1 906 126 CHRONIC EXPOSURE TO ENVIRONMENTAL LEVEL PHENANTHRENE INDUCES NON-OBESITY-DEPENDENT INSULIN RESISTANCE IN MALE MICE. EPIDEMIOLOGICAL EVIDENCE SHOWS THAT THE BODY BURDEN OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) IS RELATED TO THE DISRUPTION OF GLUCOSE HOMEOSTASIS. HOWEVER, THE CONTRIBUTION OF PAHS TO THE DEVELOPMENT OF DIABETES REMAINS POORLY DOCUMENTED. IN THE CURRENT WORK, MALE KUNMING MICE RECEIVED PHENANTHRENE (PHE) (5, 50, AND 500 NG/KG) BY GAVAGE ADMINISTRATION ONCE EVERY 2 DAYS FOR 28 WEEKS. THE SIGNIFICANT ELEVATION OF HOMEOSTASIS MODEL ASSESSMENT-INSULIN RESISTANCE (HOMA-IR) AND HOMA-BETA CELL, ACCOMPANIED BY HYPERINSULINEMIA, INDICATED THE OCCURRENCE OF INSULIN RESISTANCE. THE SUPPRESSION OF THE INSULIN RECEPTOR SIGNALING PATHWAY IN SKELETAL MUSCLE MIGHT BE RESPONSIBLE FOR GLUCOSE INTOLERANCE. UNDER THE NONOBESE STATE, THE SERUM LEVELS OF RESISTIN, TUMOR NECROSIS FACTOR-ALPHA, AND INTERLEUKIN-6 WERE ELEVATED, WHEREAS THE LEVELS OF ADIPONECTIN WERE REDUCED. THESE CHANGES IN ADIPOCYTOKINE LEVELS WERE CONSISTENT WITH THEIR TRANSCRIPTION IN WHITE ADIPOSE TISSUE. THE PROMOTER METHYLATION LEVELS OF RETN (ENCODING RESISTIN) AND ADIPOQ (ENCODING ADIPONECTIN) WERE INVERSELY CORRELATED WITH THEIR MRNA LEVELS, INDICATING THAT PHE EXPOSURE COULD CAUSE THE DISRUPTION OF ADIPOCYTOKINE SECRETION VIA EPIGENETIC MODIFICATION. THE RESULTS WOULD BE HELPFUL FOR UNDERSTANDING THE PATHOGENESIS IN THE DEVELOPMENT OF T2DM CAUSED BY NONOBESOGENIC POLLUTANTS. 2020 2 1567 28 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 3 3836 34 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE. 2016 4 6564 28 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS. 2021 5 6794 27 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS. 2020 6 5189 24 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE. 2022 7 2297 23 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 8 2926 23 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 9 5878 24 SYNERGISTIC EFFECTS OF HYPERANDROGENEMIA AND OBESOGENIC WESTERN-STYLE DIET ON TRANSCRIPTION AND DNA METHYLATION IN VISCERAL ADIPOSE TISSUE OF NONHUMAN PRIMATES. POLYCYSTIC OVARY SYNDROME (PCOS) IS A MAJOR REPRODUCTIVE DISORDER THAT IS RESPONSIBLE FOR 80% OF ANOVULATORY INFERTILITY AND THAT IS ASSOCIATED WITH HYPERANDROGENEMIA, INCREASED RISK OF OBESITY, AND WHITE ADIPOSE TISSUE (WAT) DYSFUNCTION. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMBINATION OF CHRONIC TESTOSTERONE (T) TREATMENT AND AN OBESOGENIC WESTERN-STYLE DIET (WSD) EXERTS SYNERGISTIC FUNCTIONAL EFFECTS ON WAT, LEADING TO INCREASED LIPID ACCUMULATION IN VISCERAL ADIPOCYTES BY AN UNKNOWN MECHANISM. IN THIS STUDY, WE EXAMINED THE WHOLE-GENOME TRANSCRIPTIONAL RESPONSE IN VISCERAL WAT TO T AND WSD, ALONE AND IN COMBINATION. WE OBSERVED A SYNERGISTIC EFFECT OF T AND WSD ON GENE EXPRESSION, RESULTING IN UPREGULATION OF LIPID STORAGE GENES CONCOMITANT WITH ADIPOCYTE HYPERTROPHY. BECAUSE DNA METHYLATION IS KNOWN TO BE ASSOCIATED WITH BODY FAT DISTRIBUTION AND THE ETIOLOGY OF PCOS, WE CONDUCTED WHOLE-GENOME DNA METHYLATION ANALYSIS OF VISCERAL WAT. WHILE ONLY A FRACTION OF DIFFERENTIALLY EXPRESSED GENES ALSO EXHIBITED DIFFERENTIAL DNA METHYLATION, IN SILICO ANALYSIS SHOWED THAT DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN TRANSCRIPTION FACTOR BINDING MOTIFS, SUGGESTING A POTENTIAL GENE REGULATORY ROLE FOR THESE REGIONS. IN SUMMARY, THIS STUDY DEMONSTRATES THAT HYPERANDROGENEMIA ALONE DOES NOT INDUCE GLOBAL TRANSCRIPTIONAL AND EPIGENETIC RESPONSE IN YOUNG FEMALE MACAQUES UNLESS COMBINED WITH AN OBESOGENIC DIET. 2019 10 5305 30 PROTEOMICS ANALYSIS OF HUMAN OBESITY REVEALS THE EPIGENETIC FACTOR HDAC4 AS A POTENTIAL TARGET FOR OBESITY. SEDENTARY LIFESTYLE AND EXCESSIVE ENERGY INTAKE ARE PROMINENT CONTRIBUTORS TO OBESITY; A MAJOR RISK FACTORS FOR THE DEVELOPMENT OF INSULIN RESISTANCE, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. ELUCIDATING THE MOLECULAR MECHANISMS UNDERLYING THESE CHRONIC CONDITIONS IS OF RELEVANT IMPORTANCE AS IT MIGHT LEAD TO THE IDENTIFICATION OF NOVEL ANTI-OBESITY TARGETS. THE PURPOSE OF THE CURRENT STUDY IS TO INVESTIGATE DIFFERENTIALLY EXPRESSED PROTEINS BETWEEN LEAN AND OBESE SUBJECTS THROUGH A SHOT-GUN QUANTITATIVE PROTEOMICS APPROACH USING PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) EXTRACTS AS WELL AS POTENTIAL MODULATION OF THOSE PROTEINS BY PHYSICAL EXERCISE. USING THIS APPROACH, A TOTAL OF 47 PROTEINS SHOWED AT LEAST 1.5 FOLD CHANGE BETWEEN LEAN AND OBESE SUBJECTS. IN OBESE, THE PROTEOMIC PROFILING BEFORE AND AFTER 3 MONTHS OF PHYSICAL EXERCISE SHOWED DIFFERENTIAL EXPRESSION OF 38 PROTEINS. THROMBOSPONDIN 1 (TSP1) WAS AMONG THE PROTEINS THAT WERE UPREGULATED IN OBESE SUBJECTS AND THEN DECREASED BY PHYSICAL EXERCISE. CONVERSELY, THE HISTONE DEACETYLASE 4 (HDAC4) WAS DOWNREGULATED IN OBESE SUBJECTS AND THEN INDUCED BY PHYSICAL EXERCISE. THE PROTEOMIC DATA WAS FURTHER VALIDATED BY QRT-PCR, WESTERN BLOT AND IMMUNOHISTOCHEMISTRY IN BOTH PBMCS AND ADIPOSE TISSUE. WE ALSO SHOWED THAT HDAC4 LEVELS CORRELATED POSITIVELY WITH MAXIMUM OXYGEN CONSUMPTION (VO2 MAX) BUT NEGATIVELY WITH BODY MASS INDEX, PERCENT BODY FAT, AND THE INFLAMMATORY CHEMOKINE RANTES. IN FUNCTIONAL ASSAYS, OUR DATA INDICATED THAT ECTOPIC EXPRESSION OF HDAC4 SIGNIFICANTLY IMPAIRED TNF-ALPHA-DEPENDENT ACTIVATION OF NF-KAPPAB, ESTABLISHING THUS A LINK BETWEEN HDAC4 AND REGULATION OF THE IMMUNE