1  1866 123 EMERGING CROSSTALK BETWEEN LONG NON-CODING RNAS AND NRF2 SIGNALING. DIVERSE STIMULI TRIGGER NRF2 SIGNALING, WHICH IN TURN TRANSCRIPTIONALLY REGULATES AN ARRAY OF DOWNSTREAM TARGETS, PROVIDING FOR MULTIPLE LAYERS OF CONTROL. WHILE NRF2 ACTIVITY LARGELY IS GOVERNED BY POSTTRANSLATIONAL MODIFICATION OF CRITICAL THIOL RESIDUES IN THE PROTEIN PARTNER AND REDOX SENSOR KEAP1, FINE-TUNING IS PROVIDED BY ADDITIONAL MECHANISMS - INCLUDING EPIGENETIC REGULATION. HEREIN, WE REVIEW THE EMERGING SIGNIFICANCE OF LONG NON-CODING RNAS (LNCRNA) AS DOWNSTREAM TARGETS AND UPSTREAM REGULATORS OF THE NRF2 SIGNALING PATHWAY. AMONG THE ~16000 LNCRNAS IN GENCODE, SOME HAVE BEEN VALIDATED AS TRANSCRIPTIONALLY REGULATED BY NRF2 (E.G., LUCAT1, NMRAL2P, ODRUL, ROR AND TUG1), AND OTHERS HAVE BEEN IDENTIFIED AS UPSTREAM REGULATORS OF NRF2 EXPRESSION (E.G., HOTAIR, MALAT1, MEG1, NRAL AND UCA1). BIOINFORMATIC ANALYSES OF ANNOTATED HUMAN LNCRNAS IDENTIFIED PUTATIVE NRF2 BINDING SITES IN THE PROMOTER REGIONS OF 13,285 LNCRNAS. FURTHER INVESTIGATION IS WARRANTED TO VALIDATE THE MANY NOVEL LNCRNAS AS BONA FIDE NRF2-REGULATED TARGETS, AND THEIR ROLES IN NRF2 SIGNALING. NRF2 IS CONSIDERED A PROMISING THERAPEUTIC CANDIDATE FOR CANCER AND OTHER CHRONIC DISEASES; THUS, TARGETING THE ASSOCIATED LNCRNAS MIGHT PROVIDE FOR A MORE REFINED FINE-TUNING OF THE SYSTEM, DEPENDING ON CELLULAR AND PATHOPHYSIOLOGICAL CONTEXT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  6752  29 WIDESPREAD EXONIZATION OF TRANSPOSABLE ELEMENTS IN HUMAN CODING SEQUENCES IS ASSOCIATED WITH EPIGENETIC REGULATION OF TRANSCRIPTION. TRANSPOSABLE ELEMENTS (TES) HAVE LONG BEEN REGARDED AS SELFISH OR JUNK DNA HAVING LITTLE OR NO ROLE IN THE REGULATION OR FUNCTIONING OF THE HUMAN GENOME. HOWEVER, OVER THE PAST SEVERAL YEARS THIS VIEW CAME TO BE CHALLENGED AS SEVERAL STUDIES PROVIDED ANECDOTAL AS WELL AS GLOBAL EVIDENCE FOR THE CONTRIBUTION OF TES TO THE REGULATORY AND CODING NEEDS OF HUMAN GENES. IN THIS STUDY, WE EXPLORED THE INCORPORATION AND EPIGENETIC REGULATION OF CODING SEQUENCES DONATED BY TES USING GENE EXPRESSION AND OTHER ANCILLARY GENOMICS DATA FROM TWO HUMAN HEMATOPOIETIC CELL-LINES: GM12878 (A LYMPHOBLASTOID CELL LINE) AND K562 (A CHRONIC MYELOGENOUS LEUKEMIA CELL LINE). IN EACH CELL LINE, WE FOUND SEVERAL THOUSAND INSTANCES OF TES DONATING CODING SEQUENCES TO HUMAN GENES. WE COMPARED THE TRANSCRIPTOME ASSEMBLY OF THE RNA SEQUENCING (RNA-SEQ) READS WITH AND WITHOUT THE AID OF A REFERENCE TRANSCRIPTOME AND FOUND THAT THE PERCENTAGE OF GENES THAT INCORPORATE TES IN THEIR CODING SEQUENCES IS SIGNIFICANTLY GREATER THAN THAT OBTAINED FROM THE REFERENCE TRANSCRIPTOME ASSEMBLIES USING REFSEQ AND GENCODE GENE MODELS. WE ALSO USED HISTONE MODIFICATIONS CHROMATIN IMMUNOPRECIPITATION SEQUENCING (CHIP-SEQ) DATA, CAP ANALYSIS OF GENE EXPRESSION (CAGE) DATA AND DNASEI HYPERSENSITIVITY SITE (DHS) DATA TO DEMONSTRATE THE EPIGENETIC REGULATION OF THE TE DERIVED CODING SEQUENCES. OUR RESULTS SUGGEST THAT TES FORM A SIGNIFICANTLY HIGHER PERCENTAGE OF CODING SEQUENCES THAN REPRESENTED IN