1 898 138 CHRONIC EXPOSURE OF MICE TO BISPHENOL-A ALTERS UTERINE FIBROBLAST GROWTH FACTOR SIGNALING AND LEADS TO ABERRANT EPITHELIAL PROLIFERATION. UTERINE EPITHELIAL PROLIFERATION IS REGULATED IN A PARACRINE MANNER BY A COMPLEX INTERPLAY BETWEEN ESTROGEN (E) AND PROGESTERONE (P) SIGNALING, IN WHICH E STIMULATES PROLIFERATION AND P INHIBITS IT. PERTURBATION OF STEROID HORMONE SIGNALING WITHIN THE UTERINE MILIEU COULD CONTRIBUTE TO THE DEVELOPMENT OF ENDOMETRIAL HYPERPLASIA AND CANCER. IT IS WELL ESTABLISHED THAT BISPHENOL-A (BPA) IS AN ENDOCRINE-DISRUPTING CHEMICAL WITH WEAK ESTROGENIC EFFECTS, ALTHOUGH LITTLE IS KNOWN ABOUT HOW IT AFFECTS STEROID HORMONE SIGNALING IN THE ADULT UTERUS. BECAUSE BPA ACTS AS A WEAK E, WE HYPOTHESIZED THAT CHRONIC EXPOSURE TO BPA WOULD CREATE AN IMBALANCE BETWEEN E AND P SIGNALING AND CAUSE CHANGES IN THE UTERUS, SUCH AS ABERRANT EPITHELIAL PROLIFERATION. INDEED, EXPOSURE TO AN ENVIRONMENTALLY RELEVANT DOSE OF BPA HAD A UTEROTROPHIC AFFECT. BPA-TREATED MICE SHOWED INCREASED PROLIFERATION, NOTABLY IN THE GLANDULAR EPITHELIUM, WHICH ARE SITES OF ORIGIN FOR ENDOMETRIAL HYPERPLASIA AND CANCER. INCREASED PROLIFERATION APPEARED TO BE MEDIATED THROUGH A SIMILAR MECHANISM AS E-INDUCED PROLIFERATION, VIA ACTIVATION OF THE FIBROBLAST GROWTH FACTOR RECEPTOR PATHWAY AND PHOSPHORYLATION OF THE ERK1/2 MITOGEN-ACTIVATED PROTEIN KINASES IN THE EPITHELIUM. INTERESTINGLY, BPA REDUCED EXPRESSION OF HEART AND NEURAL CREST DERIVATIVES EXPRESSED 2 (HAND2), A KNOWN MEDIATOR OF THE ANTIPROLIFERATIVE EFFECTS OF P. BPA ALSO INCREASED METHYLATION OF A CPG ISLAND IN THE HAND2 GENE PROMOTER, SUGGESTING THAT BPA MAY PROMOTE EPITHELIAL PROLIFERATION THROUGH EPIGENETIC SILENCING OF ANTIPROLIFERATIVE FACTORS LIKE HAND2. COLLECTIVELY, THESE FINDINGS ESTABLISH THAT CHRONIC EXPOSURE TO BPA IMPAIRS STEROID HORMONE SIGNALING IN THE MOUSE UTERUS, AND MAY CONTRIBUTE TO THE PATHOGENESIS OF UTERINE HYPERPLASIA AND CANCER. 2019 2 5754 27 SOCIAL PSYCHOGENIC STRESS PROMOTES THE DEVELOPMENT OF ENDOMETRIOSIS IN MOUSE. EXPOSURE TO CHRONIC STRESS BEFORE AND WELL AFTER THE INDUCTION OF ENDOMETRIOSIS IS REPORTED TO INCREASE LESION SIZES IN RATS, BUT IT IS UNCLEAR WHETHER STRESS, EXPOSED SHORTLY AFTER THE INDUCTION OF ENDOMETRIOSIS, WOULD ALSO PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS, NOR IS IT CLEAR WHAT THE UNDERLYING POSSIBLE MOLECULAR MECHANISM IS. THIS STUDY WAS UNDERTAKEN TO TEST THE HYPOTHESIS THAT CHRONIC STRESS CAN PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS. A PROSPECTIVE RANDOMIZED MOUSE EXPERIMENT