1 6220 94 THE KIDNEY IS THE MAJOR SITE OF S-ADENOSYLHOMOCYSTEINE DISPOSAL IN HUMANS. S-ADENOSYLHOMOCYSTEINE (SAH), THE METABOLIC PRECURSOR OF HOMOCYSTEINE IN THE BODY, IS A POTENT INHIBITOR OF METHYLATION REACTIONS. SEVERAL METHYLATION REACTIONS PLAY A MAJOR ROLE IN EPIGENETIC REGULATION OF PROTEIN EXPRESSION, ATHEROSCLEROSIS, AND CANCER DEVELOPMENT. HERE WE STUDIED THE MECHANISMS RESPONSIBLE FOR THE MAINTENANCE OF CIRCULATING SAH LEVELS BY MEASUREMENT OF THE ARTERIO-VENOUS DIFFERENCES ACROSS THE KIDNEY, SPLANCHNIC ORGANS, AND THE LUNG IN HUMANS. THE LUNGS DID NOT REMOVE OR ADD ANY CIRCULATING SAH, WHEREAS THE LIVER RELEASED IT INTO THE HEPATIC VEINS. THE KIDNEY EXTRACTED 40% OF SAH AND THE SAH ARTERIO-VENOUS DIFFERENCE ACROSS THE KIDNEY WAS DIRECTLY AND SIGNIFICANTLY RELATED TO ITS ARTERIAL LEVELS. THUS, THE KIDNEY PLAYS A MAJOR ROLE IN MAINTAINING SAH LEVELS AND MAY, INDIRECTLY, CONTROL TISSUE TRANSMETHYLATION REACTIONS. OUR FINDINGS OF A PIVOTAL ROLE FOR THE HUMAN KIDNEY IN SULFUR AMINO ACID METABOLISM MAY ALSO ACCOUNT FOR THE INCREASED PLASMA LEVELS OF SAH IN PATIENTS WITH CHRONIC KIDNEY DISEASES. 2009 2 5587 37 ROLE OF S-ADENOSYLHOMOCYSTEINE IN CARDIOVASCULAR DISEASE AND ITS POTENTIAL EPIGENETIC MECHANISM. TRANSMETHYLATION REACTIONS UTILIZE S-ADENOSYLMETHIONINE (SAM) AS A METHYL DONOR AND ARE CENTRAL TO THE REGULATION OF MANY BIOLOGICAL PROCESSES: MORE THAN FIFTY SAM-DEPENDENT METHYLTRANSFERASES METHYLATE A BROAD SPECTRUM OF CELLULAR COMPOUNDS INCLUDING DNA, HISTONES, PHOSPHOLIPIDS AND OTHER SMALL MOLECULES. COMMON TO ALL SAM-DEPENDENT TRANSMETHYLATION REACTIONS IS THE RELEASE OF THE POTENT INHIBITOR S-ADENOSYLHOMOCYSTEINE (SAH) AS A BY-PRODUCT. SAH IS REVERSIBLY HYDROLYZED TO ADENOSINE AND HOMOCYSTEINE BY SAH HYDROLASE. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. HOWEVER, A MAJOR UNANSWERED QUESTION IS IF HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. A CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN A PARALLEL INCREASE IN INTRACELLULAR OR PLASMA SAH, WHICH IS A MORE SENSITIVE BIOMARKER OF CARDIOVASCULAR DISEASE THAN HOMOCYSTEINE AND SUGGESTS THAT SAH IS A CRITICAL PATHOLOGICAL FACTOR IN HOMOCYSTEINE-ASSOCIATED DISORDERS. PREVIOUS REPORTS INDICATE THAT SUPPLEMENTATION WITH FOLATE AND B VITAMINS EFFICIENTLY LOWERS HOMOCYSTEINE LEVELS BUT NOT PLASMA SAH LEVELS, WHICH POSSIBLY EXPLAINS THE FAILURE OF HOMOCYSTEINE-LOWERING VITAMINS TO REDUCE VASCULAR EVENTS IN SEVERAL RECENT CLINICAL INTERVENTION STUDIES. FURTHERMORE, MORE STUDIES ARE FOCUSING ON THE ROLE AND MECHANISMS OF SAH IN DIFFERENT CHRONIC DISEASES RELATED TO HYPERHOMOCYSTEINEMIA, SUCH AS CARDIOVASCULAR DISEASE, KIDNEY DISEASE, DIABETES, AND OBESITY. THIS REVIEW SUMMARIZES THE CURRENT ROLE OF SAH IN CARDIOVASCULAR DISEASE AND ITS EFFECT ON SEVERAL RELATED RISK FACTORS. IT ALSO EXPLORES POSSIBLE THE MECHANISMS, SUCH AS EPIGENETICS AND OXIDATIVE STRESS, OF SAH. THIS ARTICLE IS PART OF A DIRECTED ISSUE ENTITLED: EPIGENETIC DYNAMICS IN DEVELOPMENT AND DISEASE. 