SYSTEM. TOGETHER, THE EXPRESSION PATTERN OF HDAC4 IN OBESE SUBJECTS BEFORE AND AFTER PHYSICAL EXERCISE, ITS CORRELATION WITH VARIOUS PHYSICAL, CLINICAL AND METABOLIC PARAMETERS ALONG WITH ITS INHIBITORY EFFECT ON NF-KAPPAB ARE SUGGESTIVE OF A PROTECTIVE ROLE OF HDAC4 AGAINST OBESITY. HDAC4 COULD THEREFORE REPRESENT A POTENTIAL THERAPEUTIC TARGET FOR THE CONTROL AND MANAGEMENT OF OBESITY AND PRESUMABLY INSULIN RESISTANCE. 2013 11 2119 30 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 12 1117 28 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT. 2017 13 2022 30 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA. 2013 14 978 31 CHRONIC OXIDATIVE STRESS CAUSES ESTROGEN-INDEPENDENT AGGRESSIVE PHENOTYPE, AND EPIGENETIC INACTIVATION OF ESTROGEN RECEPTOR ALPHA IN MCF-7 BREAST CANCER CELLS. THE ROLE OF CHRONIC OXIDATIVE STRESS IN THE DEVELOPMENT AND AGGRESSIVE GROWTH OF ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER IS WELL KNOWN; HOWEVER, THE MECHANISTIC UNDERSTANDING IS NOT CLEAR. ESTROGEN-INDEPENDENT GROWTH IS ONE OF THE FEATURES OF AGGRESSIVE SUBTYPE OF BREAST CANCER. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECT OF OXIDATIVE STRESS ON ESTROGEN SENSITIVITY AND EXPRESSION OF NUCLEAR ESTROGEN RECEPTORS IN ER-POSITIVE BREAST CANCER CELLS. MCF-7 CELLS CHRONICALLY EXPOSED TO HYDROGEN PEROXIDE WERE USED AS A CELL MODEL IN THIS STUDY, AND THEIR GROWTH IN RESPONSE TO 17-BETA ESTRADIOL WAS EVALUATED BY CELL VIABILITY, CELL CYCLE, AND CELL MIGRATION ANALYSIS. RESULTS WERE FURTHER CONFIRMED AT MOLECULAR LEVEL BY ANALYSIS OF GENE EXPRESSIONS AT TRANSCRIPT AND PROTEIN LEVELS. HISTONE H3 MODIFICATIONS, EXPRESSION OF EPIGENETIC REGULATORY GENES, AND THE EFFECT OF DNA DEMETHYLATION WERE ALSO ANALYZED. LOSS OF GROWTH IN RESPONSE TO ESTROGEN WITH A DECREASE IN ERALPHA EXPRESSION WAS OBSERVED IN MCF-7 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. INCREASES IN MTTFA AND NRF1 IN THESE CELLS FURTHER SUGGESTED THE ROLE OF MITOCHONDRIA-DEPENDENT REDOX-SENSITIVE GROWTH SIGNALING AS AN ALTERNATIVE PATHWAY TO ESTROGEN-DEPENDENT GROWTH. CHANGES IN EXPRESSION OF EPIGENETIC REGULATORY GENES, LEVELS OF HISTONE H3 MODIFICATIONS AS WELL AS SIGNIFICANT RESTORATIONS OF BOTH ERALPHA EXPRESSION AND ESTROGEN RESPONSE BY 5-AZA-2'-DEOXYCYTIDINE FURTHER CONFIRMED THE EPIGENETIC BASIS FOR ESTROGEN-INDEPENDENT GROWTH IN THESE CELLS. IN CONCLUSION, RESULTS OF THIS STUDY SUGGEST THAT CHRONIC OXIDATIVE STRESS CAN CONVERT ESTROGEN-DEPENDENT NONAGGRESSIVE BREAST CANCER CELLS INTO ESTROGEN-INDEPENDENT AGGRESSIVE FORM POTENTIALLY BY EPIGENETIC MECHANISM. 