WAS CONDUCTED THAT SUBJECTED MICE WITH INDUCED ENDOMETRIOSIS TO PREDATOR STRESS. IN ADDITION, A CROSS-SECTIONAL IMMUNOHISTOCHEMISTRY STUDY WAS PERFORMED IN ECTOPIC AND EUTOPIC ENDOMETRIAL TISSUE SAMPLES FROM AGE- AND ROUGHLY MENSTRUAL PHASE-MATCHED WOMEN WITH OVARIAN ENDOMETRIOMAS. IT WAS FOUND THAT THE CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS IN MOUSE INDEPENDENT OF ENDOMETRIOSIS. IT WAS ALSO FOUND THAT CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS OF MICE WITH ENDOMETRIOSIS, AND SEEMINGLY ACTIVATED THE ADRENERGIC SIGNALLING IN ECTOPIC ENDOMETRIUM, RESULTING IN INCREASED ANGIOGENESIS AND ACCELERATED GROWTH OF ENDOMETRIOTIC LESIONS. THUS, CHRONIC PSYCHOGENIC STRESS PROMOTES ENDOMETRIOSIS DEVELOPMENT, RAISING THE POSSIBILITY THAT THE USE OF ANTI-DEPRESSANTS IN CASES OF PROLONGED AND INTENSE STRESS MIGHT FORESTALL THE NEGATIVE IMPACT OF STRESS ON THE DEVELOPMENT OF ENDOMETRIOSIS. 2017 3 978 34 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 4 3148 38 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 5 2926 29 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 6 468 35 ARGININE METHYLTRANSFERASES MEDIATE AN EPIGENETIC OVARIAN RESPONSE TO ENDOMETRIOSIS. ENDOMETRIOSIS IS ASSOCIATED WITH INFERTILITY AND DEBILITATING CHRONIC PAIN. ABNORMAL EPIGENETIC MODIFICATIONS IN THE HUMAN ENDOMETRIUM HAVE RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF THIS CONDITION. HOWEVER, WHETHER AN ALTERED EPIGENETIC LANDSCAPE CONTRIBUTES TO PATHOLOGICAL CHANGES IN THE OVARY IS UNKNOWN. USING AN ESTABLISHED BABOON ENDOMETRIOSIS MODEL, EARLY-, AND LATE-STAGE EPIGENETIC CHANGES IN THE OVARY WERE INVESTIGATED. TRANSCRIPT PROFILING OF KEY CHROMATIN-MODIFYING ENZYMES USING PATHWAY-FOCUSED PCR ARRAYS ON OVARIAN TISSUE FROM HEALTHY CONTROL ANIMALS AND AT 3 AND 15 MONTHS OF ENDOMETRIOSIS REVEALED DRAMATIC CHANGES IN GENE EXPRESSION IN A DISEASE DURATION-DEPENDENT MANNER. INGENUITY PATHWAY ANALYSIS INDICATED THAT TRANSCRIPTS FOR CHROMATIN-REMODELING ENZYMES ASSOCIATED WITH REPRODUCTIVE SYSTEM DISEASE AND CANCER DEVELOPMENT WERE ABNORMALLY REGULATED, MOST PROMINENTLY THE ARGININE METHYLTRANSFERASES CARM1, PRMT2, AND PRMT8. DOWNREGULATION OF CARM1 PROTEIN EXPRESSION WAS ALSO DETECTED IN THE OVARY, FULLY-GROWN OOCYTES AND EUTOPIC ENDOMETRIUM FOLLOWING 15 MONTHS OF ENDOMETRIOSIS. SODIUM BISULFITE SEQUENCING REVEALED DNA HYPERMETHYLATION WITHIN THE PRMT8 PROMOTER, SUGGESTING THAT DEREGULATED CPG METHYLATION MAY PLAY A ROLE IN TRANSCRIPTIONAL REPRESSION OF THIS GENE. THESE RESULTS DEMONSTRATE THAT