1  1001 151 CHRONIC TCDD EXPOSURE RESULTS IN THE DYSREGULATION OF GENE EXPRESSION IN SPLENIC B-LYMPHOCYTES AND IN THE IMPAIRMENTS IN T-CELL AND B-CELL DIFFERENTIATION IN MOUSE MODEL. 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) EXPOSURE IN HUMANS IS ASSOCIATED WITH MARKED IMMUNE SUPPRESSIONS AND INCREASED INCIDENCE OF LYMPHOBLASTIC DISEASES. TO ELUCIDATE MECHANISMS OF IMPAIRMENTS IN HUMORAL IMMUNE RESPONSES, WE USED A MURINE MODEL. FOLLOWING A 20-WEEK ADMINISTRATION OF LOW DOSES OF TCDD, WE OBSERVED SEVERELY REDUCED ANTIBODY TITERS, DRAMATICALLY DECREASED NUMBER OF SPLENIC TH1 AND TH2 CELLS AND AN INCREASE IN CD19(+) B CELLS. TRANSCRIPTIONAL PROFILING OF CD19(+) B CELLS SHOWED THAT MARKERS OF PRE-B CELLS WERE SIGNIFICANTLY ELEVATED, INDICATING DELAYED B CELL MATURATION. THESE CHANGES IN B CELLS WERE ACCOMPANIED BY DECREASES OF T HELPER CELL NUMBERS AND REDUCED IGM AND IGG TITERS. A TRANSCRIPTOME ANALYSIS OF SPLENIC B CELLS FOLLOWED BY INGENUITY PATHWAY ANALYSIS (IPA) REVEALED A SET OF DIFFERENTIALLY EXPRESSED GENES KNOWN TO PLAY ROLES IN TUMORIGENESIS, CELL-PROLIFERATION AND CELL-MIGRATION. THE MOST UP-REGULATED TRANSCRIPT GENE WAS EPH RECEPTOR A2 (EPHA2), A KNOWN ONCOGENE, AND THE MOST DOWN-REGULATED TRANSCRIPT WAS ZBTB16 THAT CODES FOR A NEGATIVE TRANSCRIPTIONAL REGULATOR IMPORTANT IN EPIGENETIC CHROMATIN REMODELING. IPA IDENTIFIED CAMP-RESPONSIVE ELEMENT MODULATOR (CREM) AND CAMP-RESPONSIVE ELEMENT BINDING PROTEIN 1 (CREB1) AS TOP UPSTREAM REGULATORS. CONSISTENTLY, A MAPPER PROMOTER DATABASE ANALYSIS SHOWED THAT ALL TOP DYSREGULATED GENES HAD CREM AND/OR CREB1 BINDING SITES IN THEIR PROMOTER REGIONS. IN SUMMARY, OUR DATA SHOWED THAT CHRONIC TCDD EXPOSURE IN MICE CAUSED SUPPRESSED HUMORAL IMMUNITY ACCOMPANIED WITH PROFOUND DYSREGULATION OF GENE EXPRESSION IN SPLENIC B-LYMPHOCYTES, LIKELY THROUGH CAMP-DEPENDENT PATHWAYS. THIS DYSREGULATION RESULTED IN IMPAIRMENTS IN T-CELL AND B-CELL DIFFERENTIATION AND ACTIVATION OF THE TUMORIGENIC TRANSCRIPTION PROGRAM.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  2466  39 EPIGENETIC THERAPY: NOVEL TRANSLATIONAL IMPLICATIONS FOR ARREST OF ENVIRONMENTAL DIOXIN-INDUCED DISEASE IN FEMALES. INCREASED TOXICANT EXPOSURE AND RESULTANT ENVIRONMENTALLY INDUCED DISEASES ARE A TRADEOFF OF INDUSTRIAL PRODUCTIVITY. DIOXIN [2,3,7,8 TETRACHLORODIBENZO-P-DIOXIN (TCDD)], A UBIQUITOUS BYPRODUCT, IS ASSOCIATED WITH A SPECTRUM OF DISEASES INCLUDING ENDOMETRIOSIS, A COMMON, CHRONIC DISEASE IN WOMEN. TCDD ACTIVATES CYTOCHROME (CYP) P450 METABOLIC ENZYMES THAT ALTER ORGAN FUNCTION TO CAUSE DISEASE. IN CONTRAST, THE TRANSCRIPTION FACTOR, KRUPPEL-LIKE FACTOR (KLF) 11, REPRESSES THESE ENZYMES VIA EPIGENETIC MECHANISMS. IN THIS STUDY, WE CHARACTERIZED THESE OPPOSING MECHANISMS IN VITRO AND IN VIVO AS WELL AS DETERMINING POTENTIAL TRANSLATIONAL IMPLICATIONS OF EPIGENETIC INHIBITOR THERAPY. KLF11 ANTAGONIZED TCDD-MEDIATED ACTIVATION OF CYP3A4 GENE EXPRESSION AND FUNCTION IN ENDOMETRIAL CELLS. THE REPRESSION WAS PHARMACOLOGICALLY REPLICATED BY SELECTIVE USE OF AN EPIGENETIC HISTONE ACETYLTRANSFERASE INHIBITOR (HATI). WE FURTHER SHOWED PHENOTYPIC RELEVANCE OF THIS MECHANISM USING AN ANIMAL MODEL FOR ENDOMETRIOSIS. FIBROTIC EXTENT IN TCDD-EXPOSED WILD-TYPE ANIMALS WAS SIMILAR TO THAT PREVIOUSLY OBSERVED IN KLF11-/- ANIMALS. WHEN TCDD-EXPOSED ANIMALS WERE TREATED WITH A HATI, CYP3 MESSENGER RNA LEVELS AND PROTEIN EXPRESSION DECREASED ALONG WITH DISEASE PROGRESSION. FIBROTIC PROGRESSION IS UBIQUITOUS IN ENVIRONMENTALLY INDUCED CHRONIC, UNTREATABLE DISEASES; THIS REPORT SHOWS THAT RELENTLESS DISEASE PROGRESSION CAN BE ARRESTED THROUGH TARGETED EPIGENETIC MODULATION OF PROTECTIVE MECHANISMS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  1447  24 DIOXIN AND ENDOMETRIOSIS: A NEW POSSIBLE RELATION BASED ON EPIGENETIC THEORY. ENDOMETRIOSIS IS A CHRONIC DISEASE CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. NOWADAYS, THE EXACT ETIOLOGY OF ENDOMETRIOSIS IS UNCLEAR AND THE INTERACTION BETWEEN A VARIETY OF ENVIRONMENTAL PHYSICAL AND CHEMICAL COMPOUNDS MAY POTENTIALLY PROMOTE THE DISEASE IN WOMEN WITH AN INDIVIDUAL SUSCEPTIBILITY. THE FIRST DEMONSTRATION OF A RELATION BETWEEN AN ENVIRONMENTAL FACTOR AND ENDOMETRIOSIS WAS OBTAINED WITH THE CHRONIC DIETARY EXPOSURE OF A PRIMATE COLONY TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). BESIDES THE WELL-KNOWN DIOXIN'S PATHWAY OF ACTION, SEVERAL PAPERS ARE FOCUSING ON THE ROLE OF EPIGENETIC MECHANISMS, A WAY THROUGH WHICH THE GENOME RESPONDS TO THE ENVIRONMENT AND CAN LEAD TO PERMANENT CHANGES IN GENE EXPRESSION UNTIL AFFECTING THE PHENOTYPES OR CAUSE DISEASE. IN THIS REVIEW, WE FOCUS ON THE POSSIBLE ROLE OF DIOXIN EPIGENETICS MODIFICATION IN ENDOMETRIOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  4986  26 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                       
5  1945  34 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  6519  38 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF INTERLEUKIN-2 GENE IN ACTIVATED T CELLS BY MORPHINE. CHRONIC MORPHINE INHIBITS INTERLEUKIN-2 (IL-2) AT BOTH THE TRANSCRIPTIONAL AND PROTEIN SYNTHESIS LEVELS. THE MOLECULAR MECHANISMS BY WHICH MORPHINE DECREASES IL-2 ARE NOT FULLY UNDERSTOOD. THE PRODUCTION OF IL-2 IS TIGHTLY REGULATED BY SEVERAL TRANSCRIPTION FACTORS THAT BIND TO THE IL-2 PROMOTER. HEREIN, WE SHOW THAT CHRONIC MORPHINE TREATMENT RESULTS IN AN INCREASE IN CAMP LEVELS WITH A CONCURRENT UP-REGULATION OF THE CAMP INDUCIBLE REPRESSOR INDUCIBLE CAMP EARLY REPRESSOR (ICER)/CAMP RESPONSE ELEMENT MODULATOR (CREM) AND DOWN-REGULATION OF P-CAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB) IN ACTIVATED T CELLS. FURTHERMORE, ICER COMPETES FOR P-CREB BINDING TO THE CAMP-RESPONSIVE ELEMENTS (CRES) SITE. THIS LEADS TO THE UNCOUPLING OF CBP/P300 THEREBY ABROGATING IL-2 TRANSCRIPTION. OVEREXPRESSION OF EITHER ANTISENSE CREM OR CREB PLASMID RESCUED MORPHINE-INDUCED INHIBITION OF IL-2 PROMOTER ACTIVITY AND PROTEIN PRODUCTION. IN ADDITION, WE ALSO FOUND THAT CHRONIC MORPHINE TREATMENT INHIBITED THE ACETYLATION AND TRIMETHYLATION OF HISTONES AND DECREASED BOTH DNA DEMETHYLATION AND ACCESSIBILITY OF THE IL-2 PROMOTER. THESE FINDINGS SUGGEST THAT CHRONIC MORPHINE TREATMENT MAY FUNCTION THROUGH BOTH TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS TO INHIBIT IL-2 PRODUCTION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  2244  31 EPIGENETIC MODULATION OF COLLAGEN 1A1: THERAPEUTIC IMPLICATIONS IN FIBROSIS AND ENDOMETRIOSIS. PROGRESSIVE FIBROSIS IS RECALCITRANT TO CONVENTIONAL THERAPY AND COMMONLY COMPLICATES CHRONIC DISEASES AND SURGICAL HEALING. WE EVALUATE HERE A NOVEL MECHANISM THAT REGULATES SCAR-TISSUE COLLAGEN (COL1A1/COL1A1) EXPRESSION AND CHARACTERIZES ITS TRANSLATIONAL RELEVANCE AS A TARGETED THERAPY FOR FIBROSIS IN AN ENDOMETRIOSIS DISEASE MODEL. ENDOMETRIOSIS IS CAUSED BY DISPLACEMENT AND IMPLANTATION OF UTERINE ENDOMETRIUM ONTO ABDOMINAL ORGANS AND SPREADS WITH PROGRESSIVE SCARRING. TRANSCRIPTION FACTOR KLF11 IS SPECIFICALLY DIMINISHED IN ENDOMETRIOSIS LESIONS. LOSS OF KLF11-MEDIATED REPRESSION OF COL1A1/COL1A1 EXPRESSION RESULTED IN INCREASED FIBROSIS. TO DETERMINE THE BIOLOGICAL SIGNIFICANCE OF COL1A1/COL1A1 EXPRESSION ON FIBROSIS, WE MODULATED ITS EXPRESSION. IN HUMAN ENDOMETRIAL-STROMAL FIBROBLASTS, KLF11 RECRUITED SIN3A/HDAC (HISTONE DEACETYLASE), RESULTING IN COL1A1-PROMOTER DEACETYLATION AND REPRESSION. THIS ROLE OF KLF11 WAS PHARMACOLOGICALLY REPLICATED BY A HISTONE ACETYL TRANSFERASE INHIBITOR (GARCINOL). IN CONTRAST, OPPOSITE EFFECTS WERE OBTAINED WITH A HDAC INHIBITOR (SUBEROYL ANILIDE HYDROXAMIC ACID), CONFIRMING REGULATORY SPECIFICITY FOR THESE RECIPROCALLY ACTIVE EPIGENETIC MECHANISMS. FIBROSIS WAS CONCORDANTLY REVERSED IN KLF11(-/-)ANIMALS BY HISTONE ACETYL TRANSFERASE INHIBITOR AND IN WILD-TYPE ANIMALS BY HDAC INHIBITOR TREATMENTS. ABERRANT LESIONAL COL1A1 REGULATION IS SIGNIFICANT BECAUSE FIBROSIS DEPENDED ON LESION RATHER THAN HOST GENOTYPE. THIS IS THE FIRST REPORT DEMONSTRATING FEASIBILITY FOR TARGETED PHARMACOLOGICAL REVERSAL OF FIBROSIS, AN INTRACTABLE PHENOTYPE OF DIVERSE CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  3886  33 KLF10 MEDIATED EPIGENETIC DYSREGULATION OF EPITHELIAL CD40/CD154 PROMOTES ENDOMETRIOSIS. ENDOMETRIOSIS IS A HIGHLY PREVALENT, CHRONIC, HETEROGENEOUS, FIBRO-INFLAMMATORY DISEASE THAT REMAINS RECALCITRANT TO CONVENTIONAL THERAPY. WE PREVIOUSLY SHOWED THAT LOSS OF KLF11, A TRANSCRIPTION FACTOR IMPLICATED IN UTERINE DISEASE, RESULTS IN PROGRESSION OF ENDOMETRIOSIS. DESPITE EXTENSIVE HOMOLOGY, CO-EXPRESSION, AND HUMAN DISEASE ASSOCIATION, LOSS OF THE PARALOG KLF10 CAUSES A UNIQUE INFLAMMATORY, CYSTIC ENDOMETRIOSIS PHENOTYPE IN CONTRAST TO FIBROTIC PROGRESSION SEEN WITH LOSS OF KLF11. WE IDENTIFY HERE FOR THE FIRST TIME A NOVEL ROLE FOR KLF10 IN ENDOMETRIOSIS. IN AN ANIMAL ENDOMETRIOSIS MODEL, UNLIKE WILD-TYPE CONTROLS, KLF10(-/-) ANIMALS DEVELOPED CYSTIC LESIONS WITH MASSIVE IMMUNE INFILTRATE AND MINIMAL PERI-LESIONAL FIBROSIS. THE KLF10(-/-) DISEASE PROGRESSION PHENOTYPE ALSO CONTRASTED WITH PROLIFIC FIBROSIS AND MINIMAL IMMUNE CELL INFILTRATION SEEN IN KLF11(-/-) ANIMALS. WE FURTHER FOUND THAT LESION GENOTYPE RATHER THAN THAT OF THE HOST DETERMINED EACH UNIQUE DISEASE PROGRESSION PHENOTYPE. MECHANISTICALLY, KLF10 REGULATED CD40/CD154-MEDIATED IMMUNE PATHWAYS. BOTH INFLAMMATORY AS WELL AS FIBROTIC PHENOTYPES ARE THE COMMONEST CLINICAL MANIFESTATIONS IN CHRONIC FIBRO-INFLAMMATORY DISEASES SUCH AS ENDOMETRIOSIS. THE COMPLEMENTARY, PARALOGOUS KLF10 AND KLF11 MODELS THEREFORE OFFER NOVEL INSIGHTS INTO THE MECHANISMS OF INFLAMMATION AND FIBROSIS IN A DISEASE-RELEVANT CONTEXT. OUR DATA SUGGESTS THAT DIVERGENCE IN UNDERLYING GENE DYSREGULATION CRITICALLY DETERMINES DISEASE-PHENOTYPE PREDOMINANCE RATHER THAN THE CONVENTIONAL PARADIGM OF INFLAMMATION BEING PRECEDENT TO FIBROTIC SCARRING. HETEROGENEITY IN CLINICAL PROGRESSION AND TREATMENT RESPONSE ARE THUS LIKELY FROM DISPARATE GENE REGULATION PROFILES. CHARACTERIZATION OF DISEASE PHENOTYPE-ASSOCIATED GENE DYSREGULATION OFFERS NOVEL APPROACHES FOR DEVELOPING TARGETED, INDIVIDUALIZED THERAPY FOR RECURRENT AND RECALCITRANT CHRONIC DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  3175  34 H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS INDUCED BY IMATINIB. INCREASING EVIDENCE SUGGESTS THAT HISTONE H2AX PLAYS A CRITICAL ROLE IN REGULATION OF TUMOR CELL APOPTOSIS AND ACTS AS A NOVEL HUMAN TUMOR SUPPRESSOR PROTEIN. HOWEVER, THE ACTION OF H2AX IN CHRONIC MYELOGENOUS LEUKEMIA (CML) CELLS IS UNKNOWN. THE DETAILED MECHANISM AND EPIGENETIC REGULATION BY H2AX REMAIN ELUSIVE IN CANCER CELLS. HERE, WE REPORT THAT H2AX WAS INVOLVED IN APOPTOSIS OF CML CELLS. OVEREXPRESSION OF H2AX INCREASED APOPTOTIC SENSITIVITY OF CML CELLS (K562) INDUCED BY IMATINIB. HOWEVER, OVEREXPRESSION OF SER139-MUTATED H2AX (BLOCKING PHOSPHORYLATION) DECREASED SENSITIVITY OF K562 CELLS TO APOPTOSIS. SIMILARLY, KNOCKDOWN OF H2AX MADE K562 CELLS RESISTANT TO APOPTOTIC INDUCTION. THESE RESULTS REVEALED THAT THE FUNCTION OF H2AX INVOLVED IN APOPTOSIS IS STRICTLY RELATED TO ITS PHOSPHORYLATION (SER139). OUR DATA FURTHER INDICATED THAT IMATINIB MAY STIMULATE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) FAMILY MEMBER P38, AND H2AX PHOSPHORYLATION FOLLOWED A SIMILAR TIME COURSE, SUGGESTING A PARALLEL RESPONSE. H2AX PHOSPHORYLATION CAN BE BLOCKED BY P38 SIRNA OR ITS INHIBITOR. THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION WAS REGULATED BY P38 MAPK PATHWAY IN K562 CELLS. HOWEVER, THE P38 MAPK DOWNSTREAM, MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE-1 AND -2, WHICH PHOSPHORYLATED HISTONE H3, WERE NOT REQUIRED FOR H2AX PHOSPHORYLATION DURING APOPTOSIS. FINALLY, WE PROVIDED EPIGENETIC EVIDENCE THAT H2AX PHOSPHORYLATION REGULATED APOPTOSIS-RELATED GENE BIM EXPRESSION. BLOCKING OF H2AX PHOSPHORYLATION INHIBITED BIM GENE EXPRESSION. TAKEN TOGETHER, THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CML CELLS INDUCED BY IMATINIB.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  2787  45 EZH2-MEDIATED EPIGENETIC MODIFICATION IS REQUIRED FOR ALLOGENEIC T CELL-INDUCED LUPUS DISEASE. BACKGROUND: THE MECHANISMS INVOLVED IN THE PATHOGENESIS OF AUTOIMMUNE DISORDERS, INCLUDING SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), HAVE NOT BEEN FULLY ELUCIDATED. SOME OF THESE MECHANISMS INVOLVE EPIGENETIC REGULATION OF GENE EXPRESSION. THE HISTONE METHYLTRANSFERASE EZH2 CONTRIBUTES TO EPIGENETIC REGULATION OF GENE EXPRESSION, IS HIGHLY EXPRESSED IN GERMINAL CENTER (GC) B CELLS AND FOLLICULAR T HELPER (T(FH)) CELLS, AND MAY BE INVOLVED IN LUPUS PATHOGENESIS. METHODS: THE MURINE BM12 MODEL OF LUPUS-LIKE CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) WAS INDUCED BY INTRA-PERITONEAL INJECTION OF NEGATIVELY ISOLATED ALLOGENEIC CD4(+) T CELLS. LUPUS-LIKE DISEASE DEVELOPMENT WAS MONITORED BY ELISA DETERMINATION OF SERUM ANTI-DSDNA AND ANTI-CHROMATIN ANTIBODY TITERS. IMMUNE CELL ACTIVATION AND EZH2 EXPRESSION WERE EVALUATED BY FLOW CYTOMETRY AND WESTERN BLOTTING. RESULTS: DECREASED AUTOANTIBODY PRODUCTION AND GC FORMATION ARE OBSERVED WHEN EZH2-DEFICIENT CD4(+) T CELLS ARE USED INSTEAD OF WILD-TYPE (WT) TO INDUCE CGVHD AND WHEN MICE THAT RECEIVE ALLOGENEIC WT DONOR T CELLS TO INDUCE CGVHD ARE TREATED WITH GSK503, AN EZH2-SPECIFIC INHIBITOR. IN THE BM12 CGVHD MODEL, WT DONOR T CELLS ARE NORMALLY FULLY ACTIVATED 1 WEEK AFTER INFUSION INTO AN ALLOGENEIC HOST, EXHIBIT A T(FH) CELL (PD-1(HI)/CXCR5(HI)) PHENOTYPE WITH UPREGULATED EZH2, AND ACTIVATE B CELLS TO FORM GERMINAL CENTERS (GCS). IN CONTRAST, EZH2-DEFICIENT DONOR T CELLS GENERATE FEWER T(FH) CELLS THAT FAIL TO ACTIVATE B CELLS OR PROMOTE GC FORMATION. DESPITE SIMILAR T-INDEPENDENT, LPS-INDUCED B CELL RESPONSES, OVA-IMMUNIZED CD4.EZH2-KO MICE HAD A SKEWED LOW-AFFINITY IGM PHENOTYPE IN COMPARISON TO SIMILARLY TREATED WT MICE. IN ADDITION, EARLY AFTER OVA IMMUNIZATION, MORE CD4(+) T CELLS FROM B6.CD4.EZH2-KO MICE HAD A CD44(LO)/CD62L(LO) PHENOTYPE, WHICH SUGGESTS ARRESTED OR DELAYED ACTIVATION, THAN CD4(+) T CELLS FROM OVALBUMIN-IMMUNIZED B6.WT MICE. CONCLUSION: EZH2 GENE DELETION OR PHARMACOLOGICAL EZH2 INHIBITION SUPPRESSES AUTOANTIBODY PRODUCTION AND GC FORMATION IN BM12 LUPUS-LIKE CGVHD AND DECREASES AFFINITY MATURATION AND ISOTYPE SWITCHING IN RESPONSE TO IMMUNIZATION WITH A T CELL-DEPENDENT ANTIGEN. EZH2 INHIBITION MAY BE USEFUL FOR THE TREATMENT OF LUPUS AND OTHER AUTOIMMUNE DISORDERS.	2020	
                                                                                                                                                                                                                                                                                               
11   912  28 CHRONIC EXPOSURE TO WATER POLLUTANT TRICHLOROETHYLENE INCREASED EPIGENETIC DRIFT IN CD4(+) T CELLS. AIM: AUTOIMMUNE DISEASE AND CD4(+) T-CELL ALTERATIONS ARE INDUCED IN MICE EXPOSED TO THE WATER POLLUTANT TRICHLOROETHYLENE (TCE). WE EXAMINED HERE WHETHER TCE ALTERED GENE-SPECIFIC DNA METHYLATION IN CD4(+) T CELLS AS A POSSIBLE MECHANISM OF IMMUNOTOXICITY. MATERIALS & METHODS: NAIVE AND EFFECTOR/MEMORY CD4(+) T CELLS FROM MICE EXPOSED TO TCE (0.5 MG/ML IN DRINKING WATER) FOR 40 WEEKS WERE EXAMINED BY BISULFITE NEXT-GENERATION DNA SEQUENCING. RESULTS: A PROBABILISTIC MODEL CALCULATED FROM MULTIPLE GENES SHOWED THAT TCE DECREASED METHYLATION CONTROL IN CD4(+) T CELLS. DATA FROM INDIVIDUAL GENES FITTED TO A QUADRATIC REGRESSION MODEL SHOWED THAT TCE INCREASED GENE-SPECIFIC METHYLATION VARIANCE IN BOTH CD4 SUBSETS. CONCLUSION: TCE INCREASED EPIGENETIC DRIFT OF SPECIFIC CPG SITES IN CD4(+) T CELLS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  1986  41 EPIGENETIC ALTERATIONS MAY REGULATE TEMPORARY REVERSAL OF CD4(+) T CELL ACTIVATION CAUSED BY TRICHLOROETHYLENE EXPOSURE. PREVIOUS STUDIES HAVE SHOWN THAT SHORT-TERM (4 WEEKS) OR CHRONIC (32 WEEKS) EXPOSURE TO TRICHLOROETHYLENE (TCE) IN DRINKING WATER OF FEMALE MRL+/+ MICE GENERATED CD4(+) T CELLS THAT SECRETED INCREASED LEVELS OF INTERFERON (IFN)-GAMMA AND EXPRESSED AN ACTIVATED (CD44(HI)CD62L(LO)) PHENOTYPE. IN CONTRAST, THE CURRENT STUDY OF SUBCHRONIC TCE EXPOSURE SHOWED THAT MIDWAY IN THE DISEASE PROCESS BOTH OF THESE PARAMETERS OF CD4(+) T CELL ACTIVATION WERE REVERSED. THIS PHASE OF THE DISEASE PROCESS MAY REPRESENT AN ATTEMPT BY THE BODY TO COUNTERACT THE INFLAMMATORY EFFECTS OF TCE. THE DECREASE IN CD4(+) T CELL PRODUCTION OF IFN-GAMMA FOLLOWING SUBCHRONIC TCE EXPOSURE COULD NOT BE ATTRIBUTED TO SKEWING TOWARD A TH2 OR TH17 PHENOTYPE OR TO AN INCREASE IN TREG CELLS. INSTEAD, THE SUPPRESSION CORRESPONDED TO ALTERATIONS IN MARKERS USED TO ASSESS DNA METHYLATION, NAMELY INCREASED EXPRESSION OF RETROTRANSPOSONS IAP (INTRACISTERNAL A PARTICLE) AND MUERV (MURINE ENDOGENOUS RETROVIRUS). ALSO OBSERVED WAS AN INCREASE IN THE EXPRESSION OF DNMT1 (DNA METHYLTRANSFERASE-1) AND DECREASED EXPRESSION OF SEVERAL GENES KNOWN TO BE DOWNREGULATED BY DNA METHYLATION, NAMELY IFNG, IL2, AND CDKN1A. CD4(+) T CELLS FROM A SECOND STUDY IN WHICH MRL+/+ MICE WERE TREATED FOR 17 WEEKS WITH TCE SHOWED A SIMILAR INCREASE IN IAP AND DECREASE IN CDKN1A. IN ADDITION, DNA COLLECTED FROM THE CD4(+) T CELLS IN THE SECOND STUDY SHOWED TCE-DECREASED GLOBAL DNA METHYLATION. THUS, THESE RESULTS DESCRIBED THE BIPHASIC NATURE OF TCE-INDUCED ALTERATIONS IN CD4(+) T CELL FUNCTION AND SUGGESTED THAT THESE CHANGES REPRESENTED POTENTIALLY REVERSIBLE ALTERATIONS IN EPIGENETIC PROCESSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  2439  25 EPIGENETIC SILENCING OF THE MLH1 PROMOTER IN RELATION TO THE DEVELOPMENT OF GASTRIC CANCER AND ITS USE AS A BIOMARKER FOR PATIENTS WITH MICROSATELLITE INSTABILITY: A SYSTEMATIC ANALYSIS. BACKGROUND/AIMS: HUMAN MUTL HOMOLOG 1 (MLH1) PROMOTER METHYLATION WAS REPORTED IN GASTRIC CANCER (GC). THIS STUDY DETERMINED THE CLINICOPATHOLOGICAL, PROGNOSTIC, AND DIAGNOSTIC EFFECTS OF MLH1 PROMOTER METHYLATION IN GC. METHODS: THE COMBINED ODDS RATIO (OR) OR HAZARD RATIO (HR) AND THEIR CORRESPONDING 95% CONFIDENCE INTERVALS (95% CI) WERE CALCULATED. THE POOLED SENSITIVITY, SPECIFICITY, AND AREA UNDER THE CURVE (AUC) WERE ANALYZED. RESULTS: A TOTAL OF 4654 GC PATIENTS AND 3669 NON-MALIGNANT CONTROLS WERE IDENTIFIED IN THIS SYSTEMATIC ANALYSIS. MLH1 PROMOTER METHYLATION WAS SIGNIFICANTLY HIGHER IN GC SAMPLES THAN IN GASTRIC ADENOMAS, CHRONIC GASTRITIS, ADJACENT TISSUES, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES, BUT IT EXHIBITED A SIMILAR FREQUENCY IN GC VS. INTESTINAL METAPLASIA AND DYSPLASIA SAMPLES. MLH1 PROMOTER METHYLATION CORRELATED WITH AGE AND MICROSATELLITE INSTABILITY (MSI), BUT IT WAS NOT ASSOCIATED WITH GENDER, H. PYLORI INFECTION, SMOKING, DRINKING BEHAVIORS, PATHOLOGICAL HISTOLOGY, TUMOR DIFFERENTIATION, CLINICAL STAGE, LYMPH NODE STATUS, DISTANT METASTASIS, OR OVERALL SURVIVAL OF GC. MLH1 PROMOTER METHYLATION EXHIBITED A POOR SENSITIVITY VALUE (< 0.5) IN PATIENTS WITH GC COMPARED WITH ADJACENT TISSUES, GASTRIC ADENOMAS, CHRONIC GASTRITIS, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES. THE POOLED SENSITIVITY, SPECIFICITY, AND AUC OF MLH1 PROMOTER METHYLATION IN GC WITH MSI VS. GC WITH MICROSATELLITE STABILITY (MSS) SAMPLES WERE 0.64, 0.96, AND 0.90, RESPECTIVELY. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE DETECTION OF MLH1 PROMOTER METHYLATION MAY BE A POTENTIAL PROGNOSTIC BIOMARKER FOR GC PATIENTS WITH MSI.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  2391  37 EPIGENETIC REPRESSION OF DNA MISMATCH REPAIR BY INFLAMMATION AND HYPOXIA IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED COLORECTAL CANCER. SPORADIC HUMAN MISMATCH REPAIR (MMR)-DEFICIENT COLORECTAL CANCERS ACCOUNT FOR APPROXIMATELY 12.5% OF ALL CASES OF COLORECTAL CANCER. MMR-DEFICIENT COLORECTAL CANCERS ARE CLASSICALLY CHARACTERIZED BY RIGHT-SIDED LOCATION, MULTIFOCALITY, MUCINOUS HISTOLOGY, AND LYMPHOCYTIC INFILTRATION. HOWEVER, TUMORS IN GERM-LINE MMR-DEFICIENT MOUSE MODELS LACK THESE HISTOPATHOLOGIC FEATURES. MICE LACKING THE HETEROTRIMERIC G PROTEIN ALPHA SUBUNIT GIALPHA2 DEVELOP CHRONIC COLITIS AND MULTIFOCAL, RIGHT-SIDED CANCERS WITH MUCINOUS HISTOPATHOLOGY, SIMILAR TO HUMAN MMR-DEFICIENT COLORECTAL CANCER. YOUNG GIALPHA2-/- COLONIC EPITHELIUM HAS NORMAL MMR EXPRESSION BUT SELECTIVELY LOSES MLH1 AND CONSEQUENTLY PMS2 EXPRESSION FOLLOWING INFLAMMATION. GIALPHA2-/- CANCERS HAVE MICROSATELLITE INSTABILITY. MLH1 IS EPIGENETICALLY SILENCED NOT BY PROMOTER HYPERMETHYLATION BUT BY DECREASED HISTONE ACETYLATION. CHRONICALLY INFLAMED GIALPHA2-/- COLONIC MUCOSA CONTAINS PATCHY HYPOXIA, WITH INCREASED CRYPT EXPRESSION OF THE HYPOXIA MARKERS DEC-1 AND BNIP3. CHROMATIN IMMUNOPRECIPITATION IDENTIFIED INCREASED BINDING OF THE TRANSCRIPTIONAL REPRESSOR DEC-1 TO THE PROXIMAL MLH1 PROMOTER IN HYPOXIC YAMC CELLS AND COLITIC GIALPHA2-/- CRYPTS. TREATING GIALPHA2-/- MICE WITH THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY DECREASED COLITIS ACTIVITY AND RESCUED MLH1 EXPRESSION IN CRYPT EPITHELIAL CELLS, WHICH WAS ASSOCIATED WITH INCREASED ACETYL HISTONE H3 LEVELS AND DECREASED DEC-1 BINDING AT THE PROXIMAL MLH1 PROMOTER, CONSISTENT WITH A HISTONE DEACETYLASE-DEPENDENT MECHANISM. THESE DATA LINK CHRONIC HYPOXIC INFLAMMATION, EPIGENETIC MMR PROTEIN DOWN-REGULATION, DEVELOPMENT OF MMR-DEFICIENT COLORECTAL CANCER, AND THE FIRSTMOUSE MODEL OF SOMATICALLY ACQUIRED MMR-DEFICIENT COLORECTAL CANCER.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  6820  32 [GASTRIC CARCINOMA AND CHRONIC GASTRITIS: EPIGENETIC REGULATION OF CDH1 (E-CADHERIN), CDKN2A (P16INK4A), PTGS2 (COX-2) AND EGFR GENES THROUGH METHYLATION]. THE GENETIC AND EPIGENETIC ALTERATIONS ARE BEING STUDIED AS ONE OF THE CAUSES OF GASTRIC CANCER (GC) PROGRESSION AND DEVELOPMENT. DNA METHYLATION IS AN EPIGENETIC ALTERATION WHICH LEADS TO SUPPRESSOR GENE SILENCING AND PROTO-ONCOGENE ACTIVATION, PLAYING AN IMPORTANT ROLE IN CARCINOGENESIS. THE HISTOLOGICAL TYPES OF GASTRIC CARCINOMA HAVE DIFFERENT GENETIC PATHS AND THE KNOWLEDGE OF THE MOLECULAR BASES OF TUMORAL PROGRESSION LEADS TO DIAGNOSTIC ACCURACY AND ATTEMPTED THERAPY. CDH1 (E-CADHERIN) AND CDKN2A (P16(INK4A)) GENES ARE THOUGHT TO BE TUMORAL SUPPRESSOR GENES AND PTGS2 (COX-2) AND GENES ARE INVOLVED IN TUMOUR REGULATION AND GROWTH. IN ONE HAND, GENE SILENCING AS AN EPIGENETIC PHENOMENON, AND IN THE OTHER HAND, GENE EXPRESSION ENHANCEMENT DUE TO POSSIBLE DEMETHYLATION, SIMULTANEOUSLY, CAN FACILITATE CARCINOGENESIS AND TUMORAL PROGRESSION. OUR AIM WAS TO RELATE CDH1, P16(INK4A), COX-2 AND EGFR GENES DNA METHYLATION WITH THE SEVERAL HISTOLOGICAL TYPES OF GASTRIC CARCINOMA AND CHRONIC GASTRITIS. WE STUDIED 55 FORMALIN FIXED PARAFFIN EMBEDDED GASTRIC BIOPSIES: 35 WERE GC SPECIMENS (12 DIFFUSE TYPE, 15 INTESTINAL TYPE AND 8 INDETERMINATE TYPE, ACCORDING TO LAUREN'S CLASSIFICATION) AND 20 SAMPLES HAD CHRONIC GASTRITIS (CG). THE DNA WAS TREATED WITH SODIUM BISULFITE AFTER EXTRACTION AND THEN PERFORMED METHYLATION SPECIFIC PCR (MSP). STATISTICAL ANALYSIS WAS BASED ON CHI-SQUARE TEST AND EXACT FISHER'S TEST. CPG ISLAND METHYLATION WAS DETECTED IN 94% OF THE GC SAMPLES FOR CDH1, 91% FOR COX-2, 80% FOR P16(INK4A) AND NO METHYLATION WAS DETECTED IN EGFR GENE (0%). IN CG, CPG ISLAND METHYLATION WAS FOUND IN 100% FOR CDH1 AND COX-2 GENES, 90% FOR P16(INK4A) AND 20% FOR EGFR. THESE RESULTS REVEAL SIGNIFICANT DIFFERENCES IN EGFR GENE METHYLATION DISTINGUISHING GC FROM CG (P < 0, 01), SUGGESTING THAT GENE DEMETHYLATION LEADS TO MALIGNANT TRANSFORMATION AND FAVOURS THE USE OF TYROSINE-KINASE INHIBITORS IN ITS TREATMENT. GENES COX2 E P16INK4A LOWER METHYLATION IN INTESTINAL AND DIFFUSE TYPES OF GC, FAVOURS THEIR DIFFERENT ROLE IN RESPECTIVE HISTOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  1161  47 CONTINUOUS DEVELOPMENTAL AND EARLY LIFE TRICHLOROETHYLENE EXPOSURE PROMOTED DNA METHYLATION ALTERATIONS IN POLYCOMB PROTEIN BINDING SITES IN EFFECTOR/MEMORY CD4(+) T CELLS. TRICHLOROETHYLENE (TCE) IS AN INDUSTRIAL SOLVENT AND DRINKING WATER POLLUTANT ASSOCIATED WITH CD4(+) T CELL-MEDIATED AUTOIMMUNITY. IN OUR MOUSE MODEL, DISCONTINUATION OF TCE EXPOSURE DURING ADULTHOOD AFTER DEVELOPMENTAL EXPOSURE DID NOT PREVENT IMMUNOTOXICITY. TO DETERMINE WHETHER PERSISTENT EFFECTS WERE LINKED TO EPIGENETIC CHANGES WE CONDUCTED WHOLE GENOME REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO EVALUATE METHYLATION OF CPG SITES IN AUTOSOMAL CHROMOSOMES IN ACTIVATED EFFECTOR/MEMORY CD4(+) T CELLS. FEMALE MRL+/+ MICE WERE EXPOSED TO VEHICLE CONTROL OR TCE IN THE DRINKING WATER FROM GESTATION UNTIL ~37 WEEKS OF AGE [POSTNATAL DAY (PND) 259]. IN A SUBSET OF MICE, TCE EXPOSURE WAS DISCONTINUED AT ~22 WEEKS OF AGE (PND 154). AT PND 259, RRBS ASSESSMENT REVEALED MORE GLOBAL METHYLATION CHANGES IN THE CONTINUOUS EXPOSURE GROUP VS. THE DISCONTINUOUS EXPOSURE GROUP. A MAJORITY OF THE DIFFERENTIALLY METHYLATED CPG REGIONS (DMRS) ACROSS PROMOTERS, ISLANDS, AND REGULATORY ELEMENTS WERE HYPERMETHYLATED (~90%). HOWEVER, CONTINUOUS DEVELOPMENTAL TCE EXPOSURE ALTERED THE METHYLATION OF 274 CPG SITES IN PROMOTERS AND CPG ISLANDS. IN CONTRAST, ONLY 4 CPG ISLAND REGIONS WERE DIFFERENTIALLY METHYLATED (HYPERMETHYLATED) IN THE DISCONTINUOUS GROUP. INTERESTINGLY, 2 OF THESE 4 SITES WERE ALSO HYPERMETHYLATED IN THE CONTINUOUS EXPOSURE GROUP, AND BOTH OF THESE ISLAND REGIONS ARE ASSOCIATED WITH LYSINE 27 ON HISTONE H3 (H3K27) INVOLVED IN POLYCOMB COMPLEX-DEPENDENT TRANSCRIPTIONAL REPRESSION VIA H3K27 TRI-METHYLATION. CPG SITES WERE OVERLAPPED WITH THE OPEN REGULATORY ANNOTATION DATABASE. UNLIKE THE DISCONTINUOUS GROUP, CONTINUOUS TCE TREATMENT RESULTED IN 129 DMRS INCLUDING 12 UNIQUE TRANSCRIPTION FACTORS AND REGULATORY ELEMENTS; 80% OF WHICH WERE ENRICHED FOR ONE OR MORE POLYCOMB GROUP (PCG) PROTEIN BINDING REGIONS (I.E., SUZ12, EZH2, JARID2, AND MTF2). PATHWAY ANALYSIS OF THE DMRS INDICATED THAT TCE PRIMARILY ALTERED THE METHYLATION OF GENES ASSOCIATED WITH REGULATION OF CELLULAR METABOLISM AND CELL SIGNALING. THE RESULTS DEMONSTRATED THAT CONTINUOUS DEVELOPMENTAL EXPOSURE TO TCE DIFFERENTIALLY METHYLATED BINDING SITES OF PCG PROTEINS IN EFFECTOR/MEMORY CD4(+) CELLS. THERE WERE MINIMAL YET POTENTIALLY BIOLOGICALLY SIGNIFICANT EFFECTS THAT OCCURRED WHEN EXPOSURE WAS DISCONTINUED. THESE RESULTS POINT TOWARD A NOVEL MECHANISM BY WHICH CHRONIC DEVELOPMENTAL TCE EXPOSURE MAY ALTER TERMINALLY DIFFERENTIATED CD4(+) T CELL FUNCTION IN ADULTHOOD.	2019	

18   603  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19   729  33 CANCER ANGIOGENESIS INDUCED BY KAPOSI SARCOMA-ASSOCIATED HERPESVIRUS IS MEDIATED BY EZH2. EZH2 IS A COMPONENT OF THE EPIGENETIC REGULATOR PRC2 THAT SUPPRESSES GENE EXPRESSION. ELEVATED EXPRESSION OF EZH2 IS COMMON IN HUMAN CANCERS AND IS ASSOCIATED WITH TUMOR PROGRESSION AND POOR PROGNOSIS. IN THIS STUDY, WE SHOW THAT EZH2 ELEVATION IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS OF KAPOSI SARCOMA-ASSOCIATED HERPESVIRUS (KSHV), AN ONCOGENIC VIRUS THAT PROMOTES THE DEVELOPMENT OF KAPOSI SARCOMA AND OTHER MALIGNANCIES THAT OCCUR IN PATIENTS WITH CHRONIC HIV INFECTIONS. KSHV INDUCTION OF EZH2 EXPRESSION WAS ESSENTIAL FOR KSHV-INDUCED ANGIOGENESIS. HIGH EXPRESSION OF EZH2 WAS OBSERVED IN KAPOSI SARCOMA TUMORS. IN CELL CULTURE, LATENT KSHV INFECTION UPREGULATED THE EXPRESSION OF EZH2 IN HUMAN ENDOTHELIAL CELLS THROUGH THE EXPRESSION OF VFLIP AND LANA, TWO KSHV-LATENT GENES THAT ACTIVATE THE NF-KAPPAB PATHWAY. KSHV-MEDIATED UPREGULATION OF EZH2 WAS REQUIRED FOR THE INDUCTION OF EPHRIN-B2, AN ESSENTIAL PROANGIOGENIC FACTOR THAT DRIVES ENDOTHELIAL CELL TUBULE FORMATION. TAKEN TOGETHER, OUR FINDINGS INDICATE THAT KSHV REGULATES THE HOST EPIGENETIC MODIFIER EZH2 TO PROMOTE ANGIOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  4014  40 LOW-DOSE CD INDUCES HEPATIC GENE HYPERMETHYLATION, ALONG WITH THE PERSISTENT REDUCTION OF CELL DEATH AND INCREASE OF CELL PROLIFERATION IN RATS AND MICE. BACKGROUND: CADMIUM (CD) IS CLASSIFIED AS A HUMAN CARCINOGEN PROBABLY ASSOCIATED WITH EPIGENETIC CHANGES. DNA METHYLATION IS ONE OF EPIGENETIC MECHANISMS BY WHICH CELLS CONTROL GENE EXPRESSION. THEREFORE, THE PRESENT STUDY GENOME-WIDELY SCREENED THE METHYLATION-ALTERED GENES IN THE LIVER OF RATS PREVIOUSLY EXPOSED TO LOW-DOSE CD. METHODOLOGY PRINCIPAL FINDINGS: RATS WERE EXPOSED TO CD AT 20 NMOL/KG EVERY OTHER DAY FOR 4 WEEKS AND GENE METHYLATION WAS ANALYZED AT THE 48(TH) WEEK WITH METHYLATED DNA IMMUNOPRECIPITATION-CPG ISLAND MICROARRAY. AMONG THE 1629 ALTERED GENES, THERE WERE 675 GENES WHOSE PROMOTER CPG ISLANDS (CGIS) WERE HYPERMETHYLATED, 899 GENES WHOSE PROMOTER CGIS WERE HYPOMETHYLATED, AND 55 GENES WHOSE PROMOTER CGIS WERE MIXED WITH HYPER- AND HYPO-METHYLATION. CASPASE-8 GENE PROMOTER CGIS AND TNF GENE PROMOTER CGIS WERE HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, ALONG WITH A LOW APOPTOSIS RATE IN CD-TREATED RAT LIVERS. TO LINK THE ABERRANT METHYLATION OF CASPASE-8 AND TNF GENES TO THE LOW APOPTOSIS INDUCED BY LOW-DOSE CD, MICE WERE GIVEN CHRONIC EXPOSURE TO LOW-DOSE CD WITH AND WITHOUT METHYLATION INHIBITOR (5-AZA-2'-DEOXYCTIDENE, 5-AZA). AT THE 48(TH) WEEK AFTER CD EXPOSURE, LIVERS FROM CD-TREATED MICE DISPLAYED THE INCREASED CASPASE-8 CGI METHYLATION AND DECREASED CASPASE-8 PROTEIN EXPRESSION, ALONG WITH SIGNIFICANT INCREASES IN CELL PROLIFERATION AND OVEREXPRESSION OF TGF-BETA1 AND CYTOKERATIN 8/18 (THE LATTER IS A NEW MARKER OF MOUSE LIVER PRENEOPLASTIC LESIONS), ALL WHICH WERE PREVENTED BY 5-AZA TREATMENT. CONCLUSION/SIGNIFICANCE: THESE RESULTS SUGGEST THAT CD-INDUCED GLOBAL GENE HYPERMETHYLATION, MOST LIKELY CASPASE-8 GENE PROMOTER HYPERMETHYLATION THAT DOWN-REGULATED ITS EXPRESSION, LEADING TO THE DECREASED HEPATIC APOPTOSIS AND INCREASED PRENEOPLASTIC LESIONS.	2012