2015 15 5894 29 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 16 420 26 ANDROGEN-MEDIATED PERTURBATION OF THE HEPATIC CIRCADIAN SYSTEM THROUGH EPIGENETIC MODULATION PROMOTES NAFLD IN PCOS MICE. IN WOMEN, EXCESS ANDROGEN CAUSES POLYCYSTIC OVARY SYNDROME (PCOS), A COMMON FERTILITY DISORDER WITH COMORBID METABOLIC DYSFUNCTIONS INCLUDING DIABETES, OBESITY, AND NONALCOHOLIC FATTY LIVER DISEASE. USING A PCOS MOUSE MODEL, THIS STUDY SHOWS THAT CHRONIC HIGH ANDROGEN LEVELS CAUSE HEPATIC STEATOSIS WHILE HEPATOCYTE-SPECIFIC ANDROGEN RECEPTOR (AR)-KNOCKOUT RESCUES THIS PHENOTYPE. MOREOVER, THROUGH RNA-SEQUENCING AND METABOLOMIC STUDIES, WE HAVE IDENTIFIED KEY METABOLIC GENES AND PATHWAYS AFFECTED BY HYPERANDROGENISM. OUR STUDIES REVEAL THAT A LARGE NUMBER OF METABOLIC GENES ARE DIRECTLY REGULATED BY ANDROGENS THROUGH AR BINDING TO ANDROGEN RESPONSE ELEMENT SEQUENCES ON THE PROMOTER REGION OF THESE GENES. INTERESTINGLY, A NUMBER OF CIRCADIAN GENES ARE ALSO DIFFERENTIALLY REGULATED BY ANDROGENS. IN VIVO AND IN VITRO STUDIES USING A CIRCADIAN REPORTER [PERIOD2::LUCIFERASE (PER2::LUC)] MOUSE MODEL DEMONSTRATE THAT ANDROGENS CAN DIRECTLY DISRUPT THE HEPATIC TIMING SYSTEM, WHICH IS A KEY REGULATOR OF LIVER METABOLISM. CONSEQUENTLY, STUDIES SHOW THAT ANDROGENS DECREASE H3K27ME3, A GENE SILENCING MARK ON THE PROMOTER OF CORE CLOCK GENES, BY INHIBITING THE EXPRESSION OF HISTONE METHYLTRANSFERASE, EZH2, WHILE INDUCING THE EXPRESSION OF THE HISTONE DEMETHYLASE, JMJD3, WHICH IS RESPONSIBLE FOR ADDING AND REMOVING THE H3K27ME3 MARK, RESPECTIVELY. FINALLY, WE REPORT THAT UNDER HYPERANDROGENIC CONDITIONS, SOME OF THE SAME CIRCADIAN/METABOLIC GENES THAT ARE UPREGULATED IN THE MOUSE LIVER ARE ALSO ELEVATED IN NONHUMAN PRIMATE LIVERS. IN SUMMARY, THESE STUDIES NOT ONLY PROVIDE AN OVERALL UNDERSTANDING OF HOW HYPERANDROGENISM ASSOCIATED WITH PCOS AFFECTS LIVER GENE EXPRESSION AND METABOLISM BUT ALSO OFFER INSIGHT INTO THE UNDERLYING MECHANISMS LEADING TO HEPATIC STEATOSIS IN PCOS. 2022 17 2024 37 EPIGENETIC CHANGES CAUSED BY DIABETES AND THEIR POTENTIAL ROLE IN THE DEVELOPMENT OF PERIODONTITIS. AIMS/INTRODUCTION: PERIODONTAL DISEASE, A CHRONIC INFLAMMATION INDUCED BY BACTERIA, IS CLOSELY LINKED WITH DIABETES MELLITUS. MANY COMPLICATIONS ASSOCIATED WITH DIABETES ARE RELATED TO EPIGENETIC CHANGES. HOWEVER, THE EXACT EPIGENETIC CHANGES WHEREBY DIABETES AFFECTS PERIODONTAL DISEASE REMAIN LARGELY UNKNOWN. THUS, WE SOUGHT TO INVESTIGATE THE ROLE OF DIABETES-DEPENDENT EPIGENETIC CHANGES OF GINGIVAL TISSUE IN THE SUSCEPTIBILITY TO PERIODONTAL DISEASE. MATERIALS AND METHODS: WE STUDIED THE EFFECT OF STREPTOZOTOCIN-INDUCED DIABETES IN MINIPIGS ON GINGIVAL MORPHOLOGICAL AND EPIGENETIC TISSUE CHANGES. ACCORDINGLY, WE RANDOMLY DIVIDED SIX MINIPIGS INTO TWO GROUPS: STREPTOZOTOCIN-INDUCED DIABETES GROUP, N = 3; AND NON-DIABETES HEALTHY CONTROL GROUP, N = 3. AFTER 85 DAYS, ALL ANIMALS WERE KILLED, AND GINGIVAL TISSUE WAS COLLECTED FOR HISTOLOGY, DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS AND IMMUNOHISTOCHEMISTRY. RESULTS: A DIABETES MELLITUS MODEL WAS SUCCESSFULLY CREATED, AS EVIDENCED BY SIGNIFICANTLY INCREASED BLOOD GLUCOSE LEVELS, REDUCTION OF PANCREATIC INSULIN-PRODUCING BETA-CELLS AND HISTOPATHOLOGICAL CHANGES IN THE KIDNEYS. THE GINGIVAL TISSUES IN THE DIABETES GROUP PRESENTED ACANTHOSIS OF BOTH GINGIVAL SQUAMOUS EPITHELIUM AND SULCULAR/JUNCTIONAL EPITHELIUM, AND A SIGNIFICANT REDUCTION IN THE NUMBER AND LENGTH OF RETE PEGS. DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS SHOWED A TOTAL OF 1,163 AFFECTED GENES, OF WHICH 599 AND 564 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY. IMMUNOHISTOCHEMISTRY STAINING SHOWED THAT THE HYPOMETHYLATED GENES - TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-6 - WERE POSITIVELY EXPRESSED UNDER THE JUNCTIONAL EPITHELIUM AREA IN THE DIABETES GROUP. CONCLUSIONS: DIABETES MELLITUS INDUCES MORPHOLOGICAL AND EPIGENETIC CHANGES IN PERIODONTAL TISSUE, WHICH MIGHT CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PERIODONTAL DISEASES IN PATIENTS WITH DIABETES. 2021 18 422 29 ANNEXIN-A1 DEFICIENCY ATTENUATES STRESS-INDUCED TUMOR GROWTH VIA FATTY ACID METABOLISM IN MICE: AN INTEGRATED MULTIPLE OMICS ANALYSIS ON THE STRESS- MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. BACKGROUND: HIGH EMOTIONAL OR PSYCHOPHYSICAL STRESS LEVELS HAVE BEEN CORRELATED WITH AN INCREASED RISK AND PROGRESSION OF VARIOUS DISEASES. HOW STRESS IMPACTS THE GUT MICROBIOTA TO INFLUENCE METABOLISM AND SUBSEQUENT CANCER PROGRESSION IS UNCLEAR. METHODS: FECES AND SERUM SAMPLES FROM BALB/C ANXA1(+/+) AND ANXA1(-/-) MICE WITH OR WITHOUT CHRONIC RESTRAINT STRESS WERE USED FOR 16S RRNA GENE SEQUENCING AND GC-MS METABOLOMICS ANALYSIS TO INVESTIGATE THE EFFECT OF STRESS ON MICROBIOME AND METABOLOMICS DURING STRESS AND BREAST TUMORIGENESIS. BREAST TUMORS SAMPLES FROM STRESSED AND NON-STRESSED MICE WERE USED TO PERFORM WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNASEQ ANALYSIS TO CONSTRUCT THE POTENTIAL NETWORK FROM CANDIDATE HUB GENES. FINALLY, MACHINE LEARNING AND INTEGRATED ANALYSIS WERE USED TO MAP THE AXIS FROM CHRONIC RESTRAINT STRESS TO BREAST CANCER DEVELOPMENT. RESULTS: WE REPORT THAT CHRONIC STRESS PROMOTES BREAST TUMOR GROWTH VIA A STRESS-MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. CHRONIC RESTRAINT STRESS IN MICE ALTERS THE MICROBIOME COMPOSITION AND FATTY ACIDS METABOLISM AND INDUCES AN EPIGENETIC SIGNATURE IN TUMORS XENOGRAFTED AFTER STRESS. SUBSEQUENT MACHINE LEARNING AND SYSTEMIC MODELING ANALYSES IDENTIFIED A SIGNIFICANT CORRELATION AMONG MICROBIOME COMPOSITION, METABOLITES, AND DIFFERENTIALLY METHYLATED REGIONS IN STRESSED TUMORS. MOREOVER, SILENCING ANNEXIN-A1 INHIBITS THE CHANGES IN THE GUT MICROBIOME AND FATTY ACID METABOLISM AFTER STRESS AS WELL AS BASAL AND STRESS-INDUCED TUMOR GROWTH. CONCLUSIONS: THESE DATA SUPPORT A PHYSIOLOGICAL AXIS LINKING THE MICROBIOME AND METABOLITES TO CANCER EPIGENETICS AND INFLAMMATION. THE IDENTIFICATION OF THIS AXIS COULD PROPEL THE NEXT PHASE OF EXPERIMENTAL DISCOVERY IN FURTHER UNDERSTANDING THE UNDERLYING MOLECULAR MECHANISM OF TUMORIGENESIS CAUSED BY PHYSIOLOGICAL STRESS. 2022 19 1900 27 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 20 3148 33 GLUCOCORTICOID INDUCED LOSS OF OESTROGEN RECEPTOR ALPHA GENE METHYLATION AND RESTORATION OF SENSITIVITY TO FULVESTRANT IN TRIPLE NEGATIVE BREAST CANCER. THE RESPONSE TO PSYCHOLOGICAL STRESS CAN DIFFER DEPENDING ON THE TYPE AND DURATION OF THE STRESSOR. ACUTE STRESS CAN FACILITATE A "FIGHT OR FLIGHT RESPONSE" AND AID SURVIVAL, WHEREAS CHRONIC LONG-TERM STRESS WITH THE PERSISTENT RELEASE OF STRESS HORMONES SUCH AS CORTISOL HAS BEEN SHOWN TO BE DETRIMENTAL TO HEALTH. WE ARE NOW BEGINNING TO UNDERSTAND HOW THIS STRESS HORMONE RESPONSE IMPACTS IMPORTANT PROCESSES SUCH AS DNA REPAIR AND CELL PROLIFERATION PROCESSES IN BREAST CANCER. HOWEVER, IT IS NOT KNOWN WHAT EPIGENETIC CHANGES STRESS HORMONES INDUCE IN BREAST CANCER. EPIGENETIC MECHANISMS INCLUDE MODIFICATION OF DNA AND HISTONES WITHIN CHROMATIN THAT MAY BE INVOLVED IN GOVERNING THE TRANSCRIPTIONAL PROCESSES IN CANCER CELLS IN RESPONSE TO CHANGES BY ENDOGENOUS STRESS HORMONES. THE CONTRIBUTION OF ENDOGENOUS ACUTE OR LONG-TERM EXPOSURE OF GLUCOCORTICOID STRESS HORMONES, AND EXOGENOUS GLUCOCORTICOIDS TO METHYLATION PATTERNS IN BREAST CANCER TISSUES WITH DIFFERENT AETIOLOGIES REMAINS TO BE EVALUATED. IN VITRO AND IN VIVO MODELS WERE DEVELOPED TO INVESTIGATE THE EPIGENETIC MODIFICATIONS AND THEIR CONTRIBUTION TO BREAST CANCER PROGRESSION AND AETIOLOGY. A PANEL OF TRIPLE NEGATIVE BREAST CANCER CELL LINES WERE TREATED WITH THE GLUCOCORTICOID, CORTISOL WHICH RESULTED IN EPIGENETIC ALTERATION CHARACTERISED BY LOSS OF METHYLATION ON PROMOTER REGIONS OF TUMOUR SUPPRESSOR GENES INCLUDING ESR1, AND LOSS OF METHYLATION ON LINE-1 REPETITIVE ELEMENT USED AS A SURROGATE MARKER FOR GLOBAL METHYLATION. THIS WAS VERIFIED IN VIVO IN MDA-MB-231 XENOGRAFTS; THE MODEL VERIFIED THE LOSS OF METHYLATION ON ESR1 PROMOTER, AND SUBSEQUENT INCREASE IN ESR1 EXPRESSION IN PRIMARY TUMOURS IN MICE SUBJECTED TO RESTRAINT STRESS. OUR STUDY HIGHLIGHTS THAT DNA METHYLATION LANDSCAPE IN BREAST CANCER CAN BE ALTERED IN RESPONSE TO STRESS AND GLUCOCORTICOID TREATMENT. 2023