1  850 125 CHILDREN WITH CHRONIC IMMUNE THROMBOCYTOPENIA EXHIBIT HIGH EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUSES TRIM28 AND SETDB1. CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) IS AN AUTOIMMUNE DISEASE WHOSE UNDERLYING BIOLOGIC MECHANISMS REMAIN ELUSIVE. HUMAN ENDOGENOUS RETROVIRUSES (HERVS) DERIVE FROM ANCESTRAL INFECTIONS AND CONSTITUTE ABOUT 8% OF OUR GENOME. A WEALTH OF CLINICAL AND EXPERIMENTAL STUDIES HIGHLIGHTS THEIR PIVOTAL PATHOGENETIC ROLE IN AUTOIMMUNE DISEASES. EPIGENETIC MECHANISMS, SUCH AS THOSE MODULATED BY TRIM28 AND SETDB1, ARE INVOLVED IN HERV ACTIVATION AND REGULATION OF IMMUNE RESPONSE. WE ASSESSED, THROUGH A POLYMERASE CHAIN REACTION REAL-TIME TAQMAN AMPLIFICATION ASSAY, THE TRANSCRIPTION LEVELS OF POL GENES OF HERV-H, HERV-K, AND HERV-W; ENV GENES OF SYNCYTIN (SYN)1, SYN2, AND HERV-W; AS WELL AS TRIM28 AND SETDB1 IN WHOLE BLOOD FROM 34 CHILDREN WITH CITP AND AGE-MATCHED HEALTHY CONTROLS (HC). THE TRANSCRIPTIONAL LEVELS OF ALL HERV SEQUENCES, WITH THE EXCEPTION OF HERV-W-ENV, WERE SIGNIFICANTLY ENHANCED IN CHILDREN WITH CITP AS COMPARED TO HC. PATIENTS ON ELTROMBOPAG TREATMENT EXHIBITED LOWER EXPRESSION OF SYN1, SYN2, AND HERV-W-ENV AS COMPARED TO UNTREATED PATIENTS. THE MRNA CONCENTRATIONS OF TRIM28 AND SETDB1 WERE SIGNIFICANTLY HIGHER AND WERE POSITIVELY CORRELATED WITH THOSE OF HERVS IN CITP PATIENTS. THE OVER-EXPRESSIONS OF HERVS AND TRIM28/SETDB1 AND THEIR POSITIVE CORRELATIONS IN PATIENTS WITH CITP ARE SUGGESTIVE CLUES OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF THE DISEASE AND SUPPORT INNOVATIVE INTERVENTIONS TO INHIBIT HERV AND TRIM28/SETDB1 EXPRESSIONS IN PATIENTS UNRESPONSIVE TO STANDARD THERAPIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2 1791  21 EFFECT OF CHRONIC RADIATION ON THE FLAX (LINUM USITATISSIMUM L.) GENOME GROWN FOR SIX CONSECUTIVE GENERATIONS IN THE RADIOACTIVE CHERNOBYL AREA. THE GROWTH OF PLANTS UNDER CHRONIC RADIATION STRESS IN THE CHERNOBYL AREA MAY CAUSE CHANGES IN THE GENOME OF PLANTS. TO ASSESS THE EXTENT OF GENETIC AND EPIGENETIC CHANGES IN NUCLEAR DNA, SEEDS OF THE ANNUAL CROP FLAX (LINUM USITATISSIMUM L.) OF THE KYIVSKYI VARIETY, SOWN 21 YEARS AFTER THE ACCIDENT AND GROWN FOR SIX GENERATIONS IN RADIOACTIVE (RAD) AND REMEDIATED (REM) FIELDS WERE ANALYSED. FLAXSEED USED FOR SOWING FIRST GENERATION, WHICH SERVED AS A REFERENCE (REF), WAS ALSO ANALYSED. THE AFLP (AMPLIFIED FRAGMENT LENGTH POLYMORPHISM) REVEALED A HIGHER NUMBER OF SPECIFIC ECORI-MSEI LOCI (3.4-FOLD) IN POOLED FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH THE REM FIELD, INDICATING A LINK BETWEEN THE MUTATION PROCESS IN THE FLAX GENOME AND THE ONGOING ADAPTATION PROCESS. MSAP (METHYLATION-SENSITIVE AMPLIFIED POLYMORPHISM) DETECTING ECORI-MSPI AND ECORI-HPAII LOCI IN FLAX NUCLEAR DNA GENOME SHOWED NO SIGNIFICANT DIFFERENCES IN METHYLATION