2015 3 1855 31 ELEVATION IN S-ADENOSYLHOMOCYSTEINE AND DNA HYPOMETHYLATION: POTENTIAL EPIGENETIC MECHANISM FOR HOMOCYSTEINE-RELATED PATHOLOGY. CHRONIC NUTRITIONAL DEFICIENCIES IN FOLATE, CHOLINE, METHIONINE, VITAMIN B-6 AND/OR VITAMIN B-12 CAN PERTURB THE COMPLEX REGULATORY NETWORK THAT MAINTAINS NORMAL ONE-CARBON METABOLISM AND HOMOCYSTEINE HOMEOSTASIS. GENETIC POLYMORPHISMS IN THESE PATHWAYS CAN ACT SYNERGISTICALLY WITH NUTRITIONAL DEFICIENCIES TO ACCELERATE METABOLIC PATHOLOGY ASSOCIATED WITH OCCLUSIVE HEART DISEASE, BIRTH DEFECTS AND DEMENTIA. A MAJOR UNANSWERED QUESTION IS WHETHER HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR WHETHER HOMOCYSTEINEMIA IS SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. S-ADENOSYLMETHIONINE AND S-ADENOSYLHOMOCYSTEINE (SAH), AS THE SUBSTRATE AND PRODUCT OF METHYLTRANSFERASE REACTIONS, ARE IMPORTANT METABOLIC INDICATORS OF CELLULAR METHYLATION STATUS. CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN PARALLEL INCREASES IN INTRACELLULAR SAH AND POTENT PRODUCT INHIBITION OF DNA METHYLTRANSFERASES. SAH-MEDIATED DNA HYPOMETHYLATION AND ASSOCIATED ALTERATIONS IN GENE EXPRESSION AND CHROMATIN STRUCTURE MAY PROVIDE NEW HYPOTHESES FOR PATHOGENESIS OF DISEASES RELATED TO HOMOCYSTEINEMIA. 2002 4 318 29 ALCOHOL-INDUCED EPIGENETIC CHANGES IN CANCER. CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH SERIOUS NEGATIVE HEALTH EFFECTS, INCLUDING THE DEVELOPMENT OF SEVERAL CANCER TYPES. ONE OF THE PATHWAYS AFFECTED BY ALCOHOL TOXICITY IS THE ONE-CARBON METABOLISM. THE ALCOHOL-INDUCED IMPAIRMENT OF THIS METABOLIC PATHWAY RESULTS IN EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. THESE EPIGENETIC CHANGES ARE INDUCED BY FOLATE DEFICIENCY AND BY PRODUCTS OF THE ETHANOL METABOLISM. THE CHANGES INDUCED BY LONG-TERM HEAVY ETHANOL CONSUMPTION RESULT IN ELEVATIONS OF HOMOCYSTEINE AND S-ADENOSYL-HOMOCYSTEINE (SAH) AND REDUCTIONS IN S-ADENOSYLMETHIONINE (SAM) AND ANTIOXIDANT GLUTATHIONE (GSH) LEVELS, LEADING TO ABNORMAL PROMOTER GENE HYPERMETHYLATION, GLOBAL HYPOMETHYLATION, AND METABOLIC INSUFFICIENCY OF ANTIOXIDANT DEFENSE MECHANISMS. IN ADDITION, REACTIVE OXYGEN SPECIES (ROS) GENERATED DURING THE ETHANOL METABOLISM INDUCE ALTERATIONS IN DNA METHYLATION PATTERNS THAT PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. SPECIFIC EPIGENETIC CHANGES IN ESOPHAGEAL, HEPATIC, AND COLORECTAL CANCERS HAVE BEEN DETECTED IN BLOOD SAMPLES AND PROPOSED TO BE USED CLINICALLY AS EPIGENETIC BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF THESE CANCERS. ALSO, GENETIC VARIANTS OF GENES INVOLVED IN ONE-CARBON METABOLISM AND ETHANOL METABOLISM WERE FOUND TO MODULATE THE RELATIONSHIP BETWEEN ALCOHOL-INDUCED EPIGENETIC CHANGES AND CANCER RISK. FURTHERMORE, ALCOHOL METABOLISM PRODUCTS HAVE BEEN ASSOCIATED WITH AN INCREASE IN NADH LEVELS, WHICH LEAD TO HISTONE MODIFICATIONS AND CHANGES IN GENE EXPRESSION THAT IN TURN INFLUENCE CANCER SUSCEPTIBILITY. CHRONIC EXCESSIVE USE OF ALCOHOL ALSO AFFECTS SELECTED MEMBERS OF THE FAMILY OF MICRORNAS, AND AS MIRNAS COULD ACT AS EPIGENETIC REGULATORS, THIS MAY PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN CONCLUSION, TARGETING ALCOHOL-INDUCED EPIGENETIC CHANGES IN SEVERAL CANCER TYPES COULD MAKE AVAILABLE CLINICAL TOOLS FOR THE DIAGNOSIS, PROGNOSIS, AND TREATMENT OF THESE CANCERS, WITH AN IMPORTANT ROLE IN PRECISION MEDICINE. 