1 430 99 ANTICIPATION IN FAMILIES WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND OTHER LYMPHOPROLIFERATIVE DISORDERS. FIFTY-ONE PARENT-OFFSPRING PAIRS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) OR OTHER LYMPHOPROLIFERATIVE DISORDERS (NONCLL) SUCH AS MALIGNANT LYMPHOMA, MULTIPLE MYELOMA, OR OTHER TYPES OF LYMPHOCYTIC LEUKEMIA THAN CLL WERE ASCERTAINED INDEPENDENTLY IN 38 FAMILIES. THERE WERE 30 CLL-CLL PARENT-OFFSPRING PAIRS AND 21 PAIRS WITH NONCLL IN PARENTS AND/OR IN OFFSPRING. THE MEDIAN AGE OF ONSET OF DISEASE WAS 13 YEARS LOWER IN THE OFFSPRING THAN IN THE PARENTS WHEN COMPARING ALL 51 PAIRS (P < 0.001). THIS DIFFERENCE WAS MAINLY CAUSED BY A SIGNIFICANTLY LOWER AGE AT ONSET IN OFFSPRING WITH PARENTAL NONCLL (P < 0.001) WHERE PATERNAL DISEASE WAS TRANSFERRED ESPECIALLY TO SONS, WHILE AFFECTED OFFSPRING TO PARENTS WITH CLL HAVE THE SAME AGE AT DEBUT OF DISEASE THAN THEIR PARENTS (P = 0.130) AND A NEARLY EQUAL TRANSFER TO SONS AND DAUGHTERS. THE LOW-MALIGNANT FOLLICULAR SMALL B-CELL LYMPHOMA WAS THE PREDOMINANT DIAGNOSIS WITHIN NONCLL. ANTICIPATION IS POINTED OUT AS ONE LIKELY MECHANISM BEHIND THE LOWER AGE AT ONSET OF DISEASE IN OFFSPRING THAN IN PARENTS, EVEN IF A PART OF THIS DIFFERENCE IS ASCRIBED TO A GENERALLY EARLIER DIAGNOSIS WITH MODERN TECHNOLOGY IN OFFSPRING THAN IN PARENTS. 2010 2 2469 15 EPIGENETIC TRAJECTORIES OF THE PREMALIGNANT-TO-MALIGNANT TRANSITION OF CHRONIC LYMPHOCYTIC LEUKEMIA. KRETZMER AND COLLEAGUES SHOW THAT THE TRANSITION TO ALTERED METHYLOME OCCURS VERY EARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA, AND ONCE ACQUIRED, IT IS A CLONAL AND EXTREMELY STABLE CHANGE. HOWEVER, THE PRECISE TIME POINT WHEN THE LEUKEMIC CLONE STARTS DEVIATING SIGNIFICANTLY FROM THE NORMAL B-CELL DIFFERENTIATION TRAJECTORY IS STILL ELUSIVE. SEE RELATED ARTICLE BY KRETZMER ET AL., P. 54. 2021 3 3125 20 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER. 2015 4 6911 13 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 5 1607 18 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN. 2019 6 2653 21 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES. 2008 7 2997 18 GENETIC VARIANTS IN DNMT1 AND THE RISK OF CARDIAC AUTONOMIC NEUROPATHY IN WOMEN WITH TYPE 1 DIABETES. AIMS/INTRODUCTION: EPIGENETICS PARTICIPATE IN THE PATHOGENESIS OF METABOLIC MEMORY, A SITUATION IN WHICH HYPERGLYCEMIA EXERTS PROLONGED DELETERIOUS EFFECTS EVEN AFTER ITS NORMALIZATION. WE TESTED THE HYPOTHESIS THAT GENETIC VARIANTS IN AN EPIGENETIC GENE COULD PREDISPOSE TO DIABETES COMPLICATIONS. MATERIAL AND METHODS: WE ASSESSED THE FREQUENCY OF FIVE SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE GENE ENCODING DEOXYRIBONUCLEIC ACID METHYTRANSFERASE 1 (DNMT1; RS8112895, RS7254567, RS11085721, RS17291414 AND RS10854076), AND THEIR ASSOCIATIONS WITH DIABETIC KIDNEY DISEASE, RETINOPATHY, DISTAL POLYNEUROPATHY AND AUTONOMIC CARDIOVASCULAR NEUROPATHY IN 359 INDIVIDUALS WITH LONG-TERM TYPE 1 DIABETES. RESULTS: NONE OF THE SINGLE-NUCLEOTIDE POLYMORPHISMS STUDIED WAS SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE OF CHRONIC COMPLICATIONS IN THE OVERALL POPULATION. HOWEVER, AFTER SEX STRATIFICATION, THE MINOR ALLELE C OF RS11085721 CONFERRED RISK FOR CARDIOVASCULAR NEUROPATHY IN WOMEN AFTER ADJUSTMENT FOR CONFOUNDING VARIABLES (ODDS RATIO 2.32; 95% CONFIDENCE INTERVAL 1.26-4.33; P = 0.006). CONCLUSIONS: THE FACT THAT HETEROZYGOUS MUTATIONS IN DNMT1 ARE ASSOCIATED WITH HEREDITARY SENSORY AUTONOMIC NEUROPATHY PROVIDES PLAUSIBILITY TO THE PRESENT FINDING. IF CONFIRMED IN INDEPENDENT SAMPLES, IT SUGGESTS THAT GENETIC VARIANTS IN EPIGENETIC GENES MIGHT PREDISPOSE TO MORE OR FEWER EPIGENETIC CHANGES IN THE FACE OF SIMILAR METABOLIC DERANGEMENTS TRIGGERED BY HYPERGLYCEMIA, CONSTITUTING THE "GENETICS OF EPIGENETICS" FOR MICROVASCULAR DIABETES COMPLICATIONS. 2019 8 2935 27 GENETIC ALTERATION ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA. THE GENETICS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) DIFFER CONSIDERABLY FROM MOST OTHER FORMS OF HEMATOLOGIC MALIGNANCY WHICH ARE USUALLY CHARACTERIZED BY CHROMOSOME TRANSLOCATIONS. B-CLL TYPICALLY CONTAINS CHROMOSOMAL DELETIONS AND CHROMOSOMES 13Q14 AND 11Q22-->Q23 ARE THE MOST COMMON. THESE TWO REGIONS APPEAR TO SHARE A COMMON ANCESTRAL ORIGIN (AUER ET AL., 2007B). OVERALL, CHROMOSOMAL ABNORMALITIES CAN BE FOUND IN THE MAJORITY OF PATIENTS WITH B-CLL WHEN USING SENSITIVE TECHNIQUES (DOHNERET AL., 2000) AND POSSIBLY REFLECTS AN UNDERLYING PREDISPOSITION, WITH A SMALL BUT SIGNIFICANT NUMBER OF FAMILIAL CASES. ALTHOUGH SINGLE AND CONSISTENT ABNORMALITIES ARE MOST COMMON, MULTIPLE REARRANGEMENTS CAN OCCUR, OFTEN WITH DISEASE PROGRESSION (FEGANETAL., 1995; DOHNER ET AL., 2000). REGIONS OF RECURRENT DELETION SUGGEST THE PRESENCE OF TUMOR SUPPRESSOR GENES IF FOLLOWING KNUDSON'S THEORETICAL 2-HIT MODEL. HOWEVER, DESPITE EXTENSIVE SEQUENCING ANALYSIS OVER THE LAST DECADE AND LACK OF PATHOGENIC MUTATIONS IDENTIFIED, THERE HAS BEEN A MOVE AWAY FROM THIS SUGGESTED HYPOTHESIS AND ALTERNATIVE MECHANISMS OF GENE INACTIVATION INVOLVING EPIGENETIC SILENCING OR HAPLOINSUFFICIENCY MAY BE CONSIDERED AS MORE LIKELY IN THIS DISEASE. THIS REVIEW FOCUSES ON THE COMMON GENETIC ABNORMALITIES IN B-CLL AND RELATES THEM TO SOME OF THE MORE RECENT HYPOTHESES ON INACTIVATION OF GENES WITHIN THESE REGIONS OF DELETION. 