1 603 126 BETULINIC ACID INHIBITS ENDOMETRIOSIS THROUGH SUPPRESSION OF ESTROGEN RECEPTOR BETA SIGNALING PATHWAY. ENDOMETRIOSIS IS AN INFLAMMATORY GYNECOLOGICAL DISORDER CHARACTERIZED BY ENDOMETRIAL TISSUE GROWTH LOCATED OUTSIDE OF THE UTERINE CAVITY IN ADDITION TO CHRONIC PELVIC PAIN AND INFERTILITY. IN THIS STUDY, WE AIM TO DEVELOP A POTENTIAL THERAPEUTIC TREATMENT BASED ON THE PATHOGENESIS AND MECHANISM OF ENDOMETRIOSIS. OUR PRELIMINARY DATA SHOWED THAT THE EXPRESSION OF ESTROGEN RECEPTOR BETA (ERBETA) WAS SIGNIFICANTLY INCREASED, WHILE ERALPHA WAS SIGNIFICANTLY DECREASED, IN ENDOMETRIOTIC CELLS COMPARED TO NORMAL ENDOMETRIAL CELLS. FURTHER INVESTIGATION SHOWED THAT BETULINIC ACID (BA) TREATMENT SUPPRESSED ERBETA EXPRESSION THROUGH EPIGENETIC MODIFICATION ON THE ERBETA PROMOTER, WHILE HAD NO EFFECT ON ERALPHA EXPRESSION. IN ADDITION, BA TREATMENT SUPPRESSES ERBETA TARGET GENES, INCLUDING SUPEROXIDE DISMUTASE 2 (SOD2), NUCLEAR RESPIRATORY FACTOR-1 (NRF1), CYCLOOXYGENASE 2 (COX2), AND MATRIX METALLOPROTEINASE-1 (MMP1), SUBSEQUENTLY INCREASING OXIDATIVE STRESS, TRIGGERING MITOCHONDRIAL DYSFUNCTION, DECREASING ELEVATED PROINFLAMMATORY CYTOKINES, AND EVENTUALLY SUPPRESSING ENDOMETRIOTIC CELL PROLIFERATION, MIMICKING THE EFFECT OF ERBETA KNOCKDOWN. ON THE OTHER HAND, GAIN OF ERBETA BY LENTIVIRUS INFECTION IN NORMAL ENDOMETRIAL CELLS RESULTED IN INCREASED CELL PROLIFERATION AND PROINFLAMMATORY CYTOKINE RELEASE, WHILE BA TREATMENT DIMINISHED THIS EFFECT THROUGH ERBETA SUPPRESSION WITH SUBSEQUENT OXIDATIVE STRESS AND APOPTOSIS. OUR RESULTS INDICATE THAT ERBETA MAY BE A MAJOR DRIVING FORCE FOR THE DEVELOPMENT OF ENDOMETRIOSIS, WHILE BA INHIBITS ENDOMETRIOSIS THROUGH SPECIFIC SUPPRESSION OF THE ERBETA SIGNALING PATHWAY. THIS STUDY PROVIDES A NOVEL THERAPEUTIC STRATEGY FOR ENDOMETRIOSIS TREATMENT THROUGH BA-MEDIATED ERBETA SUPPRESSION. 2020 2 5239 44 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 3 3667 35 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 4 2668 35 ESTROGEN RECEPTORS AND ENDOMETRIOSIS. ENDOMETRIOSIS IS A FREQUENT AND CHRONIC INFLAMMATORY DISEASE WITH IMPACTS ON REPRODUCTION, HEALTH AND QUALITY OF LIFE. THIS DISORDER IS HIGHLY ESTROGEN-DEPENDENT AND THE PURPOSE OF HORMONAL TREATMENTS IS TO DECREASE THE ENDOGENOUS OVARIAN PRODUCTION OF ESTROGENS. HIGH ESTROGEN PRODUCTION IS A CONSISTENTLY OBSERVED ENDOCRINE FEATURE OF ENDOMETRIOSIS. MRNA AND PROTEIN LEVELS OF ESTROGEN RECEPTORS (ER) ARE DIFFERENT BETWEEN A NORMAL HEALTHY ENDOMETRIUM AND ECTOPIC/EUTOPIC ENDOMETRIAL LESIONS: ENDOMETRIOTIC STROMAL CELLS EXPRESS EXTRAORDINARILY HIGHER ERBETA AND SIGNIFICANTLY LOWER ERALPHA LEVELS COMPARED WITH ENDOMETRIAL STROMAL CELLS. ABERRANT EPIGENETIC REGULATION SUCH AS DNA METHYLATION IN ENDOMETRIOTIC CELLS IS ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF ENDOMETRIOSIS. ALTHOUGH THERE IS A LARGE BODY OF DATA REGARDING ERS IN ENDOMETRIOSIS, OUR UNDERSTANDING OF THE ROLES OF ERALPHA AND ERBETA IN THE PATHOGENESIS OF ENDOMETRIOSIS REMAINS INCOMPLETE. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE LINKS BETWEEN ENDOMETRIOSIS, ERS AND THE RECENT ADVANCES OF TREATMENT STRATEGIES BASED ON ERS MODULATION. WE WILL ALSO ATTEMPT TO SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF ERS AND HOW THIS COULD PAVE THE WAY TO NEW THERAPEUTIC STRATEGIES. 2020 5 978 43 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 6 2575 30 EPIGENETICS OF ESTROGEN AND PROGESTERONE RECEPTORS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY GYNECOLOGICAL DISEASE. INCREASED ESTROGEN ACTIVITY AND PROGESTERONE RESISTANCE ARE THE MAIN HORMONAL SUBSTRATE OF THIS DISEASE AND ARE ASSOCIATED WITH INFLAMMATORY RESPONSE AND DEBILITATING SYMPTOMS, INCLUDING PAIN AND INFERTILITY. ESTROGENS AND PROGESTERONE ACT VIA THEIR SPECIFIC NUCLEAR RECEPTORS. THE REGULATION OF RECEPTOR EXPRESSION BY EPIGENETICS MAYBE A CRITICAL FACTOR FOR ENDOMETRIOSIS. THE PRESENT REVIEW AIMS TO DISCUSS THE EPIGENETIC MECHANISMS RELATED TO THE EXPRESSION OF ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS, INCLUDING TWO CLASSIC EPIGENETIC MECHANISMS: DNA METHYLATION AND HISTONE MODIFICATION, AND, OTHER NON-CLASSIC MECHANISMS: MIRNAS AND LNCRNA. SEVERAL IN VITRO AND IN VIVO STUDIES SUPPORT THE KEY ROLE OF EPIGENETICS IN THE REGULATION OF THE EXPRESSION OF ERS AND PRS, WHICH MAY PROVIDE NEW MOLECULES AND TARGETS FOR THE DIAGNOSIS AND TREATMENT OF ENDOMETRIOSIS. 2020 7 3726 41 INHIBITION OF HISTONE METHYLTRANSFERASE EZH2 SUPPRESSES ENDOMETRIOTIC VESICLE DEVELOPMENT IN A RAT MODEL OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A PAINFUL GYNECOLOGICAL DISEASE WITH NO CURE AND LIMITED THERAPEUTIC OPTIONS. IT HAS BEEN HYPOTHESIZED THAT EPIGENETIC DRUGS CAN BE USED AS A NONHORMONAL TREATMENT FOR ENDOMETRIOSIS. THIS STUDY WAS CONDUCTED TO STUDY THE EFFICACY OF AN INHIBITOR OF THE HISTONE METHYLTRANSFERASE EZH2 USING AN ESTABLISHED RAT MODEL OF ENDOMETRIOSIS. WE HYPOTHESIZED THAT TREATMENT WILL BLOCK OR REDUCE THE NUMBER OF ENDOMETRIOTIC VESICLES IN THIS MODEL. WE CONDUCTED A PRECLINICAL DRUG STUDY IN FEMALE RATS WITH EXPERIMENTAL ENDOMETRIOSIS (UTERINE TISSUE TRANSPLANTED NEXT TO THE INTESTINAL MESENTERY) OR CONTROL SHAM (SUTURES ONLY). RATS WITH ENDOMETRIOSIS OR SHAM SURGERY RECEIVED EITHER TREATMENT WITH EZH2 INHIBITOR (5 MG/KG OR 10 MG/KG) OR VEHICLE (0.1%, 67% DMSO) EVERY OTHER DAY DURING 4 WEEKS. AFTER TREATMENT COMPLETION, THE NUMBER, AREA, VOLUME, AND WEIGHT OF VESICLES WERE EVALUATED. RT [2] PROFILER ARRAYS FOR NEUROPATHIC AND INFLAMMATION, EPITHELIAL TO MESENCHYMAL TRANSITION, INFLAMMATORY RESPONSE, AND AUTOIMMUNITY PATHWAYS WERE USED TO EXAMINE GENE EXPRESSION CHANGES IN THE VESICLES THAT DEVELOPED. TREATMENT WITH EZH2 INHIBITOR (10 MG/KG) SUPPRESSED THE DEVELOPMENT OF VESICLES, BY SIGNIFICANTLY DECREASING THE TOTAL VESICLE NUMBER, AREA, VOLUME, AND WEIGHT. IN ADDITION, EZH2 INHIBITION SIGNIFICANTLY INCREASED THE EXPRESSION OF CACNA1B AND FKBP1A GENES, INVOLVED IN PAIN AND PROLIFERATION, RESPECTIVELY. EZH2 INHIBITION SUPPRESSES THE GROWTH OF VESICLES WITHOUT APPARENT DETRIMENTAL EFFECTS TO OTHER ORGANS. TREATMENT WITH THIS EPIGENETIC INHIBITOR LEADS TO UPREGULATION OF A LIMITED NUMBER OF GENES RELATED TO ENDOMETRIOSIS-RELEVANT PATHWAYS. IN CONCLUSION, THESE DATA SUPPORT FOLLOW-UP STUDIES TO EVALUATE ITS POTENTIAL AS A THERAPEUTIC APPROACH FOR ENDOMETRIOSIS. 2020 8 1202 34 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 9 1891 39 ENDOMETRIOSIS. PELVIC ENDOMETRIOSIS IS A COMPLEX SYNDROME CHARACTERIZED BY AN ESTROGEN-DEPENDENT CHRONIC INFLAMMATORY PROCESS THAT AFFECTS PRIMARILY PELVIC TISSUES, INCLUDING THE OVARIES. IT IS CAUSED WHEN SHED ENDOMETRIAL TISSUE TRAVELS RETROGRADE INTO THE LOWER ABDOMINAL CAVITY. ENDOMETRIOSIS IS THE MOST COMMON CAUSE OF CHRONIC PELVIC PAIN IN WOMEN AND IS ASSOCIATED WITH INFERTILITY. THE UNDERLYING PATHOLOGIC MECHANISMS IN THE INTRACAVITARY ENDOMETRIUM AND EXTRAUTERINE ENDOMETRIOTIC TISSUE INVOLVE DEFECTIVELY PROGRAMMED ENDOMETRIAL MESENCHYMAL PROGENITOR/STEM CELLS. ALTHOUGH ENDOMETRIOTIC STROMAL CELLS, WHICH COMPOSE THE BULK OF ENDOMETRIOTIC LESIONS, DO NOT CARRY SOMATIC MUTATIONS, THEY DEMONSTRATE SPECIFIC EPIGENETIC ABNORMALITIES THAT ALTER EXPRESSION OF KEY TRANSCRIPTION FACTORS. FOR EXAMPLE, GATA-BINDING FACTOR-6 OVEREXPRESSION TRANSFORMS AN ENDOMETRIAL STROMAL CELL TO AN ENDOMETRIOTIC PHENOTYPE, AND STEROIDOGENIC FACTOR-1 OVEREXPRESSION CAUSES EXCESSIVE PRODUCTION OF ESTROGEN, WHICH DRIVES INFLAMMATION VIA PATHOLOGICALLY HIGH LEVELS OF ESTROGEN RECEPTOR-BETA. PROGESTERONE RECEPTOR DEFICIENCY CAUSES PROGESTERONE RESISTANCE. POPULATIONS OF ENDOMETRIAL AND ENDOMETRIOTIC EPITHELIAL CELLS ALSO HARBOR MULTIPLE CANCER DRIVER MUTATIONS, SUCH AS KRAS, WHICH MAY BE ASSOCIATED WITH THE ESTABLISHMENT OF PELVIC ENDOMETRIOSIS OR OVARIAN CANCER. IT IS NOT KNOWN HOW INTERACTIONS BETWEEN EPIGENOMICALLY DEFECTIVE STROMAL CELLS AND THE MUTATED GENES IN EPITHELIAL CELLS CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN IS MANAGED BY SUPPRESSION OF OVULATORY MENSES AND ESTROGEN PRODUCTION, CYCLOOXYGENASE INHIBITORS, AND SURGICAL REMOVAL OF PELVIC LESIONS, AND IN VITRO FERTILIZATION IS FREQUENTLY USED TO OVERCOME INFERTILITY. ALTHOUGH NOVEL TARGETED TREATMENTS ARE BECOMING AVAILABLE, AS ENDOMETRIOSIS PATHOPHYSIOLOGY IS BETTER UNDERSTOOD, PREVENTIVE APPROACHES SUCH AS LONG-TERM OVULATION SUPPRESSION MAY PLAY A CRITICAL ROLE IN THE FUTURE. 2019 10 4284 30 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 11 4310 34 MICRORNAS AND PROGESTERONE RECEPTOR SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY. ENDOMETRIOSIS IS A SIGNIFICANT DISEASE CHARACTERIZED BY INFERTILITY AND PELVIC PAIN IN WHICH ENDOMETRIAL STROMAL AND GLANDULAR TISSUE GROW IN ECTOPIC LOCATIONS. ALTERED RESPONSIVENESS TO PROGESTERONE IS A CONTRIBUTING FACTOR TO ENDOMETRIOSIS PATHOPHYSIOLOGY, BUT THE PRECISE MECHANISMS ARE POORLY UNDERSTOOD. PROGESTERONE RESISTANCE INFLUENCES BOTH THE EUTOPIC AND ECTOPIC (ENDOMETRIOTIC LESION) ENDOMETRIUM. AN INABILITY OF THE EUTOPIC ENDOMETRIUM TO PROPERLY RESPOND TO PROGESTERONE IS BELIEVED TO CONTRIBUTE TO THE INFERTILITY ASSOCIATED WITH THE DISEASE, WHILE AN ALTERED RESPONSIVENESS OF ENDOMETRIOTIC LESION TISSUE MAY CONTRIBUTE TO THE SURVIVAL OF THE ECTOPIC TISSUE AND ASSOCIATED SYMPTOMS. WOMEN WITH ENDOMETRIOSIS EXPRESS ALTERED LEVELS OF SEVERAL ENDOMETRIAL PROGESTERONE TARGET GENES WHICH MAY BE DUE TO THE ABNORMAL EXPRESSION AND/OR FUNCTION OF PROGESTERONE RECEPTORS AND/OR CHAPERONE PROTEINS, AS WELL AS INFLAMMATION, GENETICS, AND EPIGENETICS. MIRNAS ARE A CLASS OF EPIGENETIC MODULATORS PROPOSED TO PLAY A ROLE IN ENDOMETRIOSIS PATHOPHYSIOLOGY, INCLUDING THE MODULATION OF PROGESTERONE SIGNALING. IN THIS PAPER, WE SUMMARIZE THE ROLE OF PROGESTERONE RECEPTORS AND PROGESTERONE SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY, REVIEW MIRNAS, WHICH ARE OVER-EXPRESSED IN ENDOMETRIOSIS TISSUES AND FLUIDS, AND FOLLOW THIS WITH A DISCUSSION ON THE POTENTIAL REGULATION OF KEY PROGESTERONE SIGNALING COMPONENTS BY THESE MIRNAS, CONCLUDING WITH SUGGESTIONS FOR FUTURE RESEARCH ENDEAVORS IN THIS AREA. 2022 12 3795 37 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 13 3061 36 GENOME-WIDE DNA METHYLATION ANALYSIS PREDICTS AN EPIGENETIC SWITCH FOR GATA FACTOR EXPRESSION IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A GYNECOLOGICAL DISEASE DEFINED BY THE EXTRAUTERINE GROWTH OF ENDOMETRIAL-LIKE CELLS THAT CAUSE CHRONIC PAIN AND INFERTILITY. THE DISEASE IS LIMITED TO PRIMATES THAT EXHIBIT SPONTANEOUS DECIDUALIZATION, AND DISEASED CELLS ARE CHARACTERIZED BY SIGNIFICANT DEFECTS IN THE STEROID-DEPENDENT GENETIC PATHWAYS THAT TYPIFY THIS PROCESS. ALTERED DNA METHYLATION MAY UNDERLIE THESE DEFECTS, BUT FEW REGIONS WITH DIFFERENTIAL METHYLATION HAVE BEEN IMPLICATED IN THE DISEASE. WE MAPPED GENOME-WIDE DIFFERENCES IN DNA METHYLATION BETWEEN HEALTHY HUMAN ENDOMETRIAL AND ENDOMETRIOTIC STROMAL CELLS AND CORRELATED THIS WITH GENE EXPRESSION USING AN INTERACTION ANALYSIS STRATEGY. WE IDENTIFIED 42,248 DIFFERENTIALLY METHYLATED CPGS IN ENDOMETRIOSIS COMPARED TO HEALTHY CELLS. THESE EXTENSIVE DIFFERENCES WERE NOT UNIDIRECTIONAL, BUT WERE FOCUSED INTRAGENICALLY AND AT SITES DISTAL TO CLASSIC CPG ISLANDS WHERE METHYLATION STATUS WAS TYPICALLY NEGATIVELY CORRELATED WITH GENE EXPRESSION. SIGNIFICANT DIFFERENCES IN METHYLATION WERE MAPPED TO 403 GENES, WHICH INCLUDED A DISPROPORTIONALLY LARGE NUMBER OF TRANSCRIPTION FACTORS. FURTHERMORE, MANY OF THESE GENES ARE IMPLICATED IN THE PATHOLOGY OF ENDOMETRIOSIS AND DECIDUALIZATION. OUR RESULTS TREMENDOUSLY IMPROVE THE SCOPE AND RESOLUTION OF DIFFERENTIAL METHYLATION AFFECTING THE HOX GENE CLUSTERS, NUCLEAR RECEPTOR GENES, AND INTRIGUINGLY THE GATA FAMILY OF TRANSCRIPTION FACTORS. FUNCTIONAL ANALYSIS OF THE GATA FAMILY REVEALED THAT GATA2 REGULATES KEY GENES NECESSARY FOR THE HORMONE-DRIVEN DIFFERENTIATION OF HEALTHY STROMAL CELLS, BUT IS HYPERMETHYLATED AND REPRESSED IN ENDOMETRIOTIC CELLS. GATA6, WHICH IS HYPOMETHYLATED AND ABUNDANT IN ENDOMETRIOTIC CELLS, POTENTLY BLOCKED HORMONE SENSITIVITY, REPRESSED GATA2, AND INDUCED MARKERS OF ENDOMETRIOSIS WHEN EXPRESSED IN HEALTHY ENDOMETRIAL CELLS. THE UNIQUE EPIGENETIC FINGERPRINT IN ENDOMETRIOSIS SUGGESTS DNA METHYLATION IS AN INTEGRAL COMPONENT OF THE DISEASE, AND IDENTIFIES A NOVEL ROLE FOR THE GATA FAMILY AS KEY REGULATORS OF UTERINE PHYSIOLOGY-ABERRANT DNA METHYLATION IN ENDOMETRIOTIC CELLS CORRELATES WITH A SHIFT IN GATA ISOFORM EXPRESSION THAT FACILITATES PROGESTERONE RESISTANCE AND DISEASE PROGRESSION. 2014 14 2228 32 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 15 5754 23 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 16 898 36 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 17 4129 27 MECHANISMS OF ENDOMETRIAL PROGESTERONE RESISTANCE. THROUGHOUT THE REPRODUCTIVE YEARS, THE RISE AND FALL IN OVARIAN HORMONES ELICIT IN THE ENDOMETRIUM WAVES OF CELL PROLIFERATION, DIFFERENTIATION, RECRUITMENT OF INFLAMMATORY CELLS, APOPTOSIS, TISSUE BREAKDOWN AND REGENERATION. THE ACTIVATED PROGESTERONE RECEPTOR, A MEMBER OF THE SUPERFAMILY OF LIGAND-DEPENDENT TRANSCRIPTION FACTORS, IS THE MASTER REGULATOR OF THIS INTENSE TISSUE REMODELLING PROCESS IN THE UTERUS. ITS ACTIVITY IS TIGHTLY REGULATED BY INTERACTION WITH CELL-SPECIFIC TRANSCRIPTION FACTORS AND COREGULATORS AS WELL AS BY SPECIFIC POSTTRANSLATIONAL MODIFICATIONS THAT RESPOND DYNAMICALLY TO A VARIETY OF ENVIRONMENTAL AND INFLAMMATORY SIGNALS. ENDOMETRIOSIS, A CHRONIC INFLAMMATORY DISORDER, DISRUPTS COORDINATED PROGESTERONE RESPONSES THROUGHOUT THE REPRODUCTIVE TRACT, INCLUDING IN THE ENDOMETRIUM. THIS PHENOMENON IS INCREASINGLY REFERRED TO AS 'PROGESTERONE RESISTANCE'. EMERGING EVIDENCE SUGGESTS THAT PROGESTERONE RESISTANCE IN ENDOMETRIOSIS IS NOT JUST A CONSEQUENCE OF PERTURBED PROGESTERONE SIGNAL TRANSDUCTION CAUSED BY CHRONIC INFLAMMATION BUT ASSOCIATED WITH EPIGENETIC CHROMATIN CHANGES THAT DETERMINE THE INTRINSIC RESPONSIVENESS OF ENDOMETRIAL CELLS TO DIFFERENTIATION CUES. 2012 18 3047 37 GENOME-WIDE ANALYSIS OF DNA METHYLATION IN ENDOMETRIOSIS USING ILLUMINA HUMAN METHYLATION 450 K BEADCHIPS. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGIC DISORDER CHARACTERIZED BY THE PRESENCE AND GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE OF THE UTERINE CAVITY. ALTHOUGH THE EXACT ETIOLOGY REMAINS UNCLEAR, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE THOUGHT TO CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. HERE, WE USED THE ILLUMINA HUMAN METHYLATION 450 K BEADCHIP ARRAY TO ANALYZE THE GENOME-WIDE DNA METHYLATION PROFILES OF SIX ENDOMETRIOTIC LESIONS AND SIX EUTOPIC ENDOMETRIA FROM PATIENTS WITH OVARIAN ENDOMETRIOSIS AND SIX ENDOMETRIA OF WOMEN WITHOUT ENDOMETRIOSIS. COMPARED WITH THE EUTOPIC ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS, 12,159 DIFFERENTIALLY METHYLATED CPG SITES AND 375 DIFFERENTIALLY METHYLATED PROMOTER REGIONS WERE IDENTIFIED IN ENDOMETRIOTIC LESIONS. GO ANALYSES SHOWED THAT THESE PUTATIVE DIFFERENTIALLY METHYLATED GENES WERE PRIMARILY ASSOCIATED WITH IMMUNE RESPONSE, INFLAMMATORY RESPONSE, RESPONSE TO STEROID HORMONE STIMULUS, CELL ADHESION, NEGATIVE REGULATION OF APOPTOSIS, AND ACTIVATION OF THE MAPK ACTIVITY. IN ADDITION, THE EXPRESSION LEVELS OF DNMT1, DNMT3A, DNMT3B, AND MBD2 IN ENDOMETRIOTIC LESIONS AND EUTOPIC ENDOMETRIA WERE SIGNIFICANTLY DECREASED COMPARED WITH CONTROL ENDOMETRIA. OUR FINDINGS SUGGEST THAT ABERRANT DNA METHYLATION STATUS IN ENDOMETRIOTIC LESIONS MAY PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS AND PROGRESSION OF ENDOMETRIOSIS. 2019 19 476 42 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 20 2602 38 EPIGENETICS, ENDOMETRIOSIS AND SEX STEROID RECEPTORS: AN UPDATE ON THE EPIGENETIC REGULATORY MECHANISMS OF ESTROGEN AND PROGESTERONE RECEPTORS IN PATIENTS WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS A BENIGN GYNECOLOGICAL DISEASE AFFECTING APPROXIMATELY 10% OF REPRODUCTIVE-AGED WOMEN AND IS DEFINED AS THE PRESENCE OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. ENDOMETRIOSIS CAN CAUSE A VARIETY OF HEALTH PROBLEMS, FROM PELVIC DISCOMFORT TO CATAMENIAL PNEUMOTHORAX, BUT IT'S MAINLY LINKED WITH SEVERE AND CHRONIC PELVIC PAIN, DYSMENORRHEA, AND DEEP DYSPAREUNIA, AS WELL AS REPRODUCTIVE ISSUES. THE PATHOGENESIS OF ENDOMETRIOSIS INVOLVES AN ENDOCRINE DYSFUNCTION, WITH ESTROGEN DEPENDENCY AND PROGESTERONE RESISTANCE, AND INFLAMMATORY MECHANISM ACTIVATION, TOGETHER WITH IMPAIRED CELL PROLIFERATION AND NEUROANGIOGENESIS. THE PRESENT CHAPTER AIMS TO DISCUSS THE MAIN EPIGENETIC MECHANISMS RELATED TO ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS. THERE ARE NUMEROUS EPIGENETIC MECHANISMS PARTICIPATING IN ENDOMETRIOSIS, REGULATING THE EXPRESSION OF THE GENES ENCODING THESE RECEPTORS BOTH INDIRECTLY, THROUGH THE REGULATION OF TRANSCRIPTION FACTORS, AND DIRECTLY, THROUGH DNA METHYLATION, HISTONE MODIFICATIONS, MICRO RNAS AND LONG NONCODING RNAS. THIS REPRESENTS AN OPEN FIELD OF INVESTIGATION, WHICH MAY LEAD TO IMPORTANT CLINICAL IMPLICATIONS SUCH AS THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF ENDOMETRIOSIS AND THE IDENTIFICATION OF SPECIFIC AND EARLY BIOMARKERS FOR THE DISEASE. 2023