1 334 111 ALTERATIONS IN DEOXYRIBONUCLEIC ACID (DNA) METHYLATION PATTERNS OF CALCA, TIMP3, MMP2, AND IGF2R ARE ASSOCIATED WITH CHRONIC CYSTITIS IN A CYCLOPHOSPHAMIDE-INDUCED MOUSE MODEL. OBJECTIVE: TO DETERMINE WHETHER EPIGENETIC CHANGES OCCUR DURING CYCLOPHOSPHAMIDE-INDUCED CHRONIC BLADDER INFLAMMATION IN MICE. MATERIALS AND METHODS: EPIGENETIC CHANGES PLAY A ROLE IN THE REGULATION OF INFLAMMATORY GENES IN NONCANCER DISEASES SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, EPIGENETIC (DEOXYRIBONUCLEIC ACID [DNA] METHYLATION) CHANGES DURING CHRONIC BLADDER INFLAMMATION HAVE NOT BEEN PREVIOUSLY DESCRIBED. CHRONIC CYSTITIS WAS INDUCED IN 3 GROUPS OF ADULT CD-1 MALE MICE USING MULTIPLE WEIGHT-BASED INTRAPERITONEAL CYCLOPHOSPHAMIDE INJECTIONS DURING A 3-MONTH PERIOD. HISTOPATHOLOGIC AND METHYLIGHT ASSAYS WERE PERFORMED ON SPECIMENS WITH CHRONIC BLADDER INFLAMMATION AT MULTIPLE POINTS TO MONITOR CYSTITIS PROGRESSION AND DNA METHYLATION CHANGES COMPARED WITH THE CONTROL SPECIMENS. RESULTS: HISTOPATHOLOGIC ANALYSIS SHOWED THE MOST EXTENSIVE EDEMA AND UROTHELIAL SLOUGHING AT THE 1-MONTH POINT. METHYLIGHT ANALYSES REVEALED STATISTICALLY SIGNIFICANT CHANGES IN DNA METHYLATION ASSOCIATED WITH THE CALCA, TIMP3, MMP2, AND IGF2R GENES IN THE CHRONIC BLADDER INJURY MODEL. THE CHANGES IN DNA METHYLATION ASSOCIATED WITH CHRONIC CYSTITIS WERE DNA HYPOMETHYLATION OF THE CALCA GENE IN THE CONTROL TISSUE AND DNA HYPERMETHYLATION FOR THE CALCA, TIMP3, MMP2, AND IGF2R GENES COMPARED WITH THAT IN THE CONTROL TISSUE. CONCLUSION: DNA METHYLATION CHANGES WERE NOTED IN THE CALCA, TIMP3, MMP2, AND IGF2R GENES DURING CHRONIC CYSTITIS IN A MURINE MODEL. EPIGENETIC CHANGES APPEAR TO PLAY A ROLE IN THE REGULATION OF INFLAMMATORY BLADDER GENES DURING CHRONIC CYSTITIS; HOWEVER, ADDITIONAL STUDIES ARE NEEDED TO ELUCIDATE THE PATHWAYS ASSOCIATED WITH THESE GENES. 2013 2 2403 34 EPIGENETIC REPROGRAMMING: A POSSIBLE ETIOLOGICAL FACTOR IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS? PURPOSE: THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS IS POORLY UNDERSTOOD. THE POSSIBILITY THAT EPIGENETIC REPROGRAMMING MAY HAVE A ROLE IS DISCUSSED. MATERIALS AND METHODS: A LITERATURE SEARCH WAS PERFORMED WITH THE ENTREZ-PUBMED(R) DATABASE USING THE KEY WORDS URINARY BLADDER, EPIGENETICS, EPIGENETIC MECHANISMS, INTERSTITIAL CYSTITIS, DIAGNOSIS, ETIOLOGY, UROTHELIAL CELLS, MAST CELLS, NERVE FIBERS, NERVES, NERVE GROWTH FACTOR, RECURRENT INJURY, STEM CELLS, INFLAMMATORY MEDIATORS AND DEMETHYLASES. RESULTS: THE UROEPITHELIUM IS INTIMATELY ASSOCIATED WITH THE NERVOUS SYSTEM. SENSORY INPUT AT THE APICAL SURFACE OF UMBRELLA CELLS REGULATES BLADDER FUNCTION VIA A TRANSMURAL SIGNALING PATHWAY. WHEN UMBRELLA CELLS ARE SHED IN RESPONSE TO NOXIOUS STIMULI, STEM CELLS IN THE BASAL LAYER BECOME EXPOSED. THE POLYCOMB GROUP GENES ARE KEY IN THE MAINTENANCE OF ADULT STEM CELLS. THE POLYCOMB GROUP GENES MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION BY METHYLATING LYSINE 27 OF HISTONE H3 (H3K27ME3). JMJD3, AN ENZYME DEMETHYLATING H3K27ME3, ANTAGONIZES POLYCOMB GROUP GENES MEDIATED SILENCING. INFLAMMATORY STIMULI ARE STRONG INDUCERS OF JMJD3 AND MAY REVERSE GENE SILENCING IN STEM CELLS, MODIFYING THE DIFFERENTIATION PATTERN. EPIGENETIC PROCESSES INVOLVING H3K27 METHYLATION ARE MULTISTABLE PROCESSES. TRANSIENT SIGNALING, EG BY LIPOPOLYSACCHARIDE, TRIGGERS EPIGENETIC REPROGRAMMING AND ESTABLISHES ONE OF THE ALTERNATIVE REGULATORY STATES. ONCE ESTABLISHED SUCH STATES CAN BE MAINTAINED AND PROPAGATED EVEN IN THE ABSENCE OF THE INITIAL SIGNAL. CONCLUSIONS: WE POSTULATE THAT SIMILAR EPIGENETIC REPROGRAMMING MECHANISMS IN THE BLADDER MAY PROVIDE AN EXPLANATION FOR UROEPITHELIAL, MAST CELLS AND NERVE CELL ABNORMALITIES IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS, AS WELL AS PROPAGATION OF THIS ALTERED STATE IN THE ABSENCE OF THE SIGNAL THAT MAY HAVE TRIGGERED IT. IT ALSO PROVIDES A NEW EXPERIMENTAL PARADIGM FOR EXPLORING THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. DATA SUPPORTING THIS HYPOTHESIS WOULD PROVIDE A RATIONALE FOR NEW DIAGNOSTIC AS WELL AS TREATMENT OPTIONS FOR BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. 2009 3 6837 25 [INTERSTITIAL CYSTITIS: THE LATEST FINDINGS ON ITS AETIOPATHOGENESIS]. NEW FINDINGS PROVIDE PROGRESS IN THE UNDERSTANDING OF THE COMPLICATED AETIOPATHOGENESIS OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS), WHOSE CAUSALITIES HAVE ONLY BEEN DECIPHERED IN FRAGMENTS SO FAR. AN INCREASINGLY COMPLEX NETWORK OF PATHOMECHANISMS IS EMERGING, IN WHICH THE FREQUENTLY MENTIONED MAST CELLS AND UROTHELIAL CHANGES SEEM TO BE ONLY A FRAGMENT OF THE PATHOLOGICAL CHANGES. THE LATEST FINDINGS REGARDING A POSSIBLE GENETIC AND EPIGENETIC PREDISPOSITION ARE BASED ON PEDIGREE ANALYSES, DETECTION OF SINGLE NUCLEOTIDE POLYMORPHISMS AND SIGNIFICANT CHANGES IN DIFFERENTIALLY EXPRESSED GENES. MULTIPLE ALTERATIONS CAN BE DETECTED AT THE MOLECULAR LEVEL. PLATELET-ACTIVATING FACTOR, VEGF, CORTICOTROPIN-RELEASING HORMONE AND THE INFLAMMASOME ARE IMPORTANT PLAYERS IN UNDERSTANDING THE DISEASE, BUT THE PATHOMECHANISM UNDERLYING THE "ACTIVATION" OF IC REMAINS UNCLEAR. NEW STARTING POINTS COULD BE THE DETECTION OF VIRUSES (EPSTEIN-BARR VIRUS, BK POLYOMAVIRUSES) OR BACTERIAL INFLAMMATION BY PATHOGENS THAT CANNOT BE DETECTED IN STANDARD CULTURES. 2021 4 329 28 ALPHA-OXOGLUTARATE INHIBITS THE PROLIFERATION OF IMMORTALIZED NORMAL BLADDER EPITHELIAL CELLS VIA AN EPIGENETIC SWITCH INVOLVING ARID1A. INTERSTITIAL CYSTITIS (IC) IS A CHRONIC URINARY TRACT DISEASE THAT IS CHARACTERIZED BY UNPLEASANT SENSATIONS, SUCH AS PERSISTENT PELVIC PAIN, IN THE ABSENCE OF INFECTION OR OTHER IDENTIFIABLE CAUSES. WE PREVIOUSLY PERFORMED COMPREHENSIVE METABOLOMICS PROFILING OF URINE SAMPLES FROM IC PATIENTS USING NUCLEAR MAGNETIC RESONANCE AND GAS-CHROMATOGRAPHY/MASS SPECTROMETRY AND FOUND THAT URINARY ALPHA-OXOGLUTARATE (ALPHA-OG), WAS SIGNIFICANTLY ELEVATED. ALPHA-OG, A TRICARBOXYLIC ACID (TCA) CYCLE INTERMEDIATE, REPORTEDLY FUNCTIONS TO SUPPRESS THE PROLIFERATION OF IMMORTALIZED NORMAL HUMAN BLADDER EPITHELIAL CELLS. HERE, WE IDENTIFIED AT-RICH INTERACTIVE DOMAIN 1 A (ARID1A), A KEY CHROMATIN REMODELER, AS BEING HYPOMETHYLATED AND UPREGULATED BY ALPHA-OG TREATMENT. THIS WAS DONE THROUGH EPIC DNA METHYLATION PROFILING AND SUBSEQUENT BIOCHEMICAL APPROACHES, INCLUDING QUANTITATIVE RT-PCR AND WESTERN BLOT ANALYSES. FURTHERMORE, WE FOUND THAT ALPHA-OG ALMOST COMPLETELY SUPPRESSES TEN-ELEVEN TRANSLOCATION (TET) ACTIVITY, BUT DOES NOT AFFECT DNA METHYLTRANSFERASE (DNMT) ACTIVITY. ALTOGETHER, OUR STUDIES REVEAL THE POTENTIAL ROLE OF ALPHA-OG IN EPIGENETIC REMODELING THROUGH ITS EFFECTS ON ARID1A AND TET EXPRESSION IN THE BLADDER. THIS MAY PROVIDE A NEW POSSIBLE THERAPEUTIC STRATEGY IN TREATING IC. 2018 5 6671 26 UROPATHOGENIC ESCHERICHIA COLI INFECTION-INDUCED EPITHELIAL TRAINED IMMUNITY IMPACTS URINARY TRACT DISEASE OUTCOME. PREVIOUS URINARY TRACT INFECTIONS (UTIS) CAN PREDISPOSE ONE TO FUTURE INFECTIONS; HOWEVER, THE UNDERLYING MECHANISMS AFFECTING RECURRENCE ARE POORLY UNDERSTOOD. WE PREVIOUSLY FOUND THAT UTIS IN MICE CAUSE DIFFERENTIAL BLADDER EPITHELIAL (UROTHELIAL) REMODELLING, DEPENDING ON DISEASE OUTCOME, THAT IMPACTS SUSCEPTIBILITY TO RECURRENT UTI. HERE WE COMPARED UROTHELIAL STEM CELL (USC) LINES ISOLATED FROM MICE WITH A HISTORY OF EITHER RESOLVED OR CHRONIC UROPATHOGENIC ESCHERICHIA COLI (UPEC) INFECTION, ELUCIDATING EVIDENCE OF MOLECULAR IMPRINTING THAT INVOLVED EPIGENETIC CHANGES, INCLUDING DIFFERENCES IN CHROMATIN ACCESSIBILITY, DNA METHYLATION AND HISTONE MODIFICATION. EPIGENETIC MARKS IN USCS FROM CHRONICALLY INFECTED MICE ENHANCED CASPASE-1-MEDIATED CELL DEATH UPON UPEC INFECTION, PROMOTING BACTERIAL CLEARANCE. INCREASED PTGS2OS2 EXPRESSION ALSO OCCURRED, POTENTIALLY CONTRIBUTING TO SUSTAINED CYCLOOXYGENASE-2 EXPRESSION, BLADDER INFLAMMATION AND MUCOSAL WOUNDING-RESPONSES ASSOCIATED WITH SEVERE RECURRENT CYSTITIS. THUS, UPEC INFECTION ACTS AS AN EPI-MUTAGEN REPROGRAMMING THE UROTHELIAL EPIGENOME, LEADING TO UROTHELIAL-INTRINSIC REMODELLING AND TRAINING OF THE INNATE RESPONSE TO SUBSEQUENT INFECTION. 2023 6 5949 18 TARGETING THE PRC2-DEPENDENT EPIGENETIC PROGRAM ALLEVIATES URINARY TRACT INFECTIONS. URINARY TRACT INFECTION (UTI) IS A PERVASIVE HEALTH PROBLEM WORLDWIDE. PATIENTS WITH A HISTORY OF UTIS SUFFER INCREASED RISK OF RECURRENT INFECTIONS, A MAJOR RISK OF ANTIBIOTIC RESISTANCE. HERE, WE SHOW THAT BLADDER INFECTIONS INDUCE EXPRESSION OF EZH2 IN BLADDER UROTHELIAL CELLS. EZH2 IS THE METHYLTRANSFERASE OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2)-A POTENT EPIGENETIC REGULATOR. UROTHELIUM-SPECIFIC INACTIVATION OF PRC2 RESULTS IN REDUCED URINE BACTERIAL BURDEN, MUTED INFLAMMATORY RESPONSE, AND DECREASED ACTIVITY OF THE NF-KAPPAB SIGNALING PATHWAY. PRC2 INACTIVATION ALSO FACILITATES PROPER REGENERATION AFTER UROTHELIAL DAMAGE FROM UTIS, BY ATTENUATING BASAL CELL HYPERPLASIA AND INCREASING UROTHELIAL DIFFERENTIATION. IN ADDITION, TREATMENT WITH EZH2-SPECIFIC SMALL-MOLECULE INHIBITORS IMPROVES OUTCOMES OF THE CHRONIC AND SEVERE BLADDER INFECTIONS IN MICE. THESE FINDINGS COLLECTIVELY SUGGEST THAT THE PRC2-DEPENDENT EPIGENETIC REPROGRAMING CONTROLS THE AMPLITUDE OF INFLAMMATION AND SEVERITY OF UTIS AND THAT EZH2 INHIBITORS MAY BE A VIABLE NON-ANTIBIOTIC STRATEGY TO MANAGE CHRONIC AND SEVERE UTIS. 2023 7 1363 24 DEVELOPMENTAL INFLUENCES ON MEDICALLY UNEXPLAINED SYMPTOMS. BACKGROUND: MEDICALLY UNEXPLAINED (OR 'FUNCTIONAL') SYMPTOMS (MUS) ARE PHYSICAL SYMPTOMS THAT PROMPT THE SUFFERER TO SEEK HEALTHCARE BUT REMAIN UNEXPLAINED AFTER AN APPROPRIATE MEDICAL EVALUATION. EXAMPLES OF MUS ALSO OCCUR IN VETERINARY MEDICINE. FOR EXAMPLE, DOMESTIC CATS SUFFER A SYNDROME COMPARABLE TO INTERSTITIAL CYSTITIS, A CHRONIC PELVIC PAIN SYNDROME OF HUMANS. METHOD: REVIEW OF CURRENT EVIDENCE SUGGESTS THE HYPOTHESIS THAT DEVELOPMENTAL FACTORS MAY PLAY A ROLE IN SOME CASES OF MUS. MATERNAL PERCEPTION OF A THREATENING ENVIRONMENT MAY BE TRANSMITTED TO THE FETUS WHEN HORMONES CROSS THE PLACENTA AND AFFECT FETAL PHYSIOLOGY, EFFECTIVELY 'PROGRAMMING' THE FETAL STRESS RESPONSE SYSTEM AND ASSOCIATED BEHAVIORS TOWARD ENHANCED VIGILANCE. AFTER BIRTH, INTENSE STRESS RESPONSES IN THE INDIVIDUAL MAY RESULT IN SIMILAR VULNERABILITY, WHICH MAY BE UNMASKED BY SUBSEQUENT STRESSORS. RESULTS: EPIGENETIC MODULATION OF GENE EXPRESSION (EMGEX) APPEARS TO PLAY A CENTRAL ROLE IN CREATION OF THIS 'SURVIVAL PHENOTYPE'. THE RECENT DEVELOPMENT OF TECHNIQUES TO IDENTIFY THE PRESENCE OF EMGEX PROVIDES NEW TOOLS TO INVESTIGATE THESE QUESTIONS, AND DRUGS AND OTHER INTERVENTIONS THAT MAY REVERSE EMGEX ARE ALSO UNDER ACTIVE INVESTIGATION. CONCLUSION: VIEWING MUS FROM THE PERSPECTIVE OF UNDERLYING DEVELOPMENTAL INFLUENCES INVOLVING EMGEX THAT AFFECT FUNCTION OF A VARIETY OF ORGANS BASED ON FAMILIAL (GENETIC AND ENVIRONMENTAL) PREDISPOSITIONS RATHER THAN FROM THE TRADITIONAL VIEWPOINT OF ISOLATED ORGAN-ORIGINATING DISEASES HAS AT LEAST TWO IMPORTANT IMPLICATIONS: IT PROVIDES A PARSIMONIOUS EXPLANATION FOR FINDINGS HERETOFORE DIFFICULT TO RECONCILE, AND IT OPENS WHOLE NEW AREAS OF INVESTIGATION INTO CAUSES AND TREATMENTS FOR THIS CLASS OF DISORDERS. 2009 8 4616 18 NERVE INJURY INCREASES BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS TO SUPPRESS BK CHANNEL ACTIVITY IN PRIMARY SENSORY NEURONS. ABNORMAL HYPEREXCITABILITY OF PRIMARY SENSORY NEURONS CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT AFTER NERVE INJURY. NERVE INJURY PROFOUNDLY REDUCES THE EXPRESSION OF BIG CONDUCTANCE CA(2+) -ACTIVATED K(+) (BK) CHANNELS IN THE DORSAL ROOT GANGLION (DRG). HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY AFFECTS BK CHANNEL ACTIVITY IN DRG NEURONS. IN THIS STUDY, WE DETERMINED THE CHANGES IN BK CHANNEL ACTIVITY IN DRG NEURONS IN A RAT MODEL OF NEUROPATHIC PAIN AND THE CONTRIBUTION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) TO REDUCED BK CHANNEL ACTIVITY. THE BK CHANNEL ACTIVITY WAS PRESENT PREDOMINANTLY IN SMALL AND MEDIUM DRG NEURONS, AND LIGATION OF L5 AND L6 SPINAL NERVES PROFOUNDLY DECREASED THE BK CURRENT DENSITY IN THESE NEURONS. BLOCKING BK CHANNELS SIGNIFICANTLY INCREASED NEURONAL EXCITABILITY IN SHAM CONTROL, BUT NOT IN NERVE-INJURED, RATS. THE BDNF CONCENTRATION IN THE DRG WAS SIGNIFICANTLY GREATER IN NERVE-INJURED RATS THAN IN CONTROL RATS. BDNF TREATMENT LARGELY REDUCED BK CURRENTS IN DRG NEURONS IN CONTROL RATS, WHICH WAS BLOCKED BY EITHER ANTI-BDNF ANTIBODY OR K252A, A TRK RECEPTOR INHIBITOR. FURTHERMORE, EITHER ANTI-BDNF ANTIBODY OR K252A REVERSED REDUCTION IN BK CURRENTS IN INJURED DRG NEURONS. BDNF TREATMENT REDUCED THE MRNA LEVELS OF BKALPHA1 SUBUNIT IN DRG NEURONS, AND ANTI-BDNF ANTIBODY ATTENUATED THE REDUCTION IN THE BKALPHA1 MRNA LEVEL IN INJURED DRG NEURONS. THESE FINDINGS SUGGEST THAT NERVE INJURY PRIMARILY DIMINISHES THE BK CHANNEL ACTIVITY IN SMALL AND MEDIUM DRG NEURONS. INCREASED BDNF LEVELS CONTRIBUTE TO REDUCED BK CHANNEL ACTIVITY IN DRG NEURONS THROUGH EPIGENETIC AND TRANSCRIPTIONAL MECHANISMS IN NEUROPATHIC PAIN. 2012 9 236 19 ADENOMYOSIS: MECHANISMS AND PATHOGENESIS. ADENOMYOSIS IS A COMMON DISORDER OF THE UTERUS, AND IS ASSOCIATED WITH AN ENLARGED UTERUS, HEAVY MENSTRUAL BLEEDING (HMB), PELVIC PAIN, AND INFERTILITY. IT IS CHARACTERIZED BY ENDOMETRIAL EPITHELIAL CELLS AND STROMAL FIBROBLASTS ABNORMALLY FOUND IN THE MYOMETRIUM WHERE THEY ELICIT HYPERPLASIA AND HYPERTROPHY OF SURROUNDING SMOOTH MUSCLE CELLS. WHILE BOTH THE MECHANISTIC PROCESSES AND THE PATHOGENESIS OF ADENOMYOSIS ARE UNCERTAIN, SEVERAL THEORIES HAVE BEEN PUT FORWARD ADDRESSING HOW THIS DISEASE DEVELOPS. THESE INCLUDE INTRINSIC OR INDUCED (1) MICROTRAUMA OF THE ENDOMETRIAL-MYOMETRIAL INTERFACE; (2) ENHANCED INVASION OF ENDOMETRIUM INTO MYOMETRIUM; (3) METAPLASIA OF STEM CELLS IN MYOMETRIUM; (4) INFILTRATION OF ENDOMETRIAL CELLS IN RETROGRADE MENSTRUAL EFFLUENT INTO THE UTERINE WALL FROM THE SEROSAL SIDE; (5) INDUCTION OF ADENOMYOTIC LESIONS BY ABERRANT LOCAL STEROID AND PITUITARY HORMONES; AND (6) ABNORMAL UTERINE DEVELOPMENT IN RESPONSE TO GENETIC AND EPIGENETIC MODIFICATIONS. DYSMENORRHEA, HMB, AND INFERTILITY ARE LIKELY RESULTS OF INFLAMMATION, NEUROGENESIS, ANGIOGENESIS, AND CONTRACTILE ABNORMALITIES IN THE ENDOMETRIAL AND MYOMETRIAL COMPONENTS. ELUCIDATING MECHANISMS UNDERLYING THE PATHOGENESIS OF ADENOMYOSIS RAISE POSSIBILITIES TO DEVELOP TARGETED THERAPIES TO AMELIORATE SYMPTOMS BEYOND THE CURRENT AGENTS THAT ARE LARGELY INEFFECTIVE. HEREIN, WE ADDRESS THESE POSSIBLE ETIOLOGIES AND DATA THAT SUPPORT UNDERLYING MECHANISMS. 2020 10 3983 36 LONG-TERM EXPOSURE TO CIGARETTE SMOKE EXTRACT INDUCES HYPOMETHYLATION AT THE RUNX3 AND IGF2-H19 LOCI IN IMMORTALIZED HUMAN UROTHELIAL CELLS. CIGARETTE SMOKING IS THE SINGLE MOST IMPORTANT EPIDEMIOLOGICAL RISK FACTOR FOR BLADDER CANCER BUT IT IS NOT KNOWN WHETHER EXPOSURE OF UROTHELIAL CELLS TO THE SYSTEMIC SOLUBLE CONTENTS OF CIGARETTE SMOKE IS DIRECTLY CAUSATIVE TO BLADDER CANCER AND THE ASSOCIATED EPIGENETIC CHANGES SUCH AS TUMOR SUPPRESSOR GENE HYPERMETHYLATION. WE UNDERTOOK THIS STUDY TO INVESTIGATE IF LONG-TERM TREATMENT OF HUMAN UROTHELIAL CELLS WITH CIGARETTE SMOKE EXTRACT (CSE) RESULTS IN TUMOR SUPPRESSOR GENE HYPERMETHYLATION, A PHENOTYPE THAT WAS PREVIOUSLY ASSOCIATED WITH LONG-TERM CONSTANT CSE TREATMENT OF AIRWAY EPITHELIAL CELLS. WE CHRONICALLY TREATED AN IMMORTALIZED HUMAN UROTHELIAL CELL LINE UROTSA WITH CSE USING A CYCLIC DAILY REGIMEN BUT THE CELLS WERE CULTURED IN CSE-FREE MEDIUM BETWEEN DAILY TREATMENTS. BISULFITE SEQUENCING AND REAL-TIME PCR ARRAY-BASED METHYLATION PROFILING WERE EMPLOYED TO EVALUATE METHYLATION CHANGES AT TUMOR SUPPRESSOR GENE LOCI IN THE CHRONICALLY CSE-TREATED CELLS VERSUS THE PASSAGE-MATCHED UNTREATED CONTROL CELLS. THE RUNX3 TUMOR SUPPRESSOR GENE PROMOTER WAS HYPOMETHYLATED WITH A SIGNIFICANT INCREASE IN PROPORTION OF THE COMPLETELY UNMETHYLATED HAPLOTYPE AFTER THE LONG-TERM CSE TREATMENT; WHEREAS RUNX3 PROMOTER HYPERMETHYLATION WAS PREVIOUSLY REPORTED FOR BLADDER CANCERS OF SMOKERS. HYPOMETHYLATION INDUCED BY THE LONG-TERM CSE TREATMENT WAS ALSO OBSERVED FOR THE IGF2-H19 LOCUS. THE METHYLATION STATUS AT THE PRSS8/PROSTASIN AND 16 ADDITIONAL LOCI HOWEVER, WAS UNAFFECTED BY THE CHRONIC CSE TREATMENT. TRANSIENT CSE TREATMENT OVER 1 DAILY REGIMEN RESULTED IN TRANSCRIPTIONAL DOWN-REGULATION OF RUNX3 AND H19, BUT ONLY THE H19 TRANSCRIPTION WAS DOWN-REGULATED IN THE CHRONICALLY CSE-TREATED UROTHELIAL CELLS. TRANSCRIPTION OF A KEY ENZYME IN ONE-CARBON METABOLISM, DIHYDROFOLATE REDUCTASE (DHFR) WAS GREATLY REDUCED BY THE LONG-TERM CSE TREATMENT, POTENTIALLY SERVING AS A MECHANISM FOR THE HYPOMETHYLATION PHENOTYPE VIA A REDUCED SUPPLY OF METHYL DONOR. IN CONCLUSION, CHRONIC CYCLIC CSE TREATMENT OF UROTHELIAL CELLS INDUCED HYPOMETHYLATION RATHER THAN HYPERMETHYLATION AT SPECIFIC LOCI. 2013 11 4428 25 MOLECULAR BASIS OF THE IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER CHARACTERIZED BY ABDOMINAL PAIN, DISCOMFORT AND BLOATING. THE PATHOPHYSIOLOGY OF IBS IS POORLY UNDERSTOOD, BUT THE PRESENCE OF PSYCHOSOCIAL BASIS IS NOW KNOWN. THERE IS AN INCREASING NUMBER OF PUBLICATIONS SUPPORTING THE ROLE OF GENETICS IN IBS. MOST OF THE VARIATIONS ARE FOUND IN GENES ASSOCIATED WITH THE BRAIN-GUT AXIS, REVEALING THE STRONG CORRELATION OF BRAIN-GUT AXIS AND IBS. MIRNAS, WHICH PLAY CRITICAL ROLES IN PHYSIOLOGICAL PROCESSES, ARE NOT WELL STUDIED IN IBS. HOWEVER, SO FAR THERE IS FOUND AN INVOLVEMENT OF ALTERATIONS IN MIRNA EXPRESSION OR SEQUENCE, IN IBS SYMPTOMS. IBS PHENOTYPE IS AFFECTED BY EPIGENETIC ALTERATION AND ENVIRONMENT. CHANGES IN DNA AND HISTONE METHYLATION ARE OBSERVED IN PATIENTS WHO SUFFERED CHILDHOOD TRAUMA OR ABUSE, RESULTING IN ALTERED GENE EXPRESSION, SUCH AS THE GLUCOCORTICOID RECEPTOR GENE. FINALLY, DIET IS ANOTHER FACTOR ASSOCIATED WITH IBS, WHICH MAY CONTRIBUTE TO SYMPTOM ONSET. CERTAIN FOODS MAY AFFECT ON BACTERIAL METABOLISM AND EPIGENETIC MODIFICATIONS, PREDISPOSING TO IBS. 2014 12 1891 23 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 13 1863 20 EMERGENCE OF MUC1 IN MAMMALS FOR ADAPTATION OF BARRIER EPITHELIA. THE MUCIN 1 (MUC1) GENE WAS DISCOVERED BASED ON ITS OVEREXPRESSION IN HUMAN BREAST CANCERS. SUBSEQUENT WORK DEMONSTRATED THAT MUC1 IS ABERRANTLY EXPRESSED IN CANCERS ORIGINATING FROM OTHER DIVERSE ORGANS, INCLUDING SKIN AND IMMUNE CELLS. THESE FINDINGS SUPPORTED A ROLE FOR MUC1 IN THE ADAPTATION OF BARRIER TISSUES TO INFECTION AND ENVIRONMENTAL STRESS. OF FUNDAMENTAL IMPORTANCE FOR THIS EVOLUTIONARY ADAPTATION WAS INCLUSION OF A SEA DOMAIN, WHICH CATALYZES AUTOPROTEOLYSIS OF THE MUC1 PROTEIN AND FORMATION OF A NON-COVALENT HETERODIMERIC COMPLEX. THE RESULTING MUC1 HETERODIMER IS POISED AT THE APICAL CELL MEMBRANE TO RESPOND TO LOSS OF HOMEOSTASIS. DISRUPTION OF THE COMPLEX RELEASES THE MUC1 N-TERMINAL (MUC1-N) SUBUNIT INTO A PROTECTIVE MUCOUS GEL. CONVERSELY, THE TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT ACTIVATES A PROGRAM OF LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING AND REPAIR. THIS MUC1-C-ACTIVATED PROGRAM APPARENTLY EVOLVED FOR BARRIER TISSUES TO MOUNT SELF-REGULATING PROLIFERATIVE, INFLAMMATORY AND REMODELING RESPONSES ASSOCIATED WITH WOUND HEALING. EMERGING EVIDENCE INDICATES THAT MUC1-C UNDERPINS INFLAMMATORY ADAPTATION OF TISSUE STEM CELLS AND IMMUNE CELLS IN THE BARRIER NICHE. THIS REVIEW FOCUSES ON HOW PROLONGED ACTIVATION OF MUC1-C BY CHRONIC INFLAMMATION IN THESE NICHES PROMOTES THE CANCER STEM CELL (CSC) STATE BY ESTABLISHING AUTO-INDUCTIVE NODES THAT DRIVE SELF-RENEWAL AND TUMORIGENICITY. 2022 14 803 24 CENTRAL CONTROL OF VISCERAL PAIN AND URINARY TRACT FUNCTION. AFFERENT INPUT FROM ADELTA AND C-FIBRES INNERVATING THE URINARY BLADDER ARE PROCESSED DIFFERENTLY BY THE BRAIN, AND HAVE DIFFERENT ROLES IN SIGNALING BLADDER SENSATION. ADELTA FIBRES THAT SIGNAL BLADDER FILLING ACTIVATE A SPINO-BULBO-SPINAL LOOP, WHICH RELAYS IN THE MIDBRAIN PERIAQUEDUCTAL GREY (PAG) AND PONTINE MICTURITION CENTRE (PMC). THE EXCITABILITY OF THIS CIRCUITRY IS REGULATED BY TONIC GABAERGIC INHIBITORY PROCESSES. IN HUMANS AND SOCIALISED ANIMALS MICTURITION IS NORMALLY UNDER VOLITIONAL CONTROL AND INFLUENCED BY A HOST OF PSYCHOSOCIAL FACTORS. HIGHER NERVOUS DECISION-MAKING IN A SOCIAL CONTEXT TO 'GO NOW' OR 'DO NOT GO' PROBABLY RESIDES IN FRONTAL CORTICAL AREAS, WHICH ACT AS A CENTRAL CONTROL SWITCH FOR MICTURITION. EXPOSURE TO PSYCHOSOCIAL STRESS CAN HAVE PROFOUNDLY DISRUPTIVE INFLUENCE ON THE PROCESS AND LEAD TO MALADAPTIVE CHANGES IN THE BLADDER. DURING SLEEPING THE VOIDING REFLEX THRESHOLD APPEARS TO BE RESET TO A HIGHER LEVEL TO PROMOTE URINARY CONTINENCE. UNDER PHYSIOLOGICAL CONDITIONS C-FIBRE BLADDER AFFERENTS ARE NORMALLY SILENT BUT ARE ACTIVATED IN INFLAMMATORY BLADDER STATES AND BY INTENSE DISTENDING PRESSURE. FOLLOWING PROLONGED STIMULATION VISCERAL NOCICEPTORS SENSITISE, LEADING TO A LOWERED THRESHOLD AND HEIGHTENED SENSITIVITY. IN ADDITION, SENSITIZATION MAY OCCUR WITHIN THE CENTRAL PAIN PROCESSING CIRCUITRY, WHICH OUTLASTS THE ORIGINAL NOCICEPTIVE INSULT. VISCERAL NOCICEPTION MAY ALSO BE INFLUENCED BY GENETIC AND ENVIRONMENTAL INFLUENCES. A PERIOD OF CHRONIC STRESS CAN PRODUCE INCREASED SENSITIVITY TO VISCERAL PAIN THAT LASTS FOR MONTHS. ADVERSE EARLY LIFE EVENTS CAN PRODUCE EVEN LONGER LASTING EPIGENETIC CHANGES, WHICH INCREASE THE INDIVIDUAL'S SUSCEPTIBILITY TO DEVELOPING VISCERAL PAIN STATES IN ADULTHOOD. 2016 15 3540 18 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 16 1637 29 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 17 4611 27 NEONATAL IMMUNE CHALLENGE FOLLOWED BY ADULT IMMUNE CHALLENGE INDUCES EPIGENETIC-SUSCEPTIBILITY TO AGGRAVATED VISCERAL HYPERSENSITIVITY. BACKGROUND: ABDOMINAL PAIN IS ONE OF THE MAJOR SYMPTOMS OF INFLAMMATORY BOWEL DISEASE (IBD). THE INFLAMMATORY MEDIATORS RELEASED BY COLON INFLAMMATION ARE KNOWN TO SENSITIZE THE AFFERENT NEURONS, WHICH IS ONE OF THE CONTRIBUTORS TO ABDOMINAL PAIN. HOWEVER, NOT ALL IBD PATIENTS HAVE ABDOMINAL PAIN, AND SOME PATIENTS REPORT ABDOMINAL PAIN DURING REMISSION, SUGGESTING CONTRIBUTIONS OF OTHER PATHOLOGICAL FACTORS TO ABDOMINAL PAIN IN IBD. EPIDEMIOLOGICAL STUDIES FOUND EARLY-LIFE GASTROINTESTINAL INFECTIONS A RISK FACTOR FOR IBD SYMPTOMS AND ADULT-LIFE GASTROINTESTINAL INFECTIONS MAY TRIGGER THE ONSET OF IBD. WE INVESTIGATED THE HYPOTHESIS THAT NEONATAL COLON IMMUNE CHALLENGE FOLLOWED BY AN ADULT COLON IMMUNE CHALLENGE UPREGULATES SPINAL CORD BDNF THAT AGGRAVATES VISCERAL SENSITIVITY OVER AND ABOVE THAT INDUCED BY ADULT COLON IMMUNE CHALLENGE ALONE. METHODS: WE INDUCED NEONATAL AND ADULT COLON IMMUNE CHALLENGES BY INTRALUMINAL ADMINISTRATION OF TRINITROBENZENE SULFONIC ACID TO THE RAT COLON. KEY RESULTS: WE FOUND THAT NEONATAL IMMUNE CHALLENGE TRIGGERS EPIGENETIC PROGRAMMING THAT UPREGULATES TYROSINE HYDROXYLASE IN THE LOCUS CERULEUS WHEN THESE RATS ARE SUBJECTED TO AN ADULT COLON IMMUNE CHALLENGE. THE UPREGULATION OF LOCUS CERULEUS TYROSINE HYDROXYLASE, UPREGULATES NOREPINEPHRINE IN THE CEREBROSPINAL FLUID THAT ACTS ON ADRENERGIC RECEPTORS TO ENHANCE PCREB BINDING TO THE CAMP RESPONSE ELEMENT, WHICH RECRUITS HISTONE ACETYLENE TRANSFERASE (HAT) TO THE BDNF GENE TO ENHANCE ITS TRANSCRIPTION RESULTING IN AGGRAVATED VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION. HAT AND ADRENERGIC RECEPTOR ANTAGONISTS BLOCK THE AGGRAVATION OF VISCERAL SENSITIVITY. CONCLUSION & INFERENCES: HAT AND ADRENERGIC RECEPTOR INHIBITORS MAY SERVE AS ALTERNATES TO OPIOIDS AND NSAIDS IN SUPPRESSING ABDOMINAL PAIN IN IBD. 2017 18 5815 23 STRESS AND GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL PROGRAMMING IN TIME AND SPACE: IMPLICATIONS FOR THE BRAIN-GUT AXIS. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ENHANCED ABDOMINAL PAIN AND ALTERED INTESTINAL BARRIER FUNCTION THAT MAY RESULT FROM A PERTURBATION IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE GLUCOCORTICOID RECEPTOR (GR) EXPLOITS DIVERSE MECHANISMS TO ACTIVATE OR SUPPRESS CONGENERIC GENE EXPRESSION, WITH REGULATORY VARIATION ASSOCIATED WITH STRESS-RELATED DISORDERS IN PSYCHIATRY AND GASTROENTEROLOGY. PURPOSE: DURING ACUTE AND CHRONIC STRESS, CORTICOTROPIN-RELEASING HORMONE DRIVES SECRETION OF ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY, ULTIMATELY LEADING TO THE RELEASE OF CORTISOL (HUMAN) AND CORTICOSTERONE (RODENT) FROM THE ADRENAL GLANDS. CORTISOL BINDS WITH THE GR IN THE CYTOSOL, TRANSLOCATES TO THE NUCLEUS, AND ACTIVATES THE NR3C1 (NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 [GR]) GENE. THIS REVIEW FOCUSES ON THE RAPIDLY DEVELOPING OBSERVATIONS THAT CORTISOL IS RESPONSIBLE FOR DRIVING CIRCADIAN AND ULTRADIAN BURSTS OF TRANSCRIPTIONAL ACTIVITY IN THE CLOCK (CLOCK CIRCADIAN REGULATOR) AND PER (PERIOD CIRCADIAN CLOCK 1) GENE FAMILIES, AND THIS RHYTHM IS DISRUPTED IN MAJOR DEPRESSIVE DISORDER, BIPOLAR DISORDER, AND STRESS-RELATED GASTROINTESTINAL AND IMMUNE DISORDERS. GLUCOCORTICOID RECEPTOR REGULATES DIFFERENT SETS OF TRANSCRIPTS IN A TISSUE-SPECIFIC MANNER, THROUGH PULSATILE WAVES OF GENE EXPRESSION THAT INCLUDES OCCUPANCY OF GLUCOCORTICOID RESPONSE ELEMENTS LOCATED WITHIN CONSTITUTIVELY OPEN SPATIAL DOMAINS IN CHROMATIN. EMERGING EVIDENCE SUPPORTS A POTENTIALLY PIVOTAL ROLE FOR EPIGENETIC REGULATION OF HOW GR INTERACTS WITH OTHER CHROMATIN REGULATORS TO CONTROL THE EXPRESSION OF ITS TARGET GENES. DYSREGULATION OF THE CENTRAL AND PERIPHERAL GR REGULOME HAS POTENTIALLY SIGNIFICANT CONSEQUENCES FOR STRESS-RELATED DISORDERS AFFECTING THE BRAIN-GUT AXIS. 2016 19 6272 17 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS. 2020 20 2295 17 EPIGENETIC REGULATION IN UTERINE FIBROIDS-THE ROLE OF TEN-ELEVEN TRANSLOCATION ENZYMES AND THEIR POTENTIAL THERAPEUTIC APPLICATION. UTERINE FIBROIDS (UFS) ARE MONOCLONAL, BENIGN TUMORS THAT CONTAIN ABNORMAL SMOOTH MUSCLE CELLS AND THE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM). ALTHOUGH BENIGN, UFS ARE A MAJOR SOURCE OF GYNECOLOGIC AND REPRODUCTIVE DYSFUNCTION, RANGING FROM MENORRHAGIA AND PELVIC PAIN TO INFERTILITY, RECURRENT MISCARRIAGE, AND PRETERM LABOR. MANY RISK FACTORS ARE INVOLVED IN THE PATHOGENESIS OF UFS VIA GENETIC AND EPIGENETIC MECHANISMS. THE LATTER INVOLVING DNA METHYLATION AND DEMETHYLATION REACTIONS PROVIDE SPECIFIC DNA METHYLATION PATTERNS THAT REGULATE GENE EXPRESSION. ACTIVE DNA DEMETHYLATION REACTIONS MEDIATED BY TEN-ELEVEN TRANSLOCATION PROTEINS (TETS) AND ELEVATED LEVELS OF 5-HYDROXYMETHYLCYTOSINE HAVE BEEN SUGGESTED TO BE INVOLVED IN UF FORMATION. THIS REVIEW PAPER SUMMARIZES THE MAIN FINDINGS REGARDING THE FUNCTION OF TET ENZYMES AND THEIR ACTIVITY DYSREGULATION THAT MAY TRIGGER THE DEVELOPMENT OF UFS. UNDERSTANDING THE ROLE THAT EPIGENETICS PLAYS IN THE PATHOGENESIS OF UFS MAY POSSIBLY LEAD TO A NEW TYPE OF PHARMACOLOGICAL FERTILITY-SPARING TREATMENT METHOD. 2022