2007 9 1729 20 DYSREGULATION OF MIR-155 EXPRESSION IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS. PSYCHOLOGICAL AND PHYSICAL STRESS CAN INDUCE DYSREGULATION OF GENE EXPRESSION VIA CHANGES IN DNA METHYLATION AND MICRORNA (MIRNA) EXPRESSION. SUCH EPIGENETIC MODIFICATIONS ARE YET TO BE INVESTIGATED IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS SUBJECT TO HIGHLY STRESSFUL TRAINING INVOLVING REPETITIVE HEAD IMPACTS. THIS STUDY EXAMINED DIFFERENCES IN DNA METHYLATION AND MIRNA EXPRESSION IN ELITE MMA FIGHTERS COMPARED TO ACTIVE CONTROLS. GLOBAL METHYLATION DIFFERENCES BETWEEN GROUPS WERE ASSESSED VIA A LINE-1 ASSAY. AT THE SAME TIME, PCR ARRAYS WERE USED TO ESTIMATE DIFFERENTIAL EXPRESSION IN SAMPLES OF 21 FIGHTERS AND 15 CONTROLS FOR 192 DIFFERENT MIRNAS ASSOCIATED WITH INFLAMMATORY DISEASES. AN INDEPENDENT-SAMPLES T-TEST FOUND NO SIGNIFICANT DIFFERENCE IN LINE-1 METHYLATION BETWEEN GROUPS. HOWEVER, AN INDEPENDENT-SAMPLES MANN-WHITNEY U TEST REVEALED A SIGNIFICANT UPREGULATION IN THE EXPRESSION OF MIR-155 IN MMA FIGHTER PLASMA. SINCE MIR-155 HAS BEEN RECOGNIZED AS AN IMPORTANT REGULATOR OF NEUROINFLAMMATION, THIS DYSREGULATION SUGGESTS A POSSIBLE EPIGENETIC MECHANISM RESPONSIBLE FOR CHRONIC INFLAMMATION ASSOCIATED WITH PROFESSIONAL-LEVEL MMA TRAINING. CONSISTENT WITH OTHER PUBLISHED WORKS, THIS STUDY HIGHLIGHTS THE POTENTIAL OF MIR-155 NOT ONLY AS A BIOMARKER FOR MONITORING LONG-TERM HEALTH RISKS LINKED TO HEAD TRAUMA BUT ALSO AS A TARGET TO REMEDIATE THE IMPACT OF CHRONIC NEUROINFLAMMATION. 2023 10 4736 23 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE. 2017 11 3991 20 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS. 2018 12 1138 17 COMPUTATIONAL METHODS FOR DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING KERNEL DISTANCE AND SCAN STATISTICS. MOTIVATION: RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE SEQUENCE OF DNA. ABNORMAL DNA METHYLATION IS ASSOCIATED WITH MANY HUMAN DISEASES. RESULTS: WE PROPOSE TWO DIFFERENT APPROACHES TO TEST FOR DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH COMPLEX TRAITS, WHILE ACCOUNTING FOR CORRELATIONS AMONG CPG SITES IN THE DMRS. THE FIRST APPROACH IS A NONPARAMETRIC METHOD USING A KERNEL DISTANCE STATISTIC AND THE SECOND ONE IS A LIKELIHOOD-BASED METHOD USING A BINOMIAL SPATIAL SCAN STATISTIC. THE KERNEL DISTANCE METHOD USES THE KERNEL FUNCTION, WHILE THE BINOMIAL SCAN STATISTIC APPROACH USES A MIXED-EFFECTS MODEL TO INCORPORATE CORRELATIONS AMONG CPG SITES. EXTENSIVE SIMULATIONS SHOW THAT BOTH APPROACHES HAVE EXCELLENT CONTROL OF TYPE I ERROR, AND BOTH HAVE REASONABLE STATISTICAL POWER. THE BINOMIAL SCAN STATISTIC APPROACH APPEARS TO HAVE HIGHER POWER, WHILE THE KERNEL DISTANCE METHOD IS COMPUTATIONALLY FASTER. THE PROPOSED METHODS ARE DEMONSTRATED USING DATA FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY. 2019 13 177 17 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS. 2022 14 6817 28 [FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY: REPORT OF SEVEN PATIENTS]. BACKGROUND: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY IS THE THIRD MOST COMMON MUSCULAR DYSTROPHY WITH AN ESTIMATED PREVALENCE OF 1 PER 20.000 AND A NORMAL LIFE EXPECTANCY IN THE MAJORITY OF PATIENTS. HOWEVER, APPROXIMATELY 15% OF PATIENTS BECOME WHEELCHAIR BOUND IN THE COURSE OF THEIR LIFE. IT IS A HEREDITARY AUTOSOMAL DOMINANT DISEASE WITH HIGH (95%) PENETRANCE BY THE AGE OF 20, BUT WITH VARIABLE DEGREE OF PHENOTYPIC EXPRESSION EVEN IN THE SAME FAMILY GROUP. SYMPTOMS FREQUENTLY START IN THE SECOND DECADE OF LIFE, WITH FACIAL AND SCAPULAR WEAKNESS. AIM: TO REPORT THE CLINICAL FEATURES OF SEVEN PATIENTS WITH THE DISEASE, SEEN AT A PUBLIC HOSPITAL. MATERIAL AND METHODS: ANALYSIS OF SEVEN PATIENTS WITH GENETIC STUDY SEEN IN A PUBLIC HOSPITAL IN SANTIAGO. RESULTS: THE AGE OF PATIENTS FLUCTUATED FROM 18 TO 61 YEARS AND FOUR WERE FEMALES. THE MEAN AGE AT ONSET OF SYMPTOMS WAS 29 YEARS AND FOUR HAD A FAMILY HISTORY OF THE DISEASE. THE USUAL PRESENTING COMPLAINT WAS ARM OR SHOULDER ASYMMETRIC WEAKNESS. FOUR PATIENTS HAD BONE PAIN. FACIAL INVOLVEMENT WAS PRESENT IN FOUR. A GENETIC STUDY WAS DONE IN FIVE PATIENTS, THE OTHER TWO PATIENTS WERE RELATIVES, CONFIRMING THE CONTRACTION OR LOWER NUMBER OF REPETITIONS IN D4Z4 REGION. AFTER 12 YEARS OF FOLLOW UP ONLY 2 PATIENTS OLDER THAN 60 YEARS CANNOT WORK AND ONE FEMALE PATIENTS IS IN A SEMI DEPENDENT STATE AT THE AGE OF 30. CONCLUSIONS: THE CLINICAL WORKUP IN THE DIAGNOSIS AND THE TIMELY INDICATION OF GENETIC STUDIES ARE HIGHLIGHTED, TO AVOID UNNECESSARY AND INVASIVE PROCEDURES. THE VARIABILITY IN THE PHENOTYPIC EXPRESSION IN A SIMILAR GENETIC DEFECT IS DISCUSSED AND THE GENETIC OR EPIGENETIC MECHANISMS OF THIS MUSCULAR DYSTROPHY ARE DESCRIBED. 2015 15 6594 20 TUMOR-AUGMENTING EFFECTS OF GESTATIONAL ARSENIC EXPOSURE ON F1 AND F2 IN MICE. THE CONSEQUENCES OF EARLY-LIFE EXPOSURE TO CHEMICALS IN THE ENVIRONMENT ARE EMERGING CONCERNS. CHRONIC EXPOSURE TO NATURALLY OCCURRING INORGANIC ARSENIC HAS BEEN KNOWN TO CAUSE VARIOUS ADVERSE HEALTH EFFECTS, INCLUDING CANCERS, IN HUMANS. ON THE OTHER HAND, ANIMAL STUDIES BY DR. M. WAALKES' GROUP REPORTED THAT ARSENITE EXPOSURE OF PREGNANT F0 FEMALES, ONLY FROM GESTATIONAL DAY 8 TO 18, INCREASED HEPATIC TUMORS IN THE F1 (ARSENITE-F1) MALES OF C3H MICE, WHOSE MALES TEND TO DEVELOP SPONTANEOUS HEPATIC TUMORS LATER IN LIFE. SINCE THIS MICE MODEL ILLUMINATED NOVEL UNIDENTIFIED CONSEQUENCES OF ARSENIC EXPOSURE, WE WISHED TO FURTHER INVESTIGATE THE BACKGROUND MECHANISMS. IN THE SAME EXPERIMENTAL MODEL, WE IDENTIFIED A VARIETY OF FACTORS THAT WERE AFFECTED BY GESTATIONAL ARSENIC EXPOSURE, INCLUDING EPIGENETIC AND GENETIC CHANGES, AS POSSIBLE CONSTITUENTS OF MULTIPLE STEPS OF LATE-ONSET HEPATIC TUMOR AUGMENTATION IN ARSENITE-F1 MALES. FURTHERMORE, OUR STUDY DISCOVERED THAT THE F2 MALES BORN TO ARSENITE-F1 MALES DEVELOPED HEPATIC TUMORS AT A SIGNIFICANTLY HIGHER RATE THAN THE CONTROL F2 MALES. THE RESULTS IMPLY THAT THE TUMOR AUGMENTING EFFECT IS INHERITED BY ARSENITE-F2 MALES THROUGH THE SPERM OF ARSENITE-F1. IN THIS ARTICLE, WE SUMMARIZED OUR STUDIES ON THE CONSEQUENCES OF GESTATIONAL ARSENITE EXPOSURE IN F1 AND F2 MICE TO DISCUSS NOVEL ASPECTS OF BIOLOGICAL EFFECTS OF GESTATIONAL ARSENIC EXPOSURE. 2017 16 1846 20 EFFECTS OF TWO TYPES OF ENERGY RESTRICTION ON METHYLATION LEVELS OF ADIPONECTIN RECEPTOR 1 AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT IN A MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA BREAST CANCER MOUSE MODEL. THE ROLE OF ADIPONECTIN AND LEPTIN SIGNALLING PATHWAYS HAS BEEN SUGGESTED TO PLAY IMPORTANT ROLES IN THE PROTECTIVE EFFECTS OF ENERGY RESTRICTION (ER) ON MAMMARY TUMOUR (MT) DEVELOPMENT. TO STUDY THE EFFECTS OF ER ON THE METHYLATION LEVELS IN ADIPONECTIN RECEPTOR 1 (ADIPOR1) AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT (LEPROT) GENES USING THE PYROSEQUENCING METHOD IN MAMMARY FAT PAD TISSUE, MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA (MMTV-TGF-ALPHA) FEMALE MICE WERE RANDOMLY ASSIGNED TO AD LIBITUM (AL), CHRONIC ER (CER, 15 % ER) OR INTERMITTENT ER (3 WEEKS AL AND 1 WEEK 60 % ER IN CYCLIC PERIODS) GROUPS AT 10 WEEKS OF AGE UNTIL 82 WEEKS OF AGE. THE METHYLATION LEVELS OF ADIPOR1 IN THE CER GROUP WERE HIGHER THAN THOSE IN THE AL GROUP AT WEEK 49/50 (P < 0.05), WHILE THE LEVELS OF METHYLATION FOR ADIPOR1 AND LEPROT GENES WERE SIMILAR AMONG THE OTHER GROUPS. ALSO, THE METHYLATION LEVELS AT CPG2 AND CPG3 REGIONS OF THE PROMOTER REGION OF THE ADIPOR1 GENE IN THE CER GROUP WERE THREE TIMES HIGHER (P < 0.05), WHILE CPG1 ISLAND OF LEPROT METHYLATION WAS SIGNIFICANTLY LOWER COMPARED WITH THE OTHER GROUPS (P < 0.05). ADIPONECTIN AND LEPTIN GENE EXPRESSION LEVELS WERE CONSISTENT WITH THE METHYLATION LEVELS. WE ALSO OBSERVED A CHANGE WITH AGEING IN METHYLATION LEVELS OF THESE GENES. THESE RESULTS INDICATE THAT DIFFERENT TYPES OF ER MODIFY METHYLATION LEVELS OF ADIPOR1 AND LEPROT IN DIFFERENT WAYS AND CER HAD A MORE SIGNIFICANT EFFECT ON METHYLATION LEVELS OF BOTH GENES. EPIGENETIC REGULATION OF THESE GENES MAY PLAY IMPORTANT ROLES IN THE PREVENTIVE EFFECTS OF ER AGAINST MT DEVELOPMENT AND AGEING PROCESSES. 2021 17 4279 21 MICRONUCLEI, INFLAMMATION AND AUTO-IMMUNE DISEASE. AUTO-IMMUNE DISEASES (AUD) ARE CHARACTERIZED BY AN IMMUNE RESPONSE TO ANTIGENIC COMPONENTS OF THE HOST ITSELF. THE ETIOLOGY OF AUD IS NOT WELL UNDERSTOOD. THE AVAILABLE EVIDENCE POINTS TO AN INTERACTION BETWEEN GENETIC, EPIGENETIC, ENVIRONMENTAL, INFECTIOUS AND LIFE-STYLE FACTORS. AUD ARE MORE PREVALENT IN WOMEN THAN IN MEN; SEX HORMONES PLAY A CRUCIAL ROLE IN THIS SEX BIAS. MICRONUCLEI (MN) EMERGED AS A NEW PLAYER IN THE INDUCTION OF AUD, BASED ON THE CAPACITY OF DNA-SENSORS TO DETECT SELF-DNA THAT LEAKS INTO THE CYTOPLASM FROM DISRUPTED MN AND INDUCE THE CGAS-STING PATHWAY TRIGGERING AN INNATE AUTO-IMMUNE RESPONSE AND CHRONIC INFLAMMATION. IT WAS FOUND THAT INFLAMMATION CAN INDUCE MN AND MN CAN INDUCE INFLAMMATION, LEADING TO A VICIOUS INFLAMMATION-OXIDATIVE-DNA DAMAGE-MN-FORMATION-CHROMOTHRIPSIS CYCLE. MN ORIGINATING FROM SEX CHROMOSOME-LOSS MAY INDUCE INFLAMMATION AND AUD. WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES REPORTING MN IN PATIENTS WITH SYSTEMIC OR ORGAN-SPECIFIC AUD. A META-ANALYSIS WAS PERFORMED ON LYMPHOCYTE MN IN DIABETES MELLITUS (10 STUDIES, 457 PATIENTS/290 CONTROLS) AND BEHCET'S DISEASE (3 STUDIES, 100 PATIENTS/70 CONTROLS) AND FOR BUCCAL MN IN DIABETES MELLITUS (11 STUDIES, 507 PATIENTS/427 CONTROLS). A STATISTICALLY SIGNIFICANT INCREASE IN PATIENTS COMPARED TO CONTROLS WAS FOUND IN THE META-ANALYSES PROVIDING AN INDICATION OF AN ASSOCIATION BETWEEN MN AND AUD. A 36%-HIGHER MEAN-MRI IN BUCCAL CELLS (3.8+/-0.7) WAS FOUND COMPARED TO LYMPHOCYTES (2.8+/-0.7)(P = 0.01). THE META-MRI IN LYMPHOCYTES AND BUCCAL CELLS (1.7 AND 3.0 RESPECTIVELY) SUGGEST THAT BUCCAL CELLS MAY BE MORE SENSITIVE. TO ASSESS THEIR RELATIVE SENSITIVITY, STUDIES WITH MEASUREMENTS FROM THE SAME SUBJECTS WOULD BE DESIRABLE. IT IS IMPORTANT THAT FUTURE STUDIES (I) INVESTIGATE, IN WELL-DESIGNED POWERED STUDIES, THE PROSPECTIVE ASSOCIATION OF MN-FORMATION WITH AUD AND (II) EXPLORE THE MOLECULAR MECHANISMS BY WHICH CHROMOSOME SHATTERING IN MN AND THE RELEASE OF CHROMATIN FRAGMENTS FROM MN LEAD TO THE FORMATION OF AUTO-ANTIBODIES. 2020 18 2637 18 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 19 5092 19 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS. 2023 20 6137 16 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022