1 1855 96 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 2 5587 50 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 6220 31 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 4 6717 30 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 5 339 33 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 6 4683 38 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 7 2833 23 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 6726 32 VITAMIN-DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. EMERGING EVIDENCE INDICATES THAT ETHANOL-INDUCED ALTERATIONS IN HEPATIC METHIONINE METABOLISM PLAY A CENTRAL ROLE IN THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). BECAUSE MALNUTRITION IS A UNIVERSAL CLINICAL FINDING IN THIS DISEASE AND HEPATIC METHIONINE METABOLISM IS DEPENDENT UPON DIETARY FOLATE AND VITAMINS B-6 AND B-12, ALD CAN BE CONSIDERED AN INDUCED NUTRITIONAL DISORDER THAT IS CONDITIONED BY ALCOHOL ABUSE. THE PRESENT REVIEW DESCRIBES THE ETIOLOGIES OF THESE 3 VITAMIN DEFICIENCIES IN ALD AND HOW THEY INTERACT WITH CHRONIC ETHANOL EXPOSURE TO ALTER HEPATIC METHIONINE METABOLISM. SUBSEQUENT SECTIONS FOCUS ON MOLECULAR MECHANISMS FOR THE INTERACTIONS OF ABERRANT METHIONINE METABOLISM WITH ETHANOL IN THE PATHOGENESIS OF ALD, IN PARTICULAR THE ROLE OF S-ADENOSYLMETHIONINE (SAM) IN REGULATING THE EPIGENETIC EXPRESSIONS OF GENES RELEVANT TO PATHWAYS OF LIVER INJURY. THE REVIEW WILL CONCLUDE WITH DESCRIPTIONS OF STUDIES ON THE EFFICACY OF SAM IN THE TREATMENT OF ALD AND WITH DISCUSSION OF POTENTIALLY FRUITFUL FUTURE AVENUES OF RESEARCH. 2011 9 315 35 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 10 318 40 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 11 2539 35 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 12 558 34 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM. 2013 13 3438 33 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 14 4217 29 METHYL DONOR NUTRIENTS IN CHRONIC KIDNEY DISEASE: IMPACT ON THE EPIGENETIC LANDSCAPE. EPIGENETIC ALTERATIONS, SUCH AS THOSE LINKED TO DNA METHYLATION, MAY POTENTIALLY PROVIDE MOLECULAR EXPLANATIONS FOR COMPLICATIONS ASSOCIATED WITH ALTERED GENE EXPRESSION IN ILLNESSES, SUCH AS CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH BOTH DNA HYPO- AND HYPERMETHYLATION HAVE BEEN OBSERVED IN THE UREMIC MILIEU, THIS REMAINS ONLY A SINGLE ASPECT OF THE EPIGENETIC LANDSCAPE AND, THUS, OF ANY BIOCHEMICAL DYSREGULATION ASSOCIATED WITH CKD. NEVERTHELESS, THE ROLE OF UREMIA-PROMOTING ALTERATIONS ON THE EPIGENETIC LANDSCAPE REGULATING GENE EXPRESSION IS STILL A NOVEL AND SCARCELY STUDIED FIELD. ALTHOUGH FEW STUDIES HAVE ACTUALLY REPORTED ALTERATIONS OF DNA METHYLATION VIA METHYL DONOR NUTRIENT INTAKE, EMERGING EVIDENCE INDICATES THAT NUTRITIONAL MODIFICATION OF THE MICROBIOME CAN AFFECT ONE-CARBON METABOLISM AND THE CAPACITY TO METHYLATE THE GENOME IN CKD. IN THIS REVIEW, WE DISCUSS THE NUTRITIONAL MODIFICATIONS THAT MAY AFFECT ONE-CARBON METABOLISM AND THE POSSIBLE IMPACT OF METHYL DONOR NUTRIENTS ON THE MICROBIOME, CKD, AND ITS PHENOTYPE. 2019 15 2158 32 EPIGENETIC MECHANISMS FOR NUTRITION DETERMINANTS OF LATER HEALTH OUTCOMES. EPIGENETIC MARKING ON GENES CAN DETERMINE WHETHER OR NOT GENES ARE EXPRESSED. EPIGENETIC REGULATION IS MEDIATED BY THE ADDITION OF METHYL GROUPS TO DNA CYTOSINE BASES, OF METHYL AND ACETYL GROUPS TO PROTEINS (HISTONES) AROUND WHICH DNA IS WRAPPED, AND BY SMALL INTERFERING RNA MOLECULES. SOME COMPONENTS OF EPIGENETIC REGULATION HAVE EVOLVED TO PERMIT CONTROL OF WHETHER MATERNAL OR PATERNAL GENES ARE EXPRESSED. THE EPIGENETIC IMPRINTING OF IGF2 EXPRESSION IS AN EXAMPLE OF MATERNAL AND PATERNAL EPIGENETIC MARKING THAT MODULATES FETAL GROWTH AND FETAL SIZE. HOWEVER, EPIGENETIC REGULATION ALSO PERMITS THE FETUS AND THE INFANT TO ADAPT GENE EXPRESSION TO THE ENVIRONMENT IN WHICH IT IS GROWING; SOMETIMES WHEN THIS ADJUSTMENT GOES AWRY, THE RISK OF CHRONIC DISEASE IS INCREASED. RECENT PROGRESS IN THE UNDERSTANDING OF NUTRITIONAL INFLUENCES ON EPIGENETICS SUGGESTS THAT NUTRIENTS THAT ARE PART OF METHYL-GROUP METABOLISM CAN SIGNIFICANTLY INFLUENCE EPIGENETICS. DURING CRITICAL PERIODS IN DEVELOPMENT, DIETARY METHYL-GROUP INTAKE (CHOLINE, METHIONINE, AND FOLATE) CAN ALTER DNA AND HISTONE METHYLATION, WHICH RESULTS IN LIFELONG CHANGES IN GENE EXPRESSION. IN RODENT MODELS, PREGNANT DAMS THAT WERE FED DIETS HIGH IN METHIONINE, FOLIC ACID, AND CHOLINE PRODUCED OFFSPRING WITH DIFFERENT COAT COLORS OR WITH KINKED TAILS. A NUMBER OF SYNDROMES IN HUMANS CAN BE CAUSED BY DEFECTIVE EPIGENETIC REGULATION, INCLUDING RETT SYNDROME. THERE ARE INTERESTING EXAMPLES OF THE EFFECTS OF NUTRITION IN EARLY LIFE THAT RESULT IN ALTERED HEALTH IN ADULTS, AND SOME OF THESE COULD BE THE RESULT OF ALTERED EPIGENETIC REGULATION OF GENE EXPRESSION. 2009 16 165 26 ABNORMAL HOMOCYSTEINE METABOLISM: AN INSIGHT OF ALZHEIMER'S DISEASE FROM DNA METHYLATION. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE IN THE CENTRAL NERVOUS SYSTEM THAT HAS COMPLEX PATHOGENESIS IN THE ELDERLY. THE CURRENT REVIEW FOCUSES ON THE EPIGENETIC MECHANISMS OF AD, ACCORDING TO THE LATEST FINDINGS. ONE OF THE BEST-CHARACTERIZED CHROMATIN MODIFICATIONS IN EPIGENETIC MECHANISMS IS DNA METHYLATION. HIGHLY REPLICABLE DATA SHOWS THAT AD OCCURRENCE IS OFTEN ACCOMPANIED BY METHYLATION LEVEL CHANGES OF THE AD-RELATED GENE. HOMOCYSTEINE (HCY) IS NOT ONLY AN INTERMEDIATE PRODUCT OF ONE-CARBON METABOLISM BUT ALSO AN IMPORTANT INDEPENDENT RISK FACTOR OF AD; IT CAN AFFECT THE COGNITIVE FUNCTION OF THE BRAIN BY CHANGING THE ONE-CARBON METABOLISM AND INTERFERING WITH THE DNA METHYLATION PROCESS, RESULTING IN CEREBROVASCULAR DISEASE. IN GENERAL, HCY MAY BE AN ENVIRONMENTAL FACTOR THAT AFFECTS AD VIA THE DNA METHYLATION PATHWAY WITH A SERIES OF CHANGES IN AD-RELATED SUBSTANCE. THIS REVIEW WILL CONCENTRATE ON THE RELATION BETWEEN DNA METHYLATION AND HCY AND TRY TO FIGURE OUT THEIR RULE IN THE PATHOPHYSIOLOGY OF AD. 2020 17 313 28 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 18 4216 31 METHYL DONOR MICRONUTRIENTS: A POTENTIAL DIETARY EPIGENETIC TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY AN ABERRANT IMMUNE RESPONSE AND PERSISTENT INFLAMMATION. ITS PATHOGENESIS REMAINS UNKNOWN; HOWEVER, A COMPLEX INTERACTION BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN SUGGESTED TO CAUSE DISEASE ONSET. SEVERAL STUDIES HAVE DEMONSTRATED THAT EPIGENETIC ALTERATIONS, SUCH AS DNA HYPOMETHYLATION, MIRNA OVEREXPRESSION, AND ALTERED HISTONE ACETYLATION, MAY CONTRIBUTE TO SLE ONSET AND THE DISEASE'S CLINICAL MANIFESTATIONS. EPIGENETIC CHANGES, ESPECIALLY METHYLATION PATTERNS, ARE MODIFIABLE AND SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS DIET. IT IS WELL KNOWN THAT METHYL DONOR NUTRIENTS, SUCH AS FOLATE, METHIONINE, CHOLINE, AND SOME B VITAMINS, PLAY A RELEVANT ROLE IN DNA METHYLATION BY PARTICIPATING AS METHYL DONORS OR COENZYMES IN ONE-CARBON METABOLISM. BASED ON THIS KNOWLEDGE, THIS CRITICAL LITERATURE REVIEW AIMED TO INTEGRATE THE EVIDENCE IN ANIMAL MODELS AND HUMANS REGARDING THE ROLE OF NUTRIENTS IN EPIGENETIC HOMEOSTASIS AND THEIR IMPACT ON IMMUNE SYSTEM REGULATION TO SUGGEST A POTENTIAL EPIGENETIC DIET THAT COULD SERVE AS ADJUVANT THERAPY IN SLE. 2023 19 4788 30 NUTRITION, EPIGENETICS, AND METABOLIC SYNDROME. SIGNIFICANCE: EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE DEMONSTRATED A CLOSE LINK BETWEEN MATERNAL NUTRITION AND CHRONIC METABOLIC DISEASE IN CHILDREN AND ADULTS. COMPELLING EXPERIMENTAL RESULTS ALSO INDICATE THAT ADVERSE EFFECTS OF INTRAUTERINE GROWTH RESTRICTION ON OFFSPRING CAN BE CARRIED FORWARD TO SUBSEQUENT GENERATIONS THROUGH COVALENT MODIFICATIONS OF DNA AND CORE HISTONES. RECENT ADVANCES: DNA METHYLATION IS CATALYZED BY S-ADENOSYLMETHIONINE-DEPENDENT DNA METHYLTRANSFERASES. METHYLATION, DEMETHYLATION, ACETYLATION, AND DEACETYLATION OF HISTONE PROTEINS ARE PERFORMED BY HISTONE METHYLTRANSFERASE, HISTONE DEMETHYLASE, HISTONE ACETYLTRANSFERASE, AND HISTONE DEACETYLTRANSFERASE, RESPECTIVELY. HISTONE ACTIVITIES ARE ALSO INFLUENCED BY PHOSPHORYLATION, UBIQUITINATION, ADP-RIBOSYLATION, SUMOYLATION, AND GLYCOSYLATION. METABOLISM OF AMINO ACIDS (GLYCINE, HISTIDINE, METHIONINE, AND SERINE) AND VITAMINS (B6, B12, AND FOLATE) PLAYS A KEY ROLE IN PROVISION OF METHYL DONORS FOR DNA AND PROTEIN METHYLATION. CRITICAL ISSUES: DISRUPTION OF EPIGENETIC MECHANISMS CAN RESULT IN OXIDATIVE STRESS, OBESITY, INSULIN RESISTANCE, DIABETES, AND VASCULAR DYSFUNCTION IN ANIMALS AND HUMANS. DESPITE A RECOGNIZED ROLE FOR EPIGENETICS IN FETAL PROGRAMMING OF METABOLIC SYNDROME, RESEARCH ON THERAPIES IS STILL IN ITS INFANCY. POSSIBLE INTERVENTIONS INCLUDE: 1) INHIBITION OF DNA METHYLATION, HISTONE DEACETYLATION, AND MICRORNA EXPRESSION; 2) TARGETING EPIGENETICALLY DISTURBED METABOLIC PATHWAYS; AND 3) DIETARY SUPPLEMENTATION WITH FUNCTIONAL AMINO ACIDS, VITAMINS, AND PHYTOCHEMICALS. FUTURE DIRECTIONS: MUCH WORK IS NEEDED WITH ANIMAL MODELS TO UNDERSTAND THE BASIC MECHANISMS RESPONSIBLE FOR THE ROLES OF SPECIFIC NUTRIENTS IN FETAL AND NEONATAL PROGRAMMING. SUCH NEW KNOWLEDGE IS CRUCIAL TO DESIGN EFFECTIVE THERAPEUTIC STRATEGIES FOR PREVENTING AND TREATING METABOLIC ABNORMALITIES IN OFFSPRING BORN TO MOTHERS WITH A PREVIOUS EXPERIENCE OF MALNUTRITION. 2012 20 4406 18 MOLECULAR ALTERATIONS IN HEPATOCARCINOGENESIS INDUCED BY DIETARY METHYL DEFICIENCY. A CHRONIC DEFICIENCY OF MAJOR DIETARY METHYL GROUP DONORS--METHIONINE, CHOLINE, FOLIC ACID, AND VITAMIN B12--CAN INDUCE THE DEVELOPMENT OF LIVER CANCER IN RODENTS. FEEDING METHYL-DEFICIENT DIETS CAUSES SEVERAL MOLECULAR ALTERATIONS, INCLUDING ALTERED LIPID METABOLISM, OXIDATIVE STRESS, DEREGULATED ONE-CARBON METABOLISM, AND A NUMBER OF EPIGENETIC ABNORMALITIES THAT RESULT IN PROGRESSIVE LIVER INJURY CULMINATING IN THE DEVELOPMENT OF PRIMARY LIVER TUMORS. IMPORTANTLY, THIS METHYL-DEFICIENT MODEL OF ENDOGENOUS HEPATOCARCINOGENESIS IS ONE OF THE MOST RELEVANT MODELS OF HUMAN LIVER CARCINOGENESIS THAT ALLOWS STUDYING LIVER CANCER PATHOGENESIS BY SUBSTANTIALLY COMPLEMENTING MANY SHORTCOMINGS OF HUMANS-ONLY STUDIES. IN THIS REVIEW, WE DESCRIBE MOLECULAR CHANGES AND THEIR ROLE IN PATHOGENESIS OF LIVER CARCINOGENESIS INDUCED BY METHYL DEFICIENCY. 2012