GENE ANNOTATION DATABASES AND THESE TE DERIVED SEQUENCES ARE EPIGENETICALLY REGULATED IN ACCORDANCE WITH THEIR EXPRESSION IN THE TWO CELL TYPES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  4538  23 MULTISCALE APPROACH TO DECIPHERING THE MOLECULAR MECHANISMS INVOLVED IN THE DIRECT AND INTERGENERATIONAL EFFECT OF IBUPROFEN ON MOSQUITO AEDES AEGYPTI. THE ANTI-INFLAMMATORY IBUPROFEN IS A UBIQUITOUS SURFACE WATER CONTAMINANT. HOWEVER, THE CHRONIC IMPACT OF THIS PHARMACEUTICAL ON AQUATIC INVERTEBRATE POPULATIONS REMAINS POORLY UNDERSTOOD. IN MODEL INSECT AEDES AEGYPTI, WE INVESTIGATED THE INTERGENERATIONAL CONSEQUENCES OF PARENTAL CHRONIC EXPOSURE TO AN ENVIRONMENTALLY RELEVANT CONCENTRATION OF IBUPROFEN. WHILE EXPOSED INDIVIDUALS DID NOT SHOW ANY PHENOTYPIC CHANGES, THEIR PROGENY SHOWED ACCELERATED DEVELOPMENT AND AN INCREASED TOLERANCE TO STARVATION. IN ORDER TO UNDERSTAND THE MECHANISTIC PROCESSES UNDERPINNING THE DIRECT AND INTERGENERATIONAL IMPACTS OF IBUPROFEN, WE COMBINED TRANSCRIPTOMIC, METABOLOMICS, AND HORMONE KINETICS STUDIES AT SEVERAL LIFE STAGES IN EXPOSED INDIVIDUALS AND THEIR PROGENY. THIS INTEGRATIVE APPROACH REVEALED MODERATE TRANSCRIPTIONAL CHANGES IN EXPOSED LARVAE CONSISTENT WITH THE PHARMACOLOGICAL MODE OF ACTION OF IBUPROFEN. PARENTAL EXPOSURE LED TO LOWER LEVELS OF SEVERAL POLAR METABOLITES IN PROGENY EGGS AND TO MAJOR TRANSCRIPTIONAL CHANGES IN THE FOLLOWING LARVAL STAGE. THESE TRANSCRIPTIONAL CHANGES, MOST LIKELY DRIVEN BY CHANGES IN THE EXPRESSION OF NUMEROUS TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS, LED TO ECDYSONE SIGNALING AND STRESS RESPONSE POTENTIATION. OVERALL, THE PRESENT STUDY ILLUSTRATES THE COMPLEXITY OF THE MOLECULAR BASIS OF THE INTERGENERATIONAL POLLUTANT RESPONSE IN INSECTS AND THE IMPORTANCE OF CONSIDERING THE ENTIRE LIFE CYCLE OF EXPOSED ORGANISMS AND OF THEIR PROGENY IN ORDER TO FULLY UNDERSTAND THE MODE OF ACTION OF POLLUTANTS AND THEIR IMPACT ON ECOSYSTEMS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  6233  19 THE LONG NONCODING RNA TUG1 CONNECTS METABOLIC CHANGES WITH KIDNEY DISEASE IN PODOCYTES. AN INCREASING AMOUNT OF EVIDENCE SUGGESTS THAT METABOLIC ALTERATIONS PLAY A KEY ROLE IN CHRONIC KIDNEY DISEASE (CKD) PATHOGENESIS. IN THIS ISSUE OF THE JCI, LONG ET AL. REPORT THAT THE LONG NONCODING RNA (LNCRNA) TAURINE-UPREGULATED 1 (TUG1) CONTRIBUTES TO CKD DEVELOPMENT. THE AUTHORS SHOW THAT TUG1 REGULATES MITOCHONDRIAL FUNCTION IN PODOCYTES BY EPIGENETIC TARGETING OF EXPRESSION OF THE TRANSCRIPTION FACTOR PPARGAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA, ENCODED BY PPARGC1A). TRANSGENIC OVEREXPRESSION OF TUG1 SPECIFICALLY IN PODOCYTES AMELIORATED DIABETES-INDUCED CKD IN MICE. TOGETHER, THESE RESULTS HIGHLIGHT AN IMPORTANT CONNECTION BETWEEN LNCRNA-MEDIATED METABOLIC ALTERATIONS IN PODOCYTES AND KIDNEY DISEASE DEVELOPMENT.