2018 5 315 32 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 6 339 29 ALTERATIONS IN HOMOCYSTEINE METABOLISM AMONG ALCOHOL DEPENDENT PATIENTS--CLINICAL, PATHOBIOCHEMICAL AND GENETIC ASPECTS. ADDICTION RESEARCH FOCUSING ON HOMOCYSTEINE METABOLISM AND ITS ASSOCIATION WITH ASPECTS OF ALCOHOL DEPENDENCE HAS REVEALED IMPORTANT FINDINGS. RECENT LITERATURE ON THIS TOPIC HAS BEEN TAKEN INTO ACCOUNT FOR THE REVIEW PROVIDED. METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) IS A KEY ENZYME IN THE HOMOCYSTEINE METABOLISM. PLASMA HOMOCYSTEINE LEVELS ARE INFLUENCED BY THE SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) MTHFR C677T. BESIDES GENETIC FACTORS, ENVIRONMENTAL FACTORS HAVE AN IMPACT ON HOMOCYSTEINE PLASMA LEVELS TOO. THUS, CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH ELEVATED HOMOCYSTEINE PLASMA CONCENTRATIONS. ELEVATION OF PLASMA HOMOCYSTEINE CONCENTRATION IS CONSIDERED AS A PREDICTOR FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES AND--AS HOMOCYSTEINE IS A CARDIOVASCULAR RISK FACTOR--MIGHT CONTRIBUTE TO THE HIGHER RISK FOR MYOCARDIAL INFARCTION AMONG ALCOHOL DEPENDENT PATIENTS. HOMOCYSTEINE ACTS AS AN N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AGONIST AND HAS EXCITOTOXIC EFFECTS. FURTHERMORE, IT HAS BEEN DEMONSTRATED THAT HOMOCYSTEINE HAS NEUROTOXIC EFFECTS ESPECIALLY ON DOPAMINERGIC NEURONS. AS THE REWARDING EFFECTS OF ALCOHOL ARE MEDIATED BY THE DOPAMINERGIC SYSTEM, A HOMOCYSTEINE-DEPENDENT IMPAIRMENT OF THE REWARD SYSTEM POSSIBLY LEADS TO AN ALTERED DRINKING BEHAVIOUR ACCORDING TO THE DEFICIT HYPOTHESIS OF ADDICTION. HOMOCYSTEINE IS INVOLVED IN THE METABOLISM OF METHYL GROUPS AND DNA-METHYLATION PLAYS A ROLE IN REGULATION OF GENE EXPRESSION. THEREFORE IT HAS BEEN SUGGESTED THAT HOMOCYSTEINE IS AN IMPORTANT EPIGENETIC FACTOR. IT REMAINS TO BE DETERMINED WHETHER ALCOHOL DEPENDENT PATIENTS BENEFIT FROM HOMOCYSTEINE LOWERING STRATEGIES, E.G., VIA SUPPLEMENTATION OF FOLATE, VITAMIN B6 AND B12. IN THIS RESPECT IT IS NOT CLEAR YET, IF A SUPPLEMENTATION THERAPY CAN REDUCE THE RISK FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES. 2008 7 2833 19 FOLATE AND DNA METHYLATION: A REVIEW OF MOLECULAR MECHANISMS AND THE EVIDENCE FOR FOLATE'S ROLE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION CRITICAL TO NORMAL GENOME REGULATION AND DEVELOPMENT. THE VITAMIN FOLATE IS A KEY SOURCE OF THE ONE CARBON GROUP USED TO METHYLATE DNA. BECAUSE NORMAL MAMMALIAN DEVELOPMENT IS DEPENDENT ON DNA METHYLATION, THERE IS ENORMOUS INTEREST IN ASSESSING THE POTENTIAL FOR CHANGES IN FOLATE INTAKE TO MODULATE DNA METHYLATION BOTH AS A BIOMARKER FOR FOLATE STATUS AND AS A MECHANISTIC LINK TO DEVELOPMENTAL DISORDERS AND CHRONIC DISEASES INCLUDING CANCER. THIS REVIEW HIGHLIGHTS THE ROLE OF DNA METHYLATION IN NORMAL GENOME FUNCTION, HOW IT CAN BE ALTERED, AND THE EVIDENCE OF THE ROLE OF FOLATE/FOLIC ACID IN THESE PROCESSES. 2012 8 6717 26 VITAMIN B SUPPLEMENTATION AND NUTRITIONAL INTAKE OF METHYL DONORS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A CRITICAL REVIEW OF THE IMPACT ON EPIGENETIC MACHINERY. CARDIOVASCULAR MORBIDITY AND MORTALITY ARE SEVERAL-FOLD HIGHER IN PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD) THAN IN THE GENERAL POPULATION. HYPERHOMOCYSTEINEMIA HAS UNDOUBTEDLY A CENTRAL ROLE IN SUCH A PROMINENT CARDIOVASCULAR BURDEN. THE LEVELS OF HOMOCYSTEINE ARE REGULATED BY METHYL DONORS (FOLATE, METHIONINE, CHOLINE, BETAINE), AND COFACTORS (VITAMIN B6, VITAMIN B12,). UREMIA-INDUCED HYPERHOMOCYSTEINEMIA HAS AS ITS MAIN TARGETS DNA METHYLTRANSFERASES, AND THIS LEADS TO AN ALTERED EPIGENETIC CONTROL OF GENES REGULATED THROUGH METHYLATION. IN RENAL PATIENTS, THE EPIGENETIC LANDSCAPE IS STRICTLY CORRELATED WITH THE UREMIC PHENOTYPE AND DEPENDENT ON DIETARY INTAKE OF MICRONUTRIENTS, INFLAMMATION, GUT MICROBIOME, INFLAMMATORY STATUS, OXIDATIVE STRESS, AND LIFESTYLE