1 2539 141 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 2 3438 82 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 3 6717 43 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 4 315 42 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 5 2833 25 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 6 1912 41 ENVIRONMENT, DIET AND CPG ISLAND METHYLATION: EPIGENETIC SIGNALS IN GASTROINTESTINAL NEOPLASIA. THE EPITHELIAL SURFACES OF THE MAMMALIAN ALIMENTARY TRACT ARE CHARACTERISED BY VERY HIGH RATES OF CELL PROLIFERATION AND DNA SYNTHESIS, AND IN HUMANS THEY ARE HIGHLY SUSCEPTIBLE TO CANCER. THE ROLE OF SOMATIC MUTATIONS AS DRIVERS OF CARCINOGENESIS IN THE ALIMENTARY TRACT IS WELL ESTABLISHED, BUT THE IMPORTANCE OF GENE SILENCING BY EPIGENETIC MECHANISMS IS INCREASINGLY RECOGNISED. METHYLATION OF CPG ISLANDS IS AN IMPORTANT COMPONENT OF THE EPIGENETIC CODE THAT REGULATES GENE EXPRESSION DURING DEVELOPMENT AND NORMAL CELLULAR DIFFERENTIATION, AND A NUMBER OF GENES ARE WELL KNOWN TO BECOME ABNORMALLY METHYLATED DURING THE DEVELOPMENT OF TUMOURS OF THE OESOPHAGUS, STOMACH AND COLORECTUM. ABERRANT PATTERNS OF DNA METHYLATION DEVELOP AS A RESULT OF PATHOLOGICAL PROCESSES SUCH AS CHRONIC INFLAMMATION, AND IN RESPONSE TO VARIOUS DIETARY FACTORS, INCLUDING IMBALANCES IN THE SUPPLY OF METHYL DONORS, PARTICULARLY FOLATES, AND EXPOSURE TO DNA METHYLTRANSFERASE INHIBITORS, WHICH INCLUDE POLYPHENOLS AND POSSIBLY ISOTHIOCYANATES FROM PLANT FOODS. HOWEVER THE IMPORTANCE OF THESE ENVIRONMENTAL INTERACTIONS IN HUMAN HEALTH AND DISEASE REMAINS TO BE ESTABLISHED. RECENT MOVES TO MODIFY THE EXPOSURE OF HUMAN POPULATIONS TO FOLATE, BY MANDATORY SUPPLEMENTATION OF CEREAL FOODS, EMPHASISE THE IMPORTANCE OF UNDERSTANDING THE SUSCEPTIBILITY OF THE HUMAN EPIGENOME TO DIETARY AND OTHER ENVIRONMENTAL EFFECTS. 2008 7 4217 33 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 8 5618 32 SARS-COV-2 INTERACTION WITH HUMAN DNA METHYL TRANSFERASE 1: A POTENTIAL RISK FOR INCREASING THE INCIDENCE OF LATER CHRONIC DISEASES IN THE SURVIVED PATIENTS. CURRENTLY, THE COVID-19 PANDEMIC IS THE MOST DISCUSSED SUBJECT IN MEDICAL RESEARCHES WORLDWIDE. AS THE KNOWLEDGE IS EXPANDED ABOUT THE DISEASE, MORE HYPOTHESES BECOME CREATED. A RECENT STUDY ON THE VIRAL PROTEIN INTERACTION MAP REVEALED THAT SARS-COV-2 OPEN READING FRAME 8 (ORF8) INTERACTS WITH HUMAN DNA METHYL TRANSFERASE1 (DNMT1), AN ACTIVE EPIGENETIC AGENT IN DNA METHYLATION. MOREOVER, DNMT1 IS A CONTRIBUTOR TO A VARIETY OF CHRONIC DISEASES WHICH COULD CAUSE SOME EPIGENETIC DYSREGULATION IN INFECTED CELLS, ESPECIALLY LEUKOCYTES, PANCREATIC BETA, AND ENDOTHELIAL CELLS. REGARDING THE FACT THAT EPIGENETIC ALTERATIONS HAVE A PARTIAL, BUT NOT COMPLETELY REVERSIBLE PHENOMENA, IT RAISES THE QUESTION THAT IF THIS INTERACTION MAY CAUSE LONG-TERM COMPLICATIONS SUCH AS DIABETES, ATHEROSCLEROSIS, CANCER, AND AUTOIMMUNE DISEASES. ACCORDINGLY, LONG FOLLOW-UP STUDIES ON THE RECOVERED PATIENTS FROM COVID-19 ARE RECOMMENDED. 2022 9 462 35 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 10 318 47 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 6199 42 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 12 2524 41 EPIGENETICS AND THE UREMIC PHENOTYPE: A MATTER OF BALANCE. EPIGENETICS, WHICH IS THE STUDY OF CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN DNA SEQUENCE, IS A NOVEL DISCIPLINE THAT HAS LANGUISHED IN THE SHADOW OF ITS GENOMIC BIG BROTHER. SO FAR, STUDIES OF THE EPIGENOME HAVE ATTRACTED LITTLE INTEREST IN NEPHROLOGY. CHRONIC KIDNEY DISEASE IS AN EXAMPLE OF COMPLEX DISEASE IN WHICH THE PHENOTYPE ARISES FROM A COMBINATION OF ENVIRONMENTAL AND HERITABLE FACTORS. EVIDENCE SUGGESTS THAT THE CONTRIBUTION MADE BY THE ENVIRONMENT MAY BE MEDIATED VIA MODIFICATIONS OF THE EPIGENOME. IN THE UREMIC MILIEU, SEVERAL FEATURES SUCH AS INFLAMMATION, DYSLIPIDEMIA, HYPERHOMOCYSTEINEMA, OXIDATIVE STRESS AS WELL AS VITAMIN AND NUTRITIONAL DEFICIENCIES MAY AFFECT ABERRANT GLOBAL DNA METHYLATION. HOWEVER, AS HYPERHOMOCYSTEINEMIA SEEMS TO PROMOTE GLOBAL DNA HYPOMETHYLATION AND PERSISTENT INFLAMMATION DNA HYPERMETHYLATION, THE EFFECTS OF THE UREMIC MILIEU ON ABERRANT GLOBAL DNA METHYLATION MAY BE COMPLEX AND CONTEXT-SENSITIVE. IT SHOULD BE EMPHASIZED THAT IN ANALOGY TO THE UNSPECIFIC NATURE OF FEVER, ABERRANT GLOBAL DNA METHYLATION IS ONLY A SIGN OF A GENERALIZED EPIGENETIC DYSREGULATION. THUS, TO PROVIDE BETTER UNDERSTANDING OF THE EFFECTS OF ABERRANT DNA METHYLATION ON THE UREMIC PHENOTYPE, FURTHER STUDIES EVALUATING SITE-SPECIFIC INFORMATION ON METHYLATION IN VARIOUS CANDIDATE GENES ARE NEEDED. THE SCIENCE OF EPIGENETICS MAY NOT ONLY UNCOVER ETIOLOGIC AND PATHOGENIC MECHANISMS IN UREMIA, BUT MAY ALSO BE OF HELP TO DEVELOP NOVEL TREATMENT STRATEGIES TARGETING THE UNACCEPTABLE HIGH DEATH RISK IN CARDIOVASCULAR COMPLICATIONS IN THIS PATIENT POPULATION. 2008 13 6013 46 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 14 1515 32 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 15 1604 28 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 16 5067 39 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 17 6720 35 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 18 2507 30 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 19 2483 35 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 1844 35 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016