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  3947  23 LNCRNA UCA1 INDUCES AUTOPHAGIC GENE EXPRESSION VIA EPIGENETIC REGULATION MEDIATED BY ATG16L1 AND MIR-132-3P IN SH-SY5Y CELLS TREATED WITH RETINOIC ACID. OBJECTIVE: EPILEPSY IS A CHRONIC BRAIN DISEASE WITH RECURRENT SEIZURES. AUTOPHAGY PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF EPILEPSY. THIS STUDY AIMED TO EXPLORE THE FUNCTION AND INTRINSIC MECHANISM OF THE LONG NON-CODING RNA (LNCRNA) UCA1/MIR-132-3P/ATG16L1 AXIS IN EPILEPSY VIA REGULATION OF AUTOPHAGY. METHODS: THE EXPRESSION OF LNCRNA UCA1, MIR-132-3P AND ATG16L1 WAS MEASURED IN SERUM FROM EPILEPTIC PATIENTS BY QUANTITATIVE RT-PCR. A SH-SY5Y CELL MODEL WAS FURTHER CONSTRUCTED USING RETINOIC ACID TO INVESTIGATE THE UCA1/ MIR-132-3P/ATG16L1 AXIS BY QUANTITATIVE RT-PCR, WESTERN BLOTTING, FLUORESCENCE IN SITU HYBRIDISATION, RNA IMMUNOPRECIPITATION, CHROMATIN IMMUNOPRECIPITATION, AND A DUAL-LUCIFERASE REPORTER GENE ASSAY. RESULTS: IN THE SERUM OF EPILEPTIC PATIENTS, THE LEVEL OF LNCRNA UCA1 AND ATG16L1 WAS REDUCED AND MIR-132-3P ELEVATED, COMPARED TO CONTROLS. SIMILARLY, IN THE SH-SY5Y CELL MODEL, THE LEVEL OF LNCRNA UCA1 AND ATG16L1 WAS REDUCED AND MIR-132-3P ELEVATED IN RETINOIC ACID-TREATED CELLS; LNCRNA UCA1 WAS MAINLY LOCATED IN THE CYTOPLASM. LNCRNA UCA1 OVEREXPRESSION WAS SHOWN TO PROMOTE AUTOPHAGIC GENE EXPRESSION, WHICH WAS REVERSED BY MIR-132-3P OVEREXPRESSION. MOREOVER, AUTOPHAGIC GENE EXPRESSION INDUCED BY MIR-132-3P KNOCKDOWN WAS REVERSED BY ATG16L1 KNOCKDOWN. BASED ON PRECIPITATION ASSAYS, LNCRNA UCA1 AND MIR-132-3P WERE SHOWN TO FORM A COMPLEX WITH THE TRANSCRIPTION FACTOR, EZH2, AND MIR-132-3P WAS SHOWN TO INTERACT WITH ATG16L1 BASED ON A LUCIFERASE ASSAY. FINALLY, LNCRNA UCA1 WAS SHOWN TO NEGATIVELY REGULATE MIR-132-3P EXPRESSION, AND MIR-132-3P WAS SHOWN TO NEGATIVELY REGULATE ATG16L1. SIGNIFICANCE: IN THIS CELL MODEL, LNCRNA UCA1 PROMOTES AUTOPHAGIC GENE EXPRESSION VIA EPIGENETIC REGULATION MEDIATED BY ATG16L1 AND MIR-132-3P.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                     
6  3000  31 GENETIC VARIATIONS IN UCA1, A LNCRNA FUNCTIONING AS A MIRNA SPONGE, DETERMINE ENDOMETRIOSIS DEVELOPMENT AND THE POTENTIAL ASSOCIATED INFERTILITY VIA REGULATING LIPOGENESIS. ENDOMETRIOSIS IS A HORMONE-ASSOCIATED DISEASE WHICH HAS BEEN CONSIDERED AS THE PRECURSOR FOR CERTAIN TYPES OF OVARIAN CANCER. IN RECENT YEARS, EMERGING EVIDENCE DEMONSTRATED POTENT ROLES OF LNCRNA IN REGULATING CANCER DEVELOPMENT. SINCE ENDOMETRIOSIS SHARES SEVERAL FEATURES WITH CANCER, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF CANCER-RELATED LNCRNAS IN ENDOMETRIOSIS, INCLUDING UCA1, GAS5 AND PTENP1. BY USING MASSARRAY SYSTEM, WE INVESTIGATED CERTAIN GENETIC VARIATIONS IN CANCER-RELATED LNCRNAS THAT CAN CHANGE THE THERMO-STABILITY, LEADING TO UP-REGULATION OR DOWN-REGULATION OF THOSE LNCRNAS. OUR DATA INDICATED THREE RISK GENETIC HAPLOTYPES IN UCA1 WHICH CAN STABILIZE THE RNA STRUCTURE AND INCREASE THE SUSCEPTIBILITY OF ENDOMETRIOSIS. OF NOTE, SUCH ALTERATIONS WERE FOUND TO BE ASSOCIATED WITH LONG-TERM PAIN AND INFERTILITY IN PATIENTS. IT HAS BEEN KNOWN THAT UCA1 CAN FUNCTION AS A CERNA TO SPONGE AND INHIBIT MIRNAS, RESULTING IN LOSS-OF-CONTROL ON DOWNSTREAM TARGET GENES. GENE NETWORK ANALYSES REVEALED