LEVEL, REACHING ABOUT 33% IN EACH OF THE GROUPS STUDIED. ON THE OTHER HAND, SIGNIFICANT CHANGES IN THE DNA METHYLATION PATTERN OF FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH CONTROLS WERE DETECTED. PAIRWISE F(ST) COMPARISON REVEALED WITHIN BOTH, ECORI-MSPI AND TRANSFORMED METHYLATION-SENSITIVE DATA SETS MORE THAN A 3-FOLD INCREASE OF GENETIC DIVERGENCE IN THE RAD FIELD COMPARED WITH BOTH CONTROLS. THESE RESULTS INDICATE THAT THE NUCLEAR GENOME OF FLAX EXPOSED TO CHRONIC RADIATION FOR SIX GENERATIONS HAS MORE MUTATIONS AND USES DNA METHYLATION AS ONE OF THE ADAPTATION MECHANISMS FOR SUSTAINABILITY UNDER ADVERSE CONDITIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 1421  25 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 6636  42 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5 2080  21 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6 1951  31 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7 1843  27 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8 1016  23 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9   16  35 4CRNA NEAT1 SPONGE ADSORPTION OF MIR-378 MODULATES ACTIVITY OF LIPOPOLYSACCHARIDE-TREATED ARTICULAR CHONDROCYTES AND INFLUENCES THE PATHOLOGICAL DEVELOPMENT OF OSTEOARTHRITIS. CONTEXT: OSTEOARTHRITIS (OA) IS A CHRONIC JOINT DISEASE THAT CAN EVENTUALLY LEAD TO DEGENERATION, FIBROSIS, FRACTURES, AND DEFECTS OF THE ARTICULAR CARTILAGE. LONG NON-CODING RNA (LNCRNA) IS A KEY SUBSTANCE IN MANY PROCESSES, SUCH AS EPIGENETIC REGULATION AND CELL-CYCLE AND CELL-DIFFERENTIATION MODULATION, AND ITS RELATIONSHIP WITH OA HAS BEEN REPEATEDLY VERIFIED. OBJECTIVE: THE STUDY INTENDED TO CLARIFY THE INFLUENCE OF LNCRNA NUCLEAR ENRICHED ABUNDANT TRANSCRIPT 1 (NEAT1), LNCRNA NEAT1, ON LIPOPOLYSACCHARIDE (LPS)-INDUCED OA CHONDROCYTES THROUGH SPONGE ADSORPTION OF MICRORNA-378 (MIR-378) AND TO PROVIDE NOVEL INSIGHTS INTO FUTURE DIAGNOSIS AND TREATMENT OF OA. DESIGN: THE RESEARCH TEAM PERFORMED AN ANIMAL STUDY. SETTING: THE STUDY TOOK PLACE IN THE DEPARTMENT OF REHABILITATION MEDICINE AT LINYI PEOPLE'S HOSPITAL IN LINYI, SHANGDONG, CHINA. ANIMALS: THE STUDY'S ANIMALS WERE 10 SPRAGUE DAWLEY (SD) RATS, 3-5 DAYS OLD AND 10-15 G IN WEIGHT, OF THE SPECIFIC-PATHOGEN-FREE (SPF) GRADE. INTERVENTION: THE RAT CHONDROCYTES FOR THE POSITIVE CONTROL GROUP (THE MODEL GROUP) WERE TREATED WITH 500 NG/ML OF LPS TO INDUCE OA. CHONDROCYTES TREATED WITH THE SAME AMOUNT OF NORMAL SALINE WERE USED AS THE NEGATIVE CONTROL GROUP. THE CHONDROCYTES OF THE LPS-INDUCED RATS WERE INTO SIX GROUPS: (1) A POSITIVE CONTROL GROUP TRANSFECTED WITH NEAT1-INTERFERING RNA, THE SH-NEAT1 GROUP; (2) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH NEAT1-INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) GROUP; (3) AN INTERVENTION GROUP CO-TRANSFECTED WITH NEAT1 INTERFERING RNA AND THE MIR-378 INHIBITOR SEQUENCE (INH-MIR-378 THE SH-NEAT1+ INH-MIR-378 GROUP; (4) A NEGATIVE CONTROL GROUP TRANSFECTED WITH NEAT1 INTERFERING RNA BUT NOT TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE, THE SH-NEAT1+ MIR-378 NEGATIVE CONTROL (NC-MIR-378) GROUP; (5) A NEGATIVE CONTROL GROUP TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE BUT NOT TRANSFECTED WITH NEAT1 INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) + INH-MIR-378 GROUP; (6) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH EITHER NEAT1 INTERFERING RNA OR THE MIR-378 INHIBITOR SEQUENCE, THE NC-NEAT1 + NC-MIR-378 GROUP. OUTCOME MEASURES: AN OA-CHONDROCYTE MODEL WAS INDUCED BY LPS AND MEASUREMENTS OF NEAT1 AND MIR-378 EXPRESSION WERE MADE BY REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION (QRT)- POLYMERASE CHAIN REACTION (PCR). THEN, SMALL NEAT1-INTERFERING RNA (SH-NEAT1), EMPTY VECTOR NEAT1 (NC-NEAT1), INHIBITOR-SEQUENCE-MIR-378 (INH-MIR-378), AND NEGATIVE-CONTROL-MIR-378 (NC-MIR-378) WERE TRANSFECTED INTO CELLS, AND CELL VIABILITY AND APOPTOSIS RATE WERE MEASURED. FINALLY, THE STUDY VERIFIED THE RELATIONSHIP BETWEEN NEAT1 AND MIR-378. RESULTS: COMPARED TO THE CONTROL GROUP, NEAT1 WAS SIGNIFICANTLY ELEVATED IN THE MODEL GROUP, AND ITS MIR-378 WAS SIGNIFICANTLY DECREASED. SILENCING NEAT1 CAN ENHANCE OA-CHONDROCYTE ACTIVITY AND DECREASE APOPTOSIS. WHEN NEAT1 AND MIR-378 WERE INHIBITED TOGETHER, AS SHOWN FORT THE NC-NEAT1 + NC-MIR-378 GROUP, NEAT1 EXPRESSION, AS WELL AS THE MULTIPLICATION AND APOPTOSIS ABILITY OF THE OA-MODEL CELLS, WERE THE SAME AS THOSE OF CELLS TRANSFECTED WITH AN EMPTY VECTOR, THE NC-NEAT1 GROUP. ALSO, THE NEAT1 + NC-MIR-378 GROUP'S CELL ACTIVITY WAS LOWER THAN THAT OF THE SH-NEAT1+NC-MIR-378 GROUP BUT HIGHER THAN THAT OF THE NC-NEAT1 + INH-MIR-378 GROUP. FINALLY, HIGHER FLUORESCENCE ACTIVITY OCCURRED FOR NEAT1-MUTANT TYPE (MUT) TRANSFECTED WITH INH-MIR-378. CONCLUSIONS: NEAT1, WHICH IS HIGHLY EXPRESSED IN OA, MEDIATES LPS-INDUCED OA-CHONDROCYTE ACTIVITY THROUGH SPONGE ADSORPTION OF MIR-378.	2022	

10 2640  23 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 2649  15 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12 5017  19 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION.	1995	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  768  30 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 3945  35 LNCRNA IL21-AS1 INTERACTS WITH HNRNPU PROTEIN TO PROMOTE IL21 OVEREXPRESSION AND ABERRANT DIFFERENTIATION OF TFH CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS. BACKGROUND: THE ABERRANT DIFFERENTIATION OF T FOLLICULAR HELPER (TFH) CELLS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). HOWEVER, THE MECHANISM OF REGULATING TFH CELLS DIFFERENTIATION REMAINS UNCLEAR. LONG NONCODING RNAS (LNCRNAS) ACT AS IMPORTANT REGULATORS IN THE PROCESSES OF INNATE AND ADAPTIVE IMMUNE RESPONSE. WHETHER LNCRNAS ARE INVOLVED IN REGULATING TFH CELL DIFFERENTIATION AND AUTOIMMUNE RESPONSES NEED TO BE FURTHER IDENTIFIED. METHODS: THE CHARACTERS AND FUNCTIONS OF HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE INVESTIGATED BY A SERIES OF BIOCHEMICAL ASSAYS AND CELL TRANSFECTION ASSAY. MIL21-AS1 REGULATING HUMORAL IMMUNE RESPONSE IN VIVO WAS EXPLORED BY KEYHOLE LIMPET HAEMOCYANIN (KLH) AND CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) MODEL. RESULTS: HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE IDENTIFIED AND CLONED. WE UNCOVERED THAT IL21-AS1 WAS HIGHLY EXPRESSED IN CD4(+) T CELLS OF SLE PATIENTS AND TFH CELLS, WHICH PROMOTED DIFFERENTIATION OF TFH CELLS. MECHANISTICALLY, IL21-AS1 BOUND HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN U AND RECRUITED ACETYLTRANSFERASES CREB-BINDING PROTEIN TO THE PROMOTER OF IL21, LEADING TO THE TRANSCRIPTIONAL ACTIVATION OF IL21 AND TFH CELLS DIFFERENTIATION THROUGH INCREASING HISTONE H3 ACETYLATION LEVEL ON IL21 PROMOTER. MOREOVER, TFH PROPORTION AND ANTIBODIES PRODUCTION WERE SIGNIFICANTLY INCREASED IN MIL21-AS KNOCK-IN MICE IMMUNIZED WITH KLH. MIL21-AS1 OVEREXPRESSION ALSO EXACERBATED THE LUPUS-LIKE PHENOTYPE IN CGVHD MICE MODEL. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT IL21-AS1 ACTIVATES IL21 TRANSCRIPTION VIA EPIGENETIC MECHANISM TO PROMOTE GERMINAL CENTRE RESPONSE, ADDING INSIGHT INTO THE MOLECULAR REGULATION OF AUTOIMMUNE PATHOGENESIS AND PROVIDING A NOVEL TARGET FOR SLE TREATMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15 1217  28 CREG PROTECTS FROM MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY REGULATING MYOCARDIAL AUTOPHAGY AND APOPTOSIS. AIMS: HUMAN CELLULAR REPRESSOR OF E1A-STIMULATED GENES (CREG) IS A SECRETED GLYCOPROTEIN THAT REGULATES TISSUE AND CELL HOMEOSTASIS AND HAS BEEN SHOWN TO ANTAGONIZE HEART FIBROSIS, WHICH INDICATES A POTENTIAL PROTECTIVE EFFECT OF CREG AGAINST CARDIOMYOCYTE CHRONIC DAMAGE. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF CREG IN MYOCARDIAL TISSUE ACUTE INJURY, IN THIS STUDY, WE AIMED TO INVESTIGATE THE ROLE OF CREG IN MYOCARDIAL ISCHEMIA/REPERFUSION (MI/R) INJURY AND CLARIFY THE MECHANISM OF ACTION. METHODS AND RESULTS: WILD-TYPE CREG (CREG(+/+)), HETEROZYGOUS CREG (CREG(+/-)) MICE AND MICE PRETREATED WITH INFUSION OF RECOMBINANT 0.3MG/KG.D CREG PROTEIN (RECREG(+/+)) WERE SUBJECTED TO 30MIN OF LEFT ASCENDING CORONARY ISCHEMIA AND 24H OF REPERFUSION. EVAN'S BLUE-TRIPHENYL- TETRAZOLIUM CHLORIDE (TTC) SOLUTION AND ECHOCARDIOGRAPHY ANALYSIS WERE USED TO EVALUATE THE EFFECTS OF CREG ON MI/R MICE. THE UNDERLYING MECHANISMS WERE FURTHER DETERMINED BY CULTURED MYOCARDIAL CELLS IN VITRO. OUR FINDINGS REVEALED THAT THE LEVEL OF CREG PROTEIN IN MOUSE HEARTS WAS SIGNIFICANTLY DECREASED AFTER MICE WERE SUBJECTED TO MI/R. MOREOVER, CREG(+/-) MICE HAD LARGER INFARCTION SIZE 2H AFTER REPERFUSION AND WORSE CARDIAC FUNCTION 28DAYS AFTER MI/R INJURY COMPARED TO THAT IN CREG(+/+) MICE. HOWEVER, RECREG(+/+) MICE COULD MAINTAIN CREG AT A HIGH LEVEL EVEN AFTER MI/R INJURY, AND MITIGATED INFARCTION SIZE AND IMPROVED CARDIAC FUNCTION SIGNIFICANTLY. IN CREG(+/-) MICE, MYOCARDIAL AUTOPHAGY WAS DYSFUNCTIONAL CHARACTERIZED BY ACCUMULATION OF LC3A AND P62, WHILE APOPTOTIC CELL NUMBER INCREASE WAS DETECTED BY CLEAVED CASPASE-3 BLOTTING AND TUNEL STAINING. CONVERSELY, DECREASED APOPTOSIS AND ACTIVATED AUTOPHAGY WERE DETECTED IN RECREG(+/+) MICE. FURTHERMORE, CHLOROQUINE, A KIND OF AUTOPHAGY BLOCKER, WAS USED TO DEMONSTRATE RECOMBINANT CREG PROTECTED CARDIOMYOCYTES AGAINST APOPTOSIS MEDIATED BY ACTIVATING AUTOPHAGY BOTH IN VIVO AND IN VITRO. FINALLY, WE FOUND CREG WAS INVOLVED INTO LYSOSOMAL PROTEIN TRANSFER AND IMPROVE CELLULAR AUTOPHAGY. CONCLUSION: CREG PROTECTS HEART AGAINST MI/R INJURY-INDUCED CARDIOMYOCYTES APOPTOSIS BY ACTIVATING LYSOSOMAL AUTOPHAGY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN AND MEGAN YINGMEI ZHANG.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 3279  25 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17 1668  35 DOWNREGULATION OF SOCS1 INCREASES INTERFERON-INDUCED ISGYLATION DURING DIFFERENTIATION OF INDUCED-PLURIPOTENT STEM CELLS TO HEPATOCYTES. BACKGROUND & AIMS: INCREASED EXPRESSION OF IFN-STIMULATED GENE 15 (ISG15) AND SUBSEQUENTLY INCREASED ISGYLATION ARE KEY FACTORS IN THE HOST RESPONSE TO VIRAL INFECTION. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE EXPRESSION OF ISG15, ISGYLATION, AND ASSOCIATED ENZYMES AT EACH STAGE OF DIFFERENTIATION FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) TO HEPATOCYTES. METHODS: TO STUDY THE REGULATION OF ISGYLATION, WE UTILIZED PATIENT SAMPLES AND IN VITRO CELL CULTURE MODELS INCLUDING IPSCS, HEPATOCYTES-LIKE CELLS, IMMORTALIZED CELL LINES, AND PRIMARY HUMAN HEPATOCYTES. PROTEIN/MRNA EXPRESSION WERE MEASURED FOLLOWING TREATMENT WITH POLY(I:C), IFNALPHA AND HCV INFECTION. RESULTS: WHEN COMPARED TO HLCS, WE OBSERVED SEVERAL NOVEL ASPECTS OF THE ISGYLATION PATHWAY IN IPSCS. THESE INCLUDE A LOWER BASELINE EXPRESSION OF THE ISGYLATION-ACTIVATING ENZYME, UBE1L, A LACK OF IFN-INDUCED EXPRESSION OF THE ISGYLATION-CONJUGATION ENZYME UBE2L6, AN ATTENUATED ACTIVATION OF THE TRANSCRIPTION FACTOR STAT1 AND CONSTITUTIVE EXPRESSION OF SOCS1. ISGYLATION WAS OBSERVED IN IPSCS FOLLOWING DOWNREGULATION OF SOCS1, WHICH FACILITATED STAT1 ACTIVATION AND SUBSEQUENTLY INCREASED EXPRESSION OF UBE2L6. INTRIGUINGLY, HCV PERMISSIVE TRANSFORMED HEPATOMA CELL LINES DEMONSTRATED HIGHER INTRINSIC EXPRESSION OF SOCS1 AND WEAKER ISGYLATION FOLLOWING IFN TREATMENT. SOCS1 DOWNREGULATION IN HCV-INFECTED HUH 7.5.1 CELLS LED TO INCREASED ISGYLATION. CONCLUSIONS: HEREIN, WE SHOW THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. FURTHERMORE, AS IPSCS DIFFERENTIATE INTO HEPATOCYTES, EPIGENETIC MECHANISMS REGULATE ISGYLATION BY MODIFYING UBE1L AND SOCS1 EXPRESSION LEVELS. OVERALL, THIS STUDY DEMONSTRATES THAT THE DEVELOPMENT OF CELL-INTRINSIC INNATE IMMUNITY DURING THE DIFFERENTIATION OF IPSCS TO HEPATOCYTES PROVIDES INSIGHT INTO CELL TYPE-SPECIFIC REGULATION OF HOST DEFENSE RESPONSES AND RELATED ONCOGENIC PROCESSES. IMPACT AND IMPLICATIONS: TO ELUCIDATE THE MECHANISM UNDERLYING REGULATION OF ISGYLATION, A KEY PROCESS IN THE INNATE IMMUNE RESPONSE, WE STUDIED CHANGES IN ISGYLATION-ASSOCIATED GENES AT THE DIFFERENT STAGES OF DIFFERENTIATION FROM IPSCS TO HEPATOCYTES. WE FOUND THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. IMPORTANTLY, EPIGENETIC REGULATION OF SOCS1 AND SUBSEQUENTLY ISGYLATION MAY BE IMPORTANT FACTORS IN THE DEVELOPMENT OF CELL TYPE-SPECIFIC HOST DEFENSE RESPONSES IN HEPATOCYTES THAT SHOULD BE CONSIDERED WHEN STUDYING CHRONIC INFECTIONS AND ONCOGENIC PROCESSES IN THE LIVER.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 5487  20 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF.	1990	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  760  20 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  515  24 ASSOCIATION OF SOCS1 (- 820) (RS33977706) GENE POLYMORPHISM WITH CHRONIC PERIODONTITIS: A CASE-CONTROL STUDY IN BRAZILIANS. IT IS EVIDENT THAT THE ACCUMULATION OF PERIODONTAL PATHOGENS OVER THE TEETH SURFACE TRIGGERS PERIODONTITIS; HOWEVER, ITS AGGRAVATION AND SEVERITY DEPEND ON OTHER ELEMENTS SUCH AS ENVIRONMENTAL FACTORS, SYSTEMIC HEALTH AND THE HOST GENETIC AND/OR EPIGENETIC BACKGROUND. TO ADDRESS THIS ISSUE, WE INVESTIGATED THE ASSOCIATION OF TWO GENETIC POLYMORPHISMS PLACED ON PROMOTER REGION OF SOCS1 GENE WITH CHRONIC PERIODONTAL DISEASE. SOCS1 REGULATES JAK/KINASE SIGNALING PATHWAY AND CHANGES IN ITS MRNA EXPRESSION HAVE BEEN RELATED TO DIFFERENT TYPES OF CANCER AND CHRONIC INFLAMMATION, INCLUDING CHRONIC PERIODONTITIS. THE FREQUENCY OF ALLELES AND GENOTYPES OF TWO POLYMORPHISMS IN SOCS1 GENE PROMOTER (POSITION - 820 (RS33977706) AND POSITION - 1478 (RS33989964)) WERE ANALYZED BY PERFORMING RFLP AND TAQMAN SYSTEM IN A TOTAL OF 257 NON-SMOKING SUBJECTS. WE FOUND A LOW FREQUENCY OF A ALLELE AND A/A GENOTYPE OF SOCS1(- 820) POLYMORPHISM IN THE CHRONIC PERIODONTITIS GROUP, ESPECIALLY WHEN SEVERE PERIODONTITIS SAMPLES WERE SEPARATELY ANALYZED (OR = 0.3933; P = 0.0084 (IC95% 0.2112 < MU < 0.7324)), SUGGESTING THAT A ALLELE PLAYS PROTECTIVE EFFECT AGAINST CHRONIC PERIODONTITIS. WE DID NOT FIND ASSOCIATION BETWEEN SOCS1-1478 POLYMORPHISM AND PERIODONTITIS. IN ADDITION, ANALYSIS OF SOCS1 (- 820/- 1478) HAPLOTYPE REVEALED THAT THE FREQUENCY OF A(- 820)/CA(- 1478) HAPLOTYPE DECREASES IN CHRP (P = 0.0089). IN CONCLUSION, OUR STUDY FOUND THAT SOCS1(- 820) POLYMORPHISM IS ASSOCIATED WITH CHRONIC PERIODONTITIS.	2015