS. THE TOP HITS WERE REPLICATED IN SAMPLES FROM AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS FOLLOWING A HYPOCALORIC DIET. ENERGY RESTRICTION AND BARIATRIC SURGERY THUS SHARE CPGS THAT MAY REPRESENT EARLY INDICATORS OF RESPONSE TO THE METABOLIC EFFECTS OF WEIGHT LOSS. THE ANALYSIS OF BARIATRIC SURGERY-ASSOCIATED DMRS SUGGESTS THAT EPIGENETIC REGULATION OF GENES INVOLVED IN ENDOTHELIAL AND ADIPOSE TISSUE FUNCTION IS KEY IN THE PATHOPHYSIOLOGY OF OBESITY.	2022	

18  6169  26 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19   382  27 AN EPIGENOME-WIDE STUDY OF BODY MASS INDEX AND DNA METHYLATION IN BLOOD USING PARTICIPANTS FROM THE SISTER STUDY COHORT. BACKGROUND/OBJECTIVES: THE RELATIONSHIP BETWEEN OBESITY AND CHRONIC DISEASE RISK IS WELL-ESTABLISHED; THE UNDERLYING BIOLOGICAL MECHANISMS DRIVING THIS RISK INCREASE MAY INCLUDE OBESITY-RELATED EPIGENETIC MODIFICATIONS. TO EXPLORE THIS HYPOTHESIS, WE CONDUCTED A GENOME-WIDE ANALYSIS OF DNA METHYLATION AND BODY MASS INDEX (BMI) USING DATA FROM A SUBSET OF WOMEN IN THE SISTER STUDY. SUBJECTS/METHODS: THE SISTER STUDY IS A COHORT OF 50 884 US WOMEN WHO HAD A SISTER WITH BREAST CANCER BUT WERE FREE OF BREAST CANCER THEMSELVES AT ENROLLMENT. STUDY PARTICIPANTS COMPLETED EXAMINATIONS WHICH INCLUDED MEASUREMENTS OF HEIGHT AND WEIGHT, AND PROVIDED BLOOD SAMPLES. BLOOD DNA METHYLATION DATA GENERATED WITH THE ILLUMINA INFINIUM HUMANMETHYLATION27 BEADCHIP ARRAY COVERING 27,589 CPG SITES WAS AVAILABLE FOR 871 WOMEN FROM A PRIOR STUDY OF BREAST CANCER AND DNA METHYLATION. TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH BMI, WE ANALYZED THIS METHYLATION DATA USING ROBUST LINEAR REGRESSION WITH ADJUSTMENT FOR AGE AND CASE STATUS. FOR THOSE CPGS PASSING THE FALSE DISCOVERY RATE SIGNIFICANCE LEVEL, WE EXAMINED THE ASSOCIATION IN A REPLICATION SET COMPRISED OF A NON-OVERLAPPING GROUP OF 187 WOMEN FROM THE SISTER STUDY WHO HAD DNA METHYLATION DATA GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. ANALYSIS OF THIS EXPANDED 450 K ARRAY IDENTIFIED ADDITIONAL BMI-ASSOCIATED SITES WHICH WERE INVESTIGATED WITH TARGETED PYROSEQUENCING. RESULTS: FOUR CPG SITES REACHED GENOME-WIDE SIGNIFICANCE (FALSE DISCOVERY RATE (FDR) Q<0.05) IN THE DISCOVERY SET AND ASSOCIATIONS FOR ALL FOUR WERE SIGNIFICANT AT STRICT BONFERRONI CORRECTION IN THE REPLICATION SET. AN ADDITIONAL 23 SITES PASSED FDR IN THE REPLICATION SET AND FIVE WERE REPLICATED BY PYROSEQUENCING IN THE DISCOVERY SET. SEVERAL OF THE GENES IDENTIFIED INCLUDING ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 AND CRHR2 HAVE BEEN LINKED TO OBESITY AND OBESITY-RELATED CHRONIC DISEASES. CONCLUSIONS: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT OBESITY-RELATED EPIGENETIC DIFFERENCES ARE DETECTABLE IN BLOOD AND MAY BE RELATED TO RISK OF CHRONIC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                    
20  5744  19 SMOKING-INDUCED EXPRESSION OF THE GPR15 GENE INDICATES ITS POTENTIAL ROLE IN CHRONIC INFLAMMATORY PATHOLOGIES. DESPITE THE DESCRIBED CLEAR EPIGENETIC EFFECTS OF SMOKING, THE EFFECT OF SMOKING ON GENOME-WIDE GENE EXPRESSION IN THE BLOOD IS OBSCURE. WE THEREFORE STUDIED THE SMOKING-INDUCED CHANGES IN THE GENE-EXPRESSION PROFILE OF THE PERIPHERAL BLOOD. RNA WAS EXTRACTED FROM THE WHOLE BLOOD OF 48 INDIVIDUALS WITH A DETAILED SMOKING HISTORY (24 NEVER-SMOKERS, 16 SMOKERS, AND 8 EX-SMOKERS). GENE-EXPRESSION PROFILES WERE EVALUATED WITH RNA SEQUENCING, AND RESULTS WERE ANALYZED SEPARATELY IN 24 MEN AND 24 WOMEN. IN THE MALE SMOKERS, 13 GENES WERE STATISTICALLY SIGNIFICANTLY (FALSE-DISCOVERY RATE <0.1) DIFFERENTIALLY EXPRESSED; IN FEMALE SMOKERS, 5 GENES. ALTHOUGH MOST OF THE DIFFERENTIALLY EXPRESSED GENES WERE DIFFERENT BETWEEN THE MALE AND FEMALE SMOKERS, THE G-PROTEIN-COUPLED RECEPTOR 15 GENE (GPR15) WAS DIFFERENTIALLY EXPRESSED IN BOTH MALE AND FEMALE SMOKERS COMPARED WITH NEVER-SMOKERS. ANALYSIS OF GPR15 METHYLATION IDENTIFIED SIGNIFICANTLY GREATER HYPOMETHYLATION IN SMOKERS COMPARED WITH THAT IN NEVER-SMOKERS. GPR15 IS THE CHEMOATTRACTANT RECEPTOR THAT REGULATES T-CELL MIGRATION AND IMMUNITY. UP-REGULATION OF GPR15 COULD EXPLAIN TO SOME EXTENT THE HEALTH HAZARDS OF SMOKING WITH REGARD TO CHRONIC INFLAMMATORY DISEASES.	2015