FATTY ACID METABOLISM AND MITOCHONDRIA BETA-OXIDATION AS THE MAJOR PATHWAYS ASSOCIATED WITH ALTERED UCA1 EXPRESSION IN ENDOMETRIOSIS PATIENTS. OUR STUDY THUS PROVIDES EVIDENCE TO HIGHLIGHT FUNCTIONAL/EPIGENETIC ROLES OF UCA1 IN ENDOMETRIOSIS DEVELOPMENT VIA REGULATING FATTY ACID METABOLISM IN WOMEN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  1129  33 COMPREHENSIVE ANALYSIS OF MRNA-LNCRNA CO-EXPRESSION PROFILES IN MOUSE BRAIN DURING INFECTION WITH TOXOPLASMA GONDII. TOXOPLASMA GONDII IS AN OBLIGATE INTRACELLULAR PROTOZOAN PARASITE WHICH SERIOUSLY THREATENS THE HEALTH OF DOMESTIC ANIMALS AND HUMANS. LONG NON-CODING RNAS (LNCRNAS) ARE NON-PROTEIN-CODING TRANSCRIPTS GREATER THAN 200 NUCLEOTIDES, WHICH ARE WIDELY INVOLVED IN TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLES OF HOST LNCRNAS IN THE RESPONSE TO T. GONDII INFECTIONS. IN THIS STUDY, USING ILLUMINA SEQUENCING TECHNOLOGY, WE ANALYZED THE EXPRESSION PROFILES OF MRNAS AND LNCRNAS IN BALB/C MOUSE BRAIN FOLLOWING INFECTION BY T. GONDII PRU STRAIN (TYPE II GENOTYPE) CYSTS. THE IDENTIFIED DIFFERENTIALLY EXPRESSED (DE) RNAS WERE SUBJECTED TO BIOINFORMATICS ANALYSIS. A TOTAL OF 2,090 ANNOTATED LNCRNAS ALONG WITH 3,577 NOVEL LNCRNAS WERE IDENTIFIED. IN THE ACUTELY INFECTED MOUSE BRAIN, A TOTAL OF 330 MRNAS AND 19 LNCRNAS WERE DYS-REGULATED, WHEREAS 136 DE MRNAS AND 9 DE LNCRNAS WERE IDENTIFIED IN CHRONICALLY INFECTED MOUSE BRAIN. GO ANALYSIS REVEALED THAT THESE DE MRNAS IDENTIFIED AT ACUTE INFECTION STAGE WERE INVOLVED IN IMMUNE RESPONSE, WHEREAS DE MRNAS FOUND AT CHRONIC INFECTION STAGE WERE MOSTLY ENRICHED IN RESPONSE TO PROTOZOAN. KEGG ANALYSIS SHOWED THAT DE MRNAS WERE SIGNIFICANTLY ENRICHED IN DISEASE RELATED PATHWAYS. IN ADDITION, THE PUTATIVE MRNA-LNCRNA CO-EXPRESSION NETWORK WAS CONSTRUCTED, AND SEVERAL HUB REGULATORY RNAS WERE IDENTIFIED BASED ON THE TRANSCRIPTOME DATA. THIS STUDY FIRSTLY CHARACTERIZED THE CO-EXPRESSION PROFILE OF MRNAS AND LNCRNAS IN MOUSE BRAIN INFECTED WITH T. GONDII AND PROVIDED A FRAMEWORK FOR FURTHER STUDIES OF THE ROLES OF LNCRNAS IN HOST NEUROPATHOLOGY DURING TOXOPLASMOSIS PROGRESSION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  6363  28 THE ROLE OF LNCRNA TUG1 IN OBESITY-RELATED DISEASES. AS THE LIVING STANDARDS OF PEOPLE ARE INCREASINGLY IMPROVED, OBESITY HAS BECOME A HOTSPOT IN OUR DAILY LIFE. OBESITY HAS BEEN FOUND AS A CHRONIC AND RECURRENT DISEASE WITH SERIOUS ADVERSE CONSEQUENCES. OVER THE PAST FEW YEARS, SEVERAL ARTICLES INDICATED THAT LONG NON-CODING RNA TAURINE INCREASED GENE 1 (LNCRNA TUG1), A USEFUL RNA, WHICH WAS INDICATED TO SHOW A RELATIONSHIP TO OBESITY- RELATED DISEASE OCCURRENCE AND DEVELOPMENT. EXOSOMES ARE RECOGNIZED AS AN EMERGING RESEARCH FIELD THAT INCLUDES SUBSTANCES ACTIVELY INVOLVED IN REGULATING THE MOLECULAR MECHANISMS OF DISEASE. THIS REVIEW SUMMARIZES THE CURRENT RELEVANT TUG1 IN DIFFERENT MOLECULAR PATHWAYS OF OBESITYASSOCIATED DISEASES, THE CORRELATION BETWEEN EXOSOMES AND TUG1, OR OBESITY-ASSOCIATED DISEASES. THE AIM IS TO EXPLORE TUG1 AS A NOVEL TARGET FOR OBESITY, WHICH CAN DEEPEN