HABITS. ALL THESE FACTORS ARE KEY CONTRIBUTORS IN METHYLOME MAINTENANCE AND IN THE MODULATION OF GENE TRANSCRIPTION THROUGH DNA HYPO- OR HYPERMETHYLATION IN CKD. THIS IS AN OVERVIEW OF THE EPIGENETIC CHANGES RELATED TO DNA METHYLATION IN PATIENTS WITH ADVANCED CKD AND ESRD. WE EXPLORED THE CURRENTLY AVAILABLE DATA ON THE MOLECULAR DYSREGULATIONS RESULTING FROM ALTERED GENE EXPRESSION IN UREMIA. SPECIAL ATTENTION WAS PAID TO THE EFFICACY OF B-VITAMINS SUPPLEMENTATION AND DIETARY INTAKE OF METHYL DONORS ON HOMOCYSTEINE LOWERING AND CARDIOVASCULAR PROTECTION. 2020 9 2539 25 EPIGENETICS IN HYPERHOMOCYSTEINEMIC STATES. A SPECIAL FOCUS ON UREMIA. AIM OF THIS ARTICLE IS TO REVIEW THE TOPIC OF EPIGENETIC CONTROL OF GENE EXPRESSION, ESPECIALLY REGARDING DNA METHYLATION, IN CHRONIC KIDNEY DISEASE AND UREMIA. HYPERHOMOCYSTEINEMIA IS CONSIDERED AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ALTHOUGH THE MOST RECENT INTERVENTION STUDIES UTILIZING FOLIC ACID ARE NEGATIVE. THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH IS ITSELF CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. THE EXTENT OF METHYLATION INHIBITION OF EACH INDIVIDUAL METHYLTRANSFERASE DEPENDS ON THE METHYL DONOR S-ADENOSYLMETHIONINE (ADOMET) AVAILABILITY, ON THE [ADOMET]/[ADOHCY] RATIO, AND ON THE INDIVIDUAL KM VALUE FOR ADOMET AND KI FOR ADOHCY. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, ALMOST UNEQUIVOCALLY SHOW. IN VIVO, DNA METHYLATION MAY BE ALSO INFLUENCED BY VARIOUS FACTORS IN DIFFERENT TISSUES, FOR EXAMPLE BY RATE OF CELL GROWTH, FOLATE STATUS, ETC. AND IMPORTANTLY INFLAMMATION. IN CHRONIC KIDNEY DISEASE AND IN UREMIA, HYPERHOMOCYSTEINEMIA IS COMMONLY SEEN, AND CAN BE ASSOCIATED WITH GLOBAL DNA HYPOMETHYLATION, AND WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION. THIS ALTERATION IS SUSCEPTIBLE OF REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. IF THIS ABNORMALITY WILL TRANSLATE ITSELF IN ALTERATIONS OF EXPRESSION OF GENES RELEVANT TO THE PATHOGENESIS OF THIS DISEASE STILL REMAINS TO BE ESTABLISHED. IN ADDITION, THESE RESULTS ESTABLISH A LINK BETWEEN THE EPIGENETIC CONTROL OF GENE EXPRESSION AND XENOBIOTIC INFLUENCES, SUCH AS FOLATE THERAPY. 2009 10 4683 36 NEW PERSPECTIVES ON FOLATE TRANSPORT IN RELATION TO ALCOHOLISM-INDUCED FOLATE MALABSORPTION--ASSOCIATION WITH EPIGENOME STABILITY AND CANCER DEVELOPMENT. FOLATES ARE MEMBERS OF THE B-CLASS OF VITAMINS, WHICH ARE REQUIRED FOR THE SYNTHESIS OF PURINES AND PYRIMIDINES, AND FOR THE METHYLATION OF ESSENTIAL BIOLOGICAL SUBSTANCES, INCLUDING PHOSPHOLIPIDS, DNA, AND NEUROTRANSMITTERS. FOLATES CANNOT BE SYNTHESIZED DE NOVO BY MAMMALS; HENCE, AN EFFICIENT INTESTINAL ABSORPTION PROCESS IS REQUIRED. INTESTINAL FOLATE TRANSPORT IS CARRIER-MEDIATED, PH-DEPENDENT AND ELECTRONEUTRAL, WITH SIMILAR AFFINITY FOR OXIDIZED AND REDUCED FOLIC ACID DERIVATIVES. THE VARIOUS TRANSPORTERS, I.E. REDUCED FOLATE CARRIER, PROTON-COUPLED FOLATE TRANSPORTER, FOLATE-BINDING PROTEIN, AND ORGANIC ANION TRANSPORTERS, ARE INVOLVED IN THE FOLATE TRANSPORT PROCESS IN VARIOUS TISSUES. ANY IMPAIRMENT IN UPTAKE OF FOLATE CAN LEAD TO A STATE OF FOLATE DEFICIENCY, THE MOST PREVALENT VITAMIN DEFICIENCY IN WORLD, AFFECTING 10% OF THE POPULATION IN THE USA. SUCH IMPAIRMENTS IN FOLATE TRANSPORT OCCUR IN A VARIETY OF CONDITIONS, INCLUDING CHRONIC USE OF ETHANOL, SOME INBORN HEREDITARY DISORDERS, AND CERTAIN DISEASES. AMONG THESE, ETHANOL INGESTION HAS BEEN THE MAJOR CONTRIBUTOR TO FOLATE DEFICIENCY. ETHANOL-ASSOCIATED FOLATE DEFICIENCY CAN DEVELOP BECAUSE OF DIETARY INADEQUACY, INTESTINAL MALABSORPTION, ALTERED HEPATOBILIARY METABOLISM, ENHANCED COLONIC METABOLISM, AND INCREASED RENAL EXCRETION. ETHANOL REDUCES THE INTESTINAL AND RENAL UPTAKE OF FOLATE BY ALTERING THE BINDING AND TRANSPORT KINETICS OF FOLATE TRANSPORT SYSTEMS. ALSO, ETHANOL REDUCES THE EXPRESSION OF FOLATE TRANSPORTERS IN BOTH INTESTINE AND KIDNEY, AND THIS MIGHT BE A CONTRIBUTING FACTOR FOR FOLATE MALABSORPTION, LEADING TO FOLATE DEFICIENCY. THE MAINTENANCE OF INTRACELLULAR FOLATE HOMEOSTASIS IS ESSENTIAL FOR THE ONE-CARBON TRANSFER REACTIONS NECESSARY FOR DNA SYNTHESIS AND BIOLOGICAL METHYLATION REACTIONS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC DETERMINANT IN GENE EXPRESSION, IN THE MAINTENANCE OF DNA INTEGRITY AND STABILITY, IN CHROMOSOMAL MODIFICATIONS, AND IN THE DEVELOPMENT OF MUTATIONS. ETHANOL, A TOXIN THAT IS CONSUMED REGULARLY, HAS BEEN FOUND TO AFFECT THE METHYLATION OF DNA. IN ADDITION TO ITS EFFECT ON DNA METHYLATION DUE TO FOLATE DEFICIENCY, ETHANOL COULD DIRECTLY EXERT ITS EFFECT THROUGH ITS INTERACTION WITH ONE-CARBON METABOLISM, IMPAIRMENT OF METHYL GROUP SYNTHESIS, AND AFFECTING THE ENZYMES REGULATING THE SYNTHESIS OF S-ADENOSYLMETHIONINE, THE PRIMARY METHYL GROUP DONOR FOR MOST BIOLOGICAL METHYLATION REACTIONS. THUS, ETHANOL PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL DISEASES THROUGH ITS POTENTIAL ABILITY TO MODULATE THE METHYLATION OF BIOLOGICAL MOLECULES. THIS REVIEW DISCUSSES THE UNDERLYING MECHANISM OF FOLATE MALABSORPTION IN ALCOHOLISM, THE MECHANISM OF METHYLATION-ASSOCIATED SILENCING OF GENES, AND HOW THE INTERACTION BETWEEN ETHANOL AND FOLATE DEFICIENCY AFFECTS THE METHYLATION OF GENES, THEREBY MODULATING EPIGENOME STABILITY AND THE RISK OF CANCER. 2009 11 5067 22 PHYSICAL ACTIVITY AND DNA METHYLATION IN HUMANS. PHYSICAL ACTIVITY IS A STRONG STIMULUS INFLUENCING THE OVERALL PHYSIOLOGY OF THE HUMAN BODY. EXERCISES LEAD TO BIOCHEMICAL CHANGES IN VARIOUS TISSUES AND EXERT AN IMPACT ON GENE EXPRESSION. EXERCISE-INDUCED CHANGES IN GENE EXPRESSION MAY BE MEDIATED BY EPIGENETIC MODIFICATIONS, WHICH REARRANGE THE CHROMATIN STRUCTURE AND THEREFORE MODULATE ITS ACCESSIBILITY FOR TRANSCRIPTION FACTORS. ONE OF SUCH EPIGENETIC MARK IS DNA METHYLATION THAT INVOLVES AN ATTACHMENT OF A METHYL GROUP TO THE FIFTH CARBON OF CYTOSINE RESIDUE PRESENT IN CG DINUCLEOTIDES (CPG). DNA METHYLATION IS CATALYZED BY A FAMILY OF DNA METHYLTRANSFERASES. THIS REVERSIBLE DNA MODIFICATION RESULTS IN THE RECRUITMENT OF PROTEINS CONTAINING METHYL BINDING DOMAIN AND FURTHER TRANSCRIPTIONAL CO-REPRESSORS LEADING TO THE SILENCING OF GENE EXPRESSION. THE ACCUMULATION OF CPG DINUCLEOTIDES, REFERRED AS CPG ISLANDS, OCCURS AT THE PROMOTER REGIONS IN A GREAT MAJORITY OF HUMAN GENES. THEREFORE, CHANGES IN DNA METHYLATION PROFILE AFFECT THE TRANSCRIPTION OF MULTIPLE GENES. A GROWING BODY OF EVIDENCE INDICATES THAT EXERCISE TRAINING MODULATES DNA METHYLATION IN MUSCLES AND ADIPOSE TISSUE. SOME OF THESE EPIGENETIC MARKERS WERE ASSOCIATED WITH A REDUCED RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE INFLUENCE OF PHYSICAL ACTIVITY ON THE DNA METHYLATION STATUS IN HUMANS. 2021 12 313 18 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 13 462 23 ARE ALTERATIONS IN DNA METHYLATION RELATED TO CKD DEVELOPMENT? THE MODIFICATIONS IN GENOMIC DNA METHYLATION ARE INVOLVED IN THE REGULATION OF NORMAL AND PATHOLOGICAL CELLULAR PROCESSES. THE EPIGENETIC REGULATION STIMULATES BIOLOGICAL PLASTICITY AS AN ADAPTIVE RESPONSE TO VARIATIONS IN ENVIRONMENTAL FACTORS. THE ROLE OF EPIGENETIC CHANGES IS VITAL FOR THE DEVELOPMENT OF SOME DISEASES, INCLUDING ATHEROGENESIS, CANCERS, AND CHRONIC KIDNEY DISEASE (CKD). THE RESULTS OF STUDIES PRESENTED IN THIS REVIEW HAVE SUGGESTED THAT ALTERED DNA METHYLATION CAN MODULATE THE EXPRESSION OF PRO-INFLAMMATORY AND PRO-FIBROTIC GENES, AS WELL THOSE ESSENTIAL FOR KIDNEY DEVELOPMENT AND FUNCTION, THUS STIMULATING RENAL DISEASE PROGRESSION. ABNORMALLY INCREASED HOMOCYSTEINE, HYPOXIA, AND INFLAMMATION HAVE BEEN SUGGESTED TO ALTER EPIGENETIC REGULATION OF GENE EXPRESSION IN CKD. STUDIES OF RENAL SAMPLES HAVE DEMONSTRATED THE RELATIONSHIP BETWEEN VARIATIONS IN DNA METHYLATION AND FIBROSIS AND VARIATIONS IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) IN HUMAN CKD. THE UNRAVELLING OF THE GENETIC-EPIGENETIC PROFILE WOULD ENHANCE OUR UNDERSTANDING OF PROCESSES UNDERLYING THE DEVELOPMENT OF CKD. THE UNDERSTANDING OF MULTIFACETED RELATIONSHIP BETWEEN DNA METHYLATION, GENES EXPRESSION, AND DISEASE DEVELOPMENT AND PROGRESSION COULD IMPROVE THE ABILITY TO IDENTIFY INDIVIDUALS AT RISK OF CKD AND ENABLE THE CHOICE OF APPROPRIATE DISEASE MANAGEMENT. 2022 14 2008 29 EPIGENETIC BASIS FOR MONOCYTE DYSFUNCTION IN PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS. BACKGROUND & AIMS: SEVERE FORMS OF ALCOHOL-RELATED LIVER DISEASE ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO INFECTIONS WHICH ARE ASSOCIATED WITH POOR PROGNOSIS. THE CELLULAR AND MOLECULAR MECHANISMS RESPONSIBLE FOR THIS ALTERED HOST DEFENSE ARE INCOMPLETELY UNDERSTOOD. METHODS: WE PERFORMED WHOLE BLOOD PHENOTYPIC ANALYSIS AND EX VIVO STIMULATION WITH VARIOUS PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS). WE INCLUDED 34 PATIENTS WITH ALCOHOL-RELATED CIRRHOSIS (18 OF WHOM HAD BIOPSY-PROVEN SEVERE ALCOHOLIC HEPATITIS [SAH]), 12 HEALTHY CONTROLS AND 11 PATIENTS WITH CHRONIC ALCOHOL CONSUMPTION WITHOUT SIGNIFICANT LIVER DISEASE. WE ALSO EVALUATED THE TRANSCRIPTOMIC (RNA-SEQ) AND CHROMATIN ACCESSIBILITY (ATAC-SEQ) PROFILES OF CD14(+) MONOCYTES FROM A SUBSET OF PATIENTS. RESULTS: CIRCULATING MONOCYTES AND CONVENTIONAL DENDRITIC CELLS (DCS) FROM PATIENTS WITH SAH DISPLAYED COMPLEX ALTERATIONS CHARACTERIZED BY INCREASED EXPRESSION OF BOTH ACTIVATING AND INHIBITORY SURFACE MARKERS AND AN IMPAIRED PRO-INFLAMMATORY RESPONSE UPON STIMULATION WITH PAMPS REPRESENTATIVE OF GRAM-NEGATIVE BACTERIA (LIPOPOLYSACCHARIDE, PAM3CSK4) OR FUNGAL PATHOGENS (ZYMOSAN). THEIR DECREASED ABILITY TO PRODUCE MORE THAN 1 CYTOKINE (POLYFUNCTIONALITY) UPON PAMP STIMULATION CORRELATED WITH THE RISK OF DEVELOPING INFECTION AT 28 DAYS OR MORTALITY AT 90 DAYS. THE PRESENCE OF ACUTE-ON-CHRONIC LIVER FAILURE IN PATIENTS WITH SAH DID NOT SIGNIFICANTLY MODIFY THE IMMUNE PROFILE OF MONOCYTES AND DCS. MOREOVER, CD14(+) MONOCYTES OF PATIENTS WITH SAH DISPLAYED ALTERED TRANSCRIPTIONAL AND EPIGENOMIC PROFILES CHARACTERIZED BY DOWNREGULATION OF KEY INNATE IMMUNE AND METABOLIC PATHWAYS AND UPREGULATION OF IMPORTANT IMMUNOMODULATORY FACTORS. CONCLUSIONS: IN PATIENTS WITH SAH, THE ALTERED TRANSCRIPTIONAL PROGRAM AND FUNCTIONAL PROPERTIES OF MONOCYTES THAT CONTRIBUTE TO PATIENTS' SUSCEPTIBILITY TO INFECTION HAVE STRONG EPIGENETIC DETERMINANTS. LAY SUMMARY: PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS ARE AT INCREASED RISK OF INFECTIONS, WHICH CONTRIBUTE TO THE POOR PROGNOSIS ASSOCIATED WITH THE DISEASE. HEREIN, WE SHOW THAT EPIGENETIC DETERMINANTS UNDERLY THE IMMUNE CELL DYSFUNCTION AND INAPPROPRIATE RESPONSES TO PATHOGENS THAT ARE ASSOCIATED WITH SEVERE ALCOHOLIC HEPATITIS. 2020 15 3438 29 HYPERHOMOCYSTEINEMIA IN UREMIA--A RED FLAG IN A DISRUPTED CIRCUIT. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ACCORDING TO MOST OBSERVATIONAL STUDIES AND TO STUDIES USING THE MENDELIAN RANDOMIZATION APPROACH, UTILIZING THE COMMON POLYMORPHISM C677T OF METHYLENE TETRAHYDROFOLATE REDUCTASE. IN CONTRAST, THE MOST RECENT SECONDARY PREVENTIVE INTERVENTION STUDIES, IN THE GENERAL POPULATION AND IN CHRONIC KIDNEY DISEASE (CKD) AND UREMIA, WHICH ARE ALL NEGATIVE (WITH THE POSSIBLE NOTABLE EXCEPTION OF STROKE), POINT TO OTHER DIRECTIONS. HOWEVER, ALL TRIALS USE FOLIC ACID IN VARIOUS DOSAGES AS A MEANS TO REDUCE HOMOCYSTEINE LEVELS, WITH THE ADDITION OF VITAMINS B6 AND B12. IT IS POSSIBLE THAT FOLIC ACID HAS NEGATIVE EFFECTS, WHICH OFFSET THE BENEFITS; ALTERNATIVELY, HOMOCYSTEINE COULD BE AN INNOCENT BY-STANDER, OR A SURROGATE OF THE REAL CULPRIT. THE LATTER POSSIBILITY LEADS US TO THE SEARCH FOR POTENTIAL CANDIDATES. FIRST, THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH BY ITSELF IS CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, SHOW. IN CKD AND IN UREMIA, HYPERHOMOCYSTEINEMIA AND HIGH INTRACELLULAR ADOHCY ARE PRESENT AND ARE ASSOCIATED WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION, SUCH AS IMPRINTED GENES, AND PSEUDOAUTOSOMAL GENES, THUS POINTING TO EPIGENETIC DYSREGULATION. THESE ALTERATIONS ARE SUSCEPTIBLE TO REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. SECOND, IT HAS TO BE KEPT IN MIND THAT HOMOCYSTEINE IS MAINLY PROTEIN-BOUND, AND ITS EFFECTS COULD BE LINKED THEREFORE TO PROTEIN HOMOCYSTEINYLATION. IN THIS RESPECT, INCREASED PROTEIN HOMOCYSTEINYLATION HAS BEEN FOUND IN UREMIA, LEADING TO ALTERATIONS IN PROTEIN FUNCTION. 2009 16 2104 27 EPIGENETIC EVENTS IN LIVER CANCER RESULTING FROM ALCOHOLIC LIVER DISEASE. EPIGENETIC MECHANISMS PLAY AN EXTENSIVE ROLE IN THE DEVELOPMENT OF LIVER CANCER (I.E., HEPATOCELLULAR CARCINOMA [HCC]) ASSOCIATED WITH ALCOHOLIC LIVER DISEASE (ALD) AS WELL AS IN LIVER DISEASE ASSOCIATED WITH OTHER CONDITIONS. FOR EXAMPLE, EPIGENETIC MECHANISMS, SUCH AS CHANGES IN THE METHYLATION AND/OR ACETYLATION PATTERN OF CERTAIN DNA REGIONS OR OF THE HISTONE PROTEINS AROUND WHICH THE DNA IS WRAPPED, CONTRIBUTE TO THE REVERSION OF NORMAL LIVER CELLS INTO PROGENITOR AND STEM CELLS THAT CAN DEVELOP INTO HCC. CHRONIC EXPOSURE TO BEVERAGE ALCOHOL (I.E., ETHANOL) CAN INDUCE ALL OF THESE EPIGENETIC CHANGES. THUS, ETHANOL METABOLISM RESULTS IN THE FORMATION OF COMPOUNDS THAT CAN CAUSE CHANGES IN DNA METHYLATION AND INTERFERE WITH OTHER COMPONENTS OF THE NORMAL PROCESSES REGULATING DNA METHYLATION. ALCOHOL EXPOSURE ALSO CAN ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION PATTERNS THROUGH A VARIETY OF MECHANISMS AND SIGNALING PATHWAYS. ALCOHOL ALSO ACTS INDIRECTLY ON ANOTHER MOLECULE CALLED TOLL-LIKE RECEPTOR 4 (TLR4) THAT IS A KEY COMPONENT IN A CRUCIAL REGULATORY PATHWAY IN THE CELLS AND WHOSE DYSREGULATION IS INVOLVED IN THE DEVELOPMENT OF HCC. FINALLY, ALCOHOL USE REGULATES AN EPIGENETIC MECHANISM INVOLVING SMALL MOLECULES CALLED MIRNAS THAT CONTROL TRANSCRIPTIONAL EVENTS AND THE EXPRESSION OF GENES IMPORTANT TO ALD. 2013 17 1269 27 CYTOSINE METHYLATION CHANGES IN ENHANCER REGIONS OF CORE PRO-FIBROTIC GENES CHARACTERIZE KIDNEY FIBROSIS DEVELOPMENT. BACKGROUND: ONE IN ELEVEN PEOPLE IS AFFECTED BY CHRONIC KIDNEY DISEASE, A CONDITION CHARACTERIZED BY KIDNEY FIBROSIS AND PROGRESSIVE LOSS OF KIDNEY FUNCTION. EPIDEMIOLOGICAL STUDIES INDICATE THAT ADVERSE INTRAUTERINE AND POSTNATAL ENVIRONMENTS HAVE A LONG-LASTING ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT. EPIGENETIC INFORMATION REPRESENTS A PLAUSIBLE CARRIER FOR MEDIATING THIS PROGRAMMING EFFECT. HERE WE DEMONSTRATE THAT GENOME-WIDE CYTOSINE METHYLATION PATTERNS OF HEALTHY AND CHRONIC KIDNEY DISEASE TUBULE SAMPLES OBTAINED FROM PATIENTS SHOW SIGNIFICANT DIFFERENCES. RESULTS: WE IDENTIFY DIFFERENTIALLY METHYLATED REGIONS AND VALIDATE THESE IN A LARGE REPLICATION DATASET. THE DIFFERENTIALLY METHYLATED REGIONS ARE RARELY OBSERVED ON PROMOTERS, BUT MOSTLY OVERLAP WITH PUTATIVE ENHANCER REGIONS, AND THEY ARE ENRICHED IN CONSENSUS BINDING SEQUENCES FOR IMPORTANT RENAL TRANSCRIPTION FACTORS. THIS INDICATES THEIR IMPORTANCE IN GENE EXPRESSION REGULATION. A CORE SET OF GENES THAT ARE KNOWN TO BE RELATED TO KIDNEY FIBROSIS, INCLUDING GENES ENCODING COLLAGENS, SHOW CYTOSINE METHYLATION CHANGES CORRELATING WITH DOWNSTREAM TRANSCRIPT LEVELS. CONCLUSIONS: OUR REPORT RAISES THE POSSIBILITY THAT EPIGENETIC DYSREGULATION PLAYS A ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT VIA INFLUENCING CORE PRO-FIBROTIC PATHWAYS AND CAN AID THE DEVELOPMENT OF NOVEL BIOMARKERS AND FUTURE THERAPEUTICS. 2013 18 3292 31 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS. 2017 19 2483 25 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 20 2873 25 FUNCTIONAL METHYLOME ANALYSIS OF HUMAN DIABETIC KIDNEY DISEASE. IN PATIENTS WITH DIABETES MELLITUS, POOR METABOLIC CONTROL HAS A LONG-LASTING IMPACT ON KIDNEY DISEASE DEVELOPMENT. EPIGENETIC CHANGES, INCLUDING CYTOSINE METHYLATION, HAVE BEEN PROPOSED AS POTENTIAL MEDIATORS OF THE LONG-LASTING EFFECT OF ADVERSE METABOLIC EVENTS. OUR UNDERSTANDING OF THE PRESENCE AND CONTRIBUTION OF METHYLATION CHANGES TO DISEASE DEVELOPMENT IS LIMITED BECAUSE OF THE LACK OF COMPREHENSIVE BASE-RESOLUTION METHYLOME INFORMATION OF HUMAN KIDNEY TISSUE SAMPLES AND SITE-SPECIFIC METHYLATION EDITING. BASE RESOLUTION, WHOLE-GENOME BISULFITE SEQUENCING METHYLOME MAPS OF HUMAN DIABETIC KIDNEY DISEASE (DKD) TUBULE SAMPLES, AND ASSOCIATED GENE EXPRESSION MEASURED BY RNA SEQUENCING HIGHLIGHTED WIDESPREAD METHYLATION CHANGES IN DKD. PATHWAY ANALYSIS HIGHLIGHTED COORDINATED (METHYLATION AND GENE EXPRESSION) CHANGES IN IMMUNE SIGNALING, INCLUDING TUMOR NECROSIS FACTOR ALPHA (TNF). CHANGES IN TNF METHYLATION CORRELATED WITH KIDNEY FUNCTION DECLINE. DCAS9-TET1-BASED LOWERING OF THE CYTOSINE METHYLATION LEVEL OF THE TNF DIFFERENTIALLY METHYLATED REGION RESULTED IN AN INCREASE IN THE TNF TRANSCRIPT LEVEL, INDICATING THAT METHYLATION OF THIS LOCUS PLAYS AN IMPORTANT ROLE IN CONTROLLING TNF EXPRESSION. INCREASING THE TNF LEVEL IN DIABETIC MICE INCREASED DISEASE SEVERITY, SUCH AS ALBUMINURIA. IN SUMMARY, OUR RESULTS INDICATE WIDESPREAD METHYLATION DIFFERENCES IN DKD KIDNEYS AND HIGHLIGHTS EPIGENETIC CHANGES IN THE TNF LOCUS AND ITS CONTRIBUTION TO THE DEVELOPMENT OF NEPHROPATHY IN PATIENTS WITH DIABETES MELLITUS. 2019