ENDOMETRIOSIS IS ASSOCIATED WITH CHANGES OF EPIGENETIC PROFILES IN THE PRIMATE OVARY AND SUGGEST THAT ARGININE METHYLTRANSFERASES PLAY A PROMINENT ROLE IN MEDIATING THE OVARIAN RESPONSE TO ENDOMETRIOSIS. OWING TO THE CRITICAL ROLE OF CARM1 IN NUCLEAR RECEPTOR-MEDIATED TRANSCRIPTION AND MAINTENANCE OF PLURIPOTENCY IN THE CLEAVAGE STAGE EMBRYO, OUR RESULTS SUGGEST THAT EPIGENETIC ALTERATIONS IN THE OVARY MAY HAVE FUNCTIONAL CONSEQUENCES FOR OOCYTE QUALITY AND THE ETIOLOGY OF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS. 2015 7 1202 44 COULD DNA HYDROXYMETHYLATION BE CRUCIAL IN INFLUENCING STEROID HORMONE SIGNALING IN ENDOMETRIAL BIOLOGY AND ENDOMETRIOSIS? ENDOMETRIOSIS AFFECTS 10% OF REPRODUCTIVE-AGED WOMEN. IT IS CHARACTERIZED BY THE GROWTH OF THE ENDOMETRIUM, OUTSIDE THE UTERUS AND IS ASSOCIATED WITH INFERTILITY AND CHRONIC ABDOMINAL PAIN. LACK OF NONINVASIVE DIAGNOSTIC TOOLS AND EARLY SCREENING TESTS RESULTS IN DELAYED TREATMENT AND SUBSEQUENTLY INCREASED DISEASE SEVERITY. ENDOMETRIOSIS IS A DISEASE ASSOCIATED WITH A DEREGULATED HORMONAL RESPONSE, THEREFORE, UNDERSTANDING THE MOLECULAR MECHANISMS THAT GOVERN THIS HORMONAL INTERPLAY IS OF PARAMOUNT IMPORTANCE. DNA METHYLATION IS AN EPIGENETIC MARK THAT REGULATES GENE EXPRESSION AND IS OFTEN ASSOCIATED WITH GENES THAT CODE FOR STEROID RECEPTORS AND ENZYMES ASSOCIATED WITH ESTROGEN SYNTHESIS AND METABOLISM IN ENDOMETRIOSIS. DNA HYDROXYMETHYLATION, WHICH IS STRUCTURALLY SIMILAR TO METHYLATION BUT FUNCTIONALLY DIFFERENT, IS A BIOLOGICALLY CRITICAL MECHANISM THAT IS ALSO KNOWN TO REGULATE GENE EXPRESSION. TEN ELEVEN TRANSLOCATION (TET) PROTEINS MEDIATE HYDROXYMETHYLATION. HOWEVER, THE ROLE OF DNA HYDROXYMETHYLATION OR TETS IN THE ENDOMETRIUM REMAINS RELATIVELY UNEXPLORED. CURRENTLY, THE "GOLD STANDARD" TECHNIQUE USED TO STUDY METHYLATION PATTERNS IS BISULFITE GENOMIC SEQUENCING. THIS TECHNIQUE ALSO DETECTS HYDROXYMETHYLATION BUT FAILS TO DISTINGUISH BETWEEN THE TWO, THEREBY LIMITING OUR UNDERSTANDING OF THESE TWO PROCESSES. THE PRESENCE OF TETS IN THE MALE AND FEMALE REPRODUCTIVE TRACT AND ITS CONTRIBUTION TO ENDOMETRIAL CANCER MAKES IT AN IMPORTANT FACTOR TO STUDY IN ENDOMETRIOSIS. THIS REVIEW SUMMARIZES THE ROLE OF DNA METHYLATION IN ABERRANT STEROID HORMONE SIGNALING AND HYPOTHESIZES THAT HYDROXYMETHYLATION COULD BE A FACTOR INFLUENCING HORMONAL INSTABILITY SEEN IN ENDOMETRIOSIS. 2020 8 5239 41 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 9 3659 35 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 10 2022 38 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 11 4987 38 PATTERNS OF CALCIUM SIGNALING: A LINK BETWEEN CHRONIC EMOTIONS AND CANCER. INTRA AND INTER-CELLULAR CALCIUM SIGNALING IS PRESENT IN ALL TYPES OF CELLS AND BODY TISSUES. IN THE HUMAN BRAIN, CALCIUM CURRENTS AND WAVES ARE RELATED TO MENTAL ACTIVITIES, INCLUDING EMOTIONS. WE PRESENT A THEORETICAL INTERPRETATION OF THESE PHENOMENA SUGGESTING THEIR INVOLVEMENT IN CHRONIC EMOTIONAL PATTERNS AND IN THE PATHOLOGY OF CANCER. RECENT DEVELOPMENTS ON BIOPHYSICS, TRANSLATIONAL BIOLOGY AND PSYCHONEUROENDOCRINOIMMUNOLOGY (PNEI) CAN SUPPORT EXPLANATORY HYPOTHESES ABOUT THE LINK BETWEEN EMOTIONAL STRESSES AND THE ORIGIN AND DEVELOPMENT OF DIFFERENT TYPES OF TUMOR CELLS. CHRONIC STRESSES MAY CAUSE PERTURBATIONS OF RHYTHMS OF THE PNEI SYSTEM, EXCESSIVE ACTIVATION OF HPA AXIS AND ABNORMAL ACTIVATION OF CALCIUM SIGNALS IN SOMATIC TISSUES, WITH DELETERIOUS EFFECTS ON DIFFERENT PARTS OF THE BODY. THE INCREASING OF CALCIUM SIGNALING INSIDE CELLS MAY LEAD TO A DEREGULATION OF DIFFERENT PATHWAYS AND EPIGENETIC SYSTEMS THAT PROMOTE THE PRODUCTION OF GENOMIC MUTATIONS IN A SECOND PHASE. IN PARTICULAR, THE HYPERACTIVATION OF THE TRANSCRIPTION NUCLEAR FACTOR KAPPAB (NF-KAPPAB), IF IS NOT COUNTERBALANCED BY THE FOLLOWING ACTIVATION OF THE NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NFE2L2 OR NRF2), INCREASES THE PRODUCTION OF OXIDATIVE CATABOLITES, AS THE ADVANCED GLYCATION END PRODUCTS (AGE), WHICH PLAY A KEY ROLE IN THE PROGRESSION OF DIFFERENT TYPES OF CANCER AND OTHER DEGENERATIVE DISEASES. CORTISOL BINDING TO GLUCOCORTICOID RECEPTOR (GR) REDUCES THE ACTIVITY OF BOTH NF-KAPPAB AND NRF2 INSIDE THE CELLS BUT INHIBITS THE CELLULAR IMMUNITY AND THE ANABOLIC PROCESSES OF TISSUE REGENERATION. THE TISSUE ATROPHY AND THE DEFECTIVE ANTI-AGEING MECHANISMS PROMOTES THE TUMORAL CELLS GROWTH AND THEIR ESCAPE FROM THE IMMUNE-SURVEILLANCE. 2017 12 3667 36 INFILTRATING MACROPHAGES INDUCE ERALPHA EXPRESSION THROUGH AN IL17A-MEDIATED EPIGENETIC MECHANISM TO SENSITIZE ENDOMETRIAL CANCER CELLS TO ESTROGEN. PERSISTENT UNOPPOSED ESTROGEN STIMULATION IS A CENTRAL ONCOGENIC MECHANISM DRIVING THE FORMATION OF TYPE I ENDOMETRIAL CANCER. RECENT EPIDEMIOLOGIC AND CLINICAL STUDIES OF ENDOMETRIAL CANCER HAVE ALSO REVEALED A ROLE FOR INSULIN RESISTANCE, CLINICALLY MANIFESTED BY CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF INFLAMMATION IN ESTROGEN-DRIVEN ENDOMETRIAL CANCER IS NOT WELL CHARACTERIZED. IN THIS STUDY, WE INVESTIGATED THE ASSOCIATION BETWEEN INFILTRATING MACROPHAGES AND ESTROGEN SENSITIVITY IN ENDOMETRIAL CANCER. EVALUATING TISSUE SAMPLES AND SERUM FROM PATIENTS WITH PRECANCEROUS LESIONS OR ENDOMETRIAL CANCER, WE FOUND THAT TISSUE MACROPHAGE INFILTRATION, BUT NOT SERUM ESTRADIOL LEVELS, CORRELATED POSITIVELY WITH ENDOMETRIAL CANCER DEVELOPMENT. FURTHERMORE, IL4/IL13-INDUCED CD68(+)CD163(+) MACROPHAGES ENHANCED THE PROLIFERATIVE EFFECTS OF ESTRADIOL IN ENDOMETRIAL CANCER CELLS BY UPREGULATING ESTROGEN RECEPTOR ALPHA (ERALPHA), BUT NOT ERBETA. MECHANISTIC INVESTIGATIONS REVEALED THAT CD68(+)CD163(+) MACROPHAGES SECRETED CYTOKINES, SUCH AS IL17A, THAT UPREGULATED ERALPHA EXPRESSION THROUGH TET1-MEDIATED EPIGENETIC MODULATION OF THE ERALPHA GENE. OVERALL, OUR FINDINGS SHOW HOW CYTOKINES PRODUCED BY INFILTRATING MACROPHAGES IN THE ENDOMETRIAL MICROENVIRONMENT CAN INDUCE EPIGENETIC UPREGULATION OF ERALPHA EXPRESSION, WHICH IN TURN SENSITIZES ENDOMETRIAL CELLS TO ESTROGEN STIMULATION. THE CONCEPT THAT INFLAMMATION-INDUCED ESTROGEN SENSITIVITY IN THE ENDOMETRIUM ACTS AS A DRIVER OF TYPE I ENDOMETRIAL CANCER HAS IMPLICATIONS FOR INFILTRATING MACROPHAGES AS A PROGNOSTIC BIOMARKER OF PROGRESSION IN THIS DISEASE SETTING. 2016 13 2228 37 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 14 2119 29 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 15 1912 40 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 16 5067 32 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 17 315 37 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 18 1641 36 DOES GUT-BREAST MICROBIOTA AXIS ORCHESTRATES CANCER PROGRESSION? BREAST CANCER, EVEN TODAY, CAN CAUSE DEATH. THEREFORE, PREVENTION AND EARLY DETECTION ARE FUNDAMENTAL FACTORS. THE MECHANISMS THAT FAVOUR IT ARE GENETIC AND EPIGENETIC, AND SEEM TO PLAY A SIGNIFICANT ROLE; ALSO, THE MICROBIOTA CAN CHANGE ESTROGEN LEVELS AND CAN INDUCE CHRONIC INFLAMMATION IN THE NEOPLASTIC SITE, ALTERNATING THE BALANCE BETWEEN PROLIFERATION AND CELL DEATH. ACTIVATED STEROID HORMONE RECEPTORS INDUCE TRANSCRIPTION OF GENES THAT ENCODE FOR PROTEINS INVOLVED IN CELL PROLIFERATION AND ACTIVATE ANOTHER TRANSDUCTION PATHWAY, INDUCING CELL CYCLE PROGRESSION AND CELL MIGRATION. THESE IMPORTANT STUDIES HAVE ALLOWED TO DEVELOP THERAPIES WITH SELECTIVE MODULATORS OF ESTROGEN RECEPTORS (SERMS), ABLE TO BLOCK THEIR PROLIFERATIVE AND PRO-TUMORIGENIC ACTION. OF FUNDAMENTAL IMPORTANCE IS ALSO THE ROLE PLAYED BY THE MICROBIOTA IN REGULATING THE METABOLISM OF ESTROGENS AND THEIR LEVELS IN THE BLOOD. THERE ARE MICROBIAL POPULATIONS THAT ARE ABLE TO PROMOTE THE DEVELOPMENT OF BREAST CANCER, THROUGH THE PRODUCTION OF ENZYMES RESPONSIBLE FOR THE DECONJUGATION OF ESTROGENS, THE INCREASE OF THESE IN THE INTESTINE, SUBSEQUENT CIRCULATION AND MIGRATION TO OTHER LOCATIONS, SUCH AS THE UDDER. OTHER MICROBIAL POPULATIONS ARE, INSTEAD, ABLE TO SYNTHESIZE ESTROGEN COMPOUNDS OR MIMIC ESTROGENIC ACTION, AND INTERFERE WITH THE METABOLISM OF DRUGS, AFFECTING THE OUTCOME OF THERAPIES. THE MICROBIAL COMPOSITION OF THE INTESTINE AND HORMONAL METABOLISM DEPEND LARGELY ON EATING HABITS; THE CONSUMPTION OF FATS AND PROTEINS FAVOURS THE INCREASE OF ESTROGEN IN THE BLOOD, UNLIKE A DIET RICH IN FIBER. THEREFORE, IN-DEPTH KNOWLEDGE OF THE MICROBIOTA PRESENT IN THE INTESTINE-BREAST AXIS COULD, IN THE FUTURE, ENCOURAGE THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO BREAST CANCERS. 2022 19 6533 36 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 20 3005 37 GENETIC, EPIGENETIC, AND STEROIDOGENIC MODULATION MECHANISMS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE, AFFECTING UP TO 10% OF REPRODUCTIVE-AGE WOMEN. THE EXACT CAUSE OF THE DISEASE IS UNKNOWN; HOWEVER, IT IS A HERITABLE CONDITION AFFECTED BY MULTIPLE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. PREVIOUS STUDIES REPORTED VARIATIONS IN THE EPIGENETIC PATTERNS OF NUMEROUS GENES KNOWN TO BE INVOLVED IN THE ABERRANT MODULATION OF CELL CYCLE STEROIDOGENESIS, ABNORMAL HORMONAL, IMMUNE AND INFLAMMATORY STATUS IN ENDOMETRIOSIS, APOPTOSIS, ADHESION, ANGIOGENESIS, PROLIFERATION, IMMUNE AND INFLAMMATORY PROCESSES, RESPONSE TO HYPOXIA, STEROIDOGENIC PATHWAY AND HORMONE SIGNALING ARE INVOLVED IN THE PATHOGENESIS OF ENDOMETRIOSIS. ACCUMULATING EVIDENCE SUGGEST THAT VARIOUS EPIGENETIC ABERRATIONS MAY CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. AMONG THEM, DNA METHYLTRANSFERASES, HISTONE DEACETYLATORS, AND NON-CODING MICRORNAS DEMONSTRATE DIFFERENTIAL EXPRESSION WITHIN ENDOMETRIOTIC LESIONS AND IN THE ENDOMETRIUM OF PATIENTS WITH ENDOMETRIOSIS. IT HAS BEEN INDICATED THAT THE IDENTIFICATION OF EPIGENETIC DIFFERENCES WITHIN THE DNA OR HISTONE PROTEINS MAY CONTRIBUTE TO THE DISCOVERY OF A USEFUL PROGNOSTIC BIOMARKER, WHICH COULD AID IN THE FUTURE EARLIER DETECTION, TIMELY DIAGNOSIS, AND INITIATION OF A NEW APPROACH TO THE TREATMENT OF ENDOMETRIOSIS, AS WELL AS INFORM US ABOUT THE EFFECTIVENESS OF TREATMENT AND THE STAGE OF THE DISEASE. AS THE ETIOLOGY OF ENDOMETRIOSIS IS HIGHLY COMPLEX AND STILL FAR FROM BEING FULLY ELUCIDATED, THE PRESENTED REVIEW FOCUSES ON DIFFERENT APPROACHES TO IDENTIFY THE GENETIC AND EPIGENETIC LINKS OF ENDOMETRIOSIS AND ITS PATHOGENESIS. 2020