THE KNOWLEDGE REGARDING THE EPIGENETIC REGULATION PATHWAY. FURTHERMORE, IT IS EXPECTED TO FOCUS ON DISEASES ASSOCIATED WITH OBESITY TREATMENT AND DIAGNOSIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  6045  34 THE COMPLEXITY OF THE NRF2 PATHWAY: BEYOND THE ANTIOXIDANT RESPONSE. THE NF-E2-RELATED FACTOR 2 (NRF2)-MEDIATED SIGNALLING PATHWAY PROVIDES LIVING ORGANISMS AN EFFICIENT AND PIVOTAL LINE OF DEFENSIVE TO COUNTERACT ENVIRONMENTAL INSULTS AND ENDOGENOUS STRESSORS. NRF2 COORDINATES THE BASAL AND INDUCIBLE EXPRESSION OF ANTIOXIDANT AND PHASE II DETOXIFICATION ENZYMES TO ADAPT TO DIFFERENT STRESS CONDITIONS. THE STABILITY AND CELLULAR DISTRIBUTION OF NRF2 IS TIGHTLY CONTROLLED BY ITS INHIBITORY BINDING PROTEIN KELCH-LIKE ECH-ASSOCIATED PROTEIN 1. NRF2 SIGNALLING IS ALSO REGULATED BY POSTTRANSLATIONAL, TRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS, AS WELL AS BY OTHER PROTEIN PARTNERS, INCLUDING P62, P21 AND IQ MOTIF-CONTAINING GTPASE ACTIVATING PROTEIN 1. MANY STUDIES HAVE DEMONSTRATED THAT NRF2 IS A PROMISING TARGET FOR PREVENTING CARCINOGENESIS AND OTHER CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND PULMONARY INJURY. HOWEVER, CONSTITUTIVE ACTIVATION OF NRF2 IN ADVANCED CANCER CELLS MAY CONFER DRUG RESISTANCE. HERE, WE REVIEW THE MOLECULAR MECHANISMS OF NRF2 SIGNALLING, THE DIVERSE CLASSES OF NRF2 ACTIVATORS, INCLUDING BIOACTIVE NUTRIENTS AND OTHER CHEMICALS, AND THE CELLULAR FUNCTIONS AND DISEASE RELEVANCE OF NRF2 AND DISCUSS THE DUAL ROLE OF NRF2 IN DIFFERENT CONTEXTS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10   861  22 CHROMATIN REMODELING FACTOR, INO80, INHIBITS PMAIP1 IN RENAL TUBULAR CELLS VIA EXCHANGE OF HISTONE VARIANT H2A.Z. FOR H2A. EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND CHROMATIN STRUCTURES IN THE KIDNEY CONTRIBUTE TOWARDS THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). IN THIS STUDY, THE ROLE OF CHROMATIN REMODELING FACTOR INOSITOL REQUIRING 80 (INO80) WAS INVESTIGATED. ALTHOUGH INO80 REGULATES TRANSCRIPTION BY ALTERING THE CHROMATIN STRUCTURE AT THE NUCLEOSOME LEVEL, ITS ROLE IN THE KIDNEY REMAINS UNKNOWN. WE DEMONSTRATED THAT THE EXPRESSION OF INO80 IN IMPAIRED KIDNEYS DECREASED IN RATS WITH UNILATERAL URETHRAL OBSTRUCTION. WE INVESTIGATED INO80 EXPRESSION IN A PROXIMAL TUBULAR CELL LINE AND OBSERVED THAT ITS EXPRESSION DECREASED UNDER HYPOXIC CONDITION. ADDITIONALLY, INO80 KNOCKDOWN PROMOTED APOPTOSIS, SUGGESTING THAT INO80 PLAYS A ROLE IN INHIBITING TUBULAR CELL APOPTOSIS. WE IDENTIFIED DOWNSTREAM TARGET GENES OF INO80 VIA GENOME-WIDE ANALYSIS USING RNA-SEQUENCES AND FOUND THAT THE EXPRESSION OF APOPTOSIS-RELATED GENES, SUCH AS TP53 AND E2F1, AND PRO-APOPTOTIC GENES, SUCH AS PMAIP1, INCREASED UPON INO80 KNOCKDOWN. CHIP-QPCR OF THE LOCI OF PMAIP1 SHOWED THAT THE AMOUNT OF H2A.Z. INCREASED INSTEAD OF DECREASING THE AMOUNT OF H2A WHEN INO80 WAS KNOCKED DOWN. THESE RESULTS INDICATED THAT INO80 PLAYS A ROLE IN THE EXCHANGE OF H2A.Z. FOR H2A IN THE PROMOTER REGION OF PMAIP1 IN TUBULAR CELLS TO INHIBIT APOPTOSIS DURING CKD PROGRESSION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  2481  41 EPIGENETIC UPREGULATION OF LNCRNAS AT 13Q14.3 IN LEUKEMIA IS LINKED TO THE IN CIS DOWNREGULATION OF A GENE CLUSTER THAT TARGETS NF-KB. NON-CODING RNAS ARE MUCH MORE COMMON THAN PREVIOUSLY THOUGHT. HOWEVER, FOR THE VAST MAJORITY OF NON-CODING RNAS, THE CELLULAR FUNCTION REMAINS ENIGMATIC. THE TWO LONG NON-CODING RNA (LNCRNA) GENES DLEU1 AND DLEU2 MAP TO A CRITICAL REGION AT CHROMOSOMAL BAND 13Q14.3 THAT IS RECURRENTLY DELETED IN SOLID TUMORS AND HEMATOPOIETIC MALIGNANCIES LIKE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WHILE NO POINT MUTATIONS HAVE BEEN FOUND IN THE PROTEIN CODING CANDIDATE GENES AT 13Q14.3, THEY ARE DEREGULATED IN MALIGNANT CELLS, SUGGESTING AN EPIGENETIC TUMOR SUPPRESSOR MECHANISM. WE THEREFORE CHARACTERIZED THE EPIGENETIC MAKEUP OF 13Q14.3 IN CLL CELLS AND FOUND HISTONE MODIFICATIONS BY CHROMATIN-IMMUNOPRECIPITATION (CHIP) THAT ARE ASSOCIATED WITH ACTIVATED TRANSCRIPTION AND SIGNIFICANT DNA-DEMETHYLATION AT THE TRANSCRIPTIONAL START SITES OF DLEU1 AND DLEU2 USING 5 DIFFERENT SEMI-QUANTITATIVE AND QUANTITATIVE METHODS (APRIMES, BIOCOBRA, MCIP, MASSARRAY, AND BISULFITE SEQUENCING). THESE EPIGENETIC ABERRATIONS WERE CORRELATED WITH TRANSCRIPTIONAL DEREGULATION OF THE NEIGHBORING CANDIDATE TUMOR SUPPRESSOR GENES, SUGGESTING A COREGULATION IN CIS OF THIS GENE CLUSTER. WE FOUND THAT THE 13Q14.3 GENES IN ADDITION TO THEIR PREVIOUSLY KNOWN FUNCTIONS REGULATE NF-KB ACTIVITY, WHICH WE COULD SHOW AFTER OVEREXPRESSION, SIRNA-MEDIATED KNOCKDOWN, AND DOMINANT-NEGATIVE MUTANT GENES BY USING WESTERN BLOTS WITH PREVIOUSLY UNDESCRIBED ANTIBODIES, BY A CUSTOMIZED ELISA AS WELL AS BY REPORTER ASSAYS. IN ADDITION, WE PERFORMED AN UNBIASED SCREEN OF 810 HUMAN MIRNAS AND IDENTIFIED THE MIR-15/16 FAMILY OF GENES AT 13Q14.3 AS THE STRONGEST INDUCERS OF NF-KB ACTIVITY. IN SUMMARY, THE TUMOR SUPPRESSOR MECHANISM AT 13Q14.3 IS A CLUSTER OF GENES CONTROLLED BY TWO LNCRNA GENES THAT ARE REGULATED BY DNA-METHYLATION AND HISTONE MODIFICATIONS AND WHOSE MEMBERS ALL REGULATE NF-KB. THEREFORE, THE TUMOR SUPPRESSOR MECHANISM IN 13Q14.3 UNDERLINES THE ROLE BOTH OF EPIGENETIC ABERRATIONS AND OF LNCRNA GENES IN HUMAN TUMORIGENESIS AND IS AN EXAMPLE OF COLOCALIZATION OF A FUNCTIONALLY RELATED GENE CLUSTER.	2013	
                                                                                                                
12  1718  32 DYSREGULATED LONG NON-CODING RNAS IN THE TEMPORAL LOBE EPILEPSY MOUSE MODEL. PURPOSE: TO PERFORM COMPREHENSIVE PROFILING OF LONG NON-CODING RNAS (LNCRNAS) IN TEMPORAL LOBE EPILEPSY. METHODS: WE PERFORMED EXTENSIVE PROFILING OF LNCRNAS AND MRNAS IN THE MOUSE PILOCARPINE MODEL IN SPECIFIC BRAIN REGIONS, THE HIPPOCAMPUS AND CORTEX, AND COMPARED THE RESULTS TO THOSE OF THE CONTROL MOUSE. DIFFERENTIALLY EXPRESSED LNCRNAS AND MRNAS WERE IDENTIFIED WITH A MICROARRAY ANALYSIS (ARRAYSTAR MOUSE LNCRNA EXPRESSION MICROARRAY V3.0). THEN, GENE ONTOLOGY (GO) AND PATHWAY ANALYSIS WERE PERFORMED TO INVESTIGATE THE POTENTIAL ROLES OF THE DIFFERENTIALLY EXPRESSED MRNAS IN THE PILOCARPINE MODEL. PROTEIN-PROTEIN INTERACTIONS TRANSCRIBED BY DYSREGULATED MRNAS WITH/WITHOUT CO-DYSREGULATED LNCRNAS WERE ANALYZED USING STRING V10 (HTTP://STRING-DB.ORG/). RESULTS: A TOTAL OF 22 AND 83 LNCRNAS WERE UP- AND DOWN-REGULATED (>/=2.0-FOLD, ALL P < .05), RESPECTIVELY, IN THE HIPPOCAMPUS OF THE EPILEPSY MODEL, WHILE 46 AND 659 LNCRNAS WERE UP- AND DOWN-REGULATED, RESPECTIVELY, IN THE CORTEX OF THE EPILEPSY MODEL. GO AND PATHWAY ANALYSIS REVEALED THAT THE DYSREGULATED MRNAS WERE CLOSELY ASSOCIATED WITH A PROCESS ALREADY KNOWN TO BE INVOLVED IN EPILEPTOGENESIS: ACUTE INFLAMMATION, CALCIUM ION REGULATION, EXTRACELLULAR MATRIX REMODELING, AND NEURONAL DIFFERENTIATION. AMONG THE LNCRNAS, WE IDENTIFIED 10 LNCRNAS COMMONLY DYSREGULATED WITH CORRESPONDING MRNAS IN THE CORTEX. THE STRING ANALYSIS SHOWED THAT THE DYSREGULATED MRNAS WERE INTERCONNECTED AROUND TWO CENTERS: THE MTOR PATHWAY-RELATED GENES AND REST PATHWAY-RELATED GENES. CONCLUSION: LNCRNAS WERE DYSREGULATED IN THE PILOCARPINE MOUSE MODEL ACCORDING TO THE BRAIN REGIONS OF THE HIPPOCAMPUS AND CORTEX. THE DYSREGULATED LNCRNAS WITH CO-DYSREGULATED MRNAS MIGHT BE POSSIBLE THERAPEUTIC TARGETS FOR THE EPIGENETIC REGULATION OF CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  4573  22 MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT, A LONG NONCODING RNA, IS OVEREXPRESSED DURING DILATED CARDIOMYOPATHY DUE TO CHRONIC CHAGAS DISEASE. LONG NONCODING RNAS (LNCRNAS) MODULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. DYSREGULATION OF THE LNCRNA KNOWN AS MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT (MIAT) HAS BEEN ASSOCIATED WITH MYOCARDIAL INFARCTION. CHAGAS DISEASE CAUSES A SEVERE INFLAMMATORY DILATED CHRONIC CARDIOMYOPATHY (CCC). WE INVESTIGATED THE ROLE OF MIAT IN CCC. A WHOLE-TRANSCRIPTOME ANALYSIS OF HEART BIOPSY SPECIMENS AND FORMALIN-FIXED, PARAFFIN-EMBEDDED SAMPLES REVEALED THAT MIAT WAS OVEREXPRESSED IN PATIENTS WITH CCC, COMPARED WITH SUBJECTS WITH NONINFLAMMATORY DILATED CARDIOMYOPATHY AND CONTROLS. THESE RESULTS WERE CONFIRMED IN A MOUSE MODEL. RESULTS SUGGEST THAT MIAT IS A SPECIFIC BIOMARKER OF CCC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14  2339  40 EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING. THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) SIGNALING AXIS SERVES AS A "MASTER REGULATOR" IN RESPONSE TO OXIDATIVE/ELECTROPHILIC STRESSES AND CHEMICAL INSULTS THROUGH THE COORDINATED INDUCTION OF A WIDE ARRAY OF CYTOPROTECTIVE GENES. THEREFORE, ACTIVATION OF NRF2 IS CONSIDERED TO BE AN IMPORTANT APPROACH FOR PREVENTING CHRONIC DISEASES TRIGGERED BY STRESSES AND TOXINS, INCLUDING CANCER. DESPITE EXTENSIVE STUDIES SUGGESTED THAT THE KEAP1-NRF2 SIGNALING PATHWAY IS SUBJECT TO MULTIPLE LAYERS OF REGULATION AT THE TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL LEVELS, THE POTENTIAL EPIGENETIC REGULATION OF NRF2 AND KEAP1 HAS BEGUN TO BE RECOGNIZED ONLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS, HERITABLE ALTERATIONS IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN THE PRIMARY DNA SEQUENCE, HAVE BEEN REPORTED TO BE PROFOUNDLY INVOLVED IN OXIDATIVE STRESS RESPONSES. IN THIS REVIEW, WE DISCUSS THE LATEST FINDINGS REGARDING THE EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING BY DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS. THE CROSSTALK AMONG THESE EPIGENETIC MODIFICATIONS IN THE REGULATION OF KEAP1-NRF2 SIGNALING PATHWAYS IS ALSO DISCUSSED. STUDIES OF THE EPIGENETIC MODIFICATION OF NRF2 AND KEAP1 HAVE NOT ONLY ENHANCED OUR UNDERSTANDING OF THIS COMPLEX CELLULAR DEFENSE SYSTEM BUT HAVE ALSO PROVIDED POTENTIAL NEW THERAPEUTIC TARGETS FOR THE PREVENTION OF CERTAIN DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  6397  26 THE ROLE OF TRANSPOSABLE ELEMENTS IN AGING AND CANCER. TRANSPOSABLE ELEMENTS (TES) CONSTITUTE A LARGE PORTION OF THE HUMAN GENOME. VARIOUS MECHANISMS AT THE TRANSCRIPTION AND POST-TRANSCRIPTION LEVELS DEVELOPED TO SUPPRESS TE ACTIVITY IN HEALTHY CONDITIONS. HOWEVER, A GROWING BODY OF EVIDENCE SUGGESTS THAT TE DYSREGULATION IS INVOLVED IN VARIOUS HUMAN DISEASES, INCLUDING AGE-RELATED DISEASES AND CANCER. IN THIS REVIEW, WE EXPLAINED HOW SENSING TES BY THE IMMUNE SYSTEM COULD INDUCE INNATE IMMUNE RESPONSES, CHRONIC INFLAMMATION, AND FOLLOWING AGE-RELATED DISEASES. WE ALSO NOTED THAT INFLAMMAGEING AND EXOGENOUS CARCINOGENS COULD TRIGGER THE UPREGULATION OF TES IN PRECANCEROUS CELLS. INCREASED INFLAMMATION COULD ENHANCE EPIGENETIC PLASTICITY AND UPREGULATION OF EARLY DEVELOPMENTAL TES, WHICH REWIRES THE TRANSCRIPTIONAL NETWORKS AND GIFT THE SURVIVAL ADVANTAGE TO THE PRECANCEROUS CELLS. IN ADDITION, UPREGULATED TES COULD INDUCE GENOME INSTABILITY, ACTIVATION OF ONCOGENES, OR INHIBITION OF TUMOR SUPPRESSORS AND CONSEQUENT CANCER INITIATION AND PROGRESSION. SO, WE SUGGEST THAT TES COULD BE CONSIDERED THERAPEUTIC TARGETS IN AGING AND CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   775  33 CELL TYPE-SPECIFIC WHOLE-GENOME LANDSCAPE OF DELTAFOSB BINDING IN THE NUCLEUS ACCUMBENS AFTER CHRONIC COCAINE EXPOSURE. BACKGROUND: THE ABILITY OF NEURONS TO RESPOND TO EXTERNAL STIMULI INVOLVES ADAPTATIONS OF GENE EXPRESSION. INDUCTION OF THE TRANSCRIPTION FACTOR DELTAFOSB IN THE NUCLEUS ACCUMBENS, A KEY BRAIN REWARD REGION, IS IMPORTANT FOR THE DEVELOPMENT OF DRUG ADDICTION. HOWEVER, A COMPREHENSIVE MAP OF DELTAFOSB'S GENE TARGETS HAS NOT YET BEEN GENERATED. METHODS: WE USED CUT&RUN (CLEAVAGE UNDER TARGETS AND RELEASE USING NUCLEASE) TO MAP THE GENOME-WIDE CHANGES IN DELTAFOSB BINDING IN THE 2 MAIN TYPES OF NUCLEUS ACCUMBENS NEURONS-D1 OR D2 MEDIUM SPINY NEURONS-AFTER CHRONIC COCAINE EXPOSURE. TO ANNOTATE GENOMIC REGIONS OF DELTAFOSB BINDING SITES, WE ALSO EXAMINED THE DISTRIBUTIONS OF SEVERAL HISTONE MODIFICATIONS. RESULTING DATASETS WERE LEVERAGED FOR MULTIPLE BIOINFORMATIC ANALYSES. RESULTS: THE MAJORITY OF DELTAFOSB PEAKS OCCUR OUTSIDE PROMOTER REGIONS, INCLUDING INTERGENIC REGIONS, AND ARE SURROUNDED BY EPIGENETIC MARKS INDICATIVE OF ACTIVE ENHANCERS. BRG1, THE CORE SUBUNIT OF THE SWI/SNF CHROMATIN REMODELING COMPLEX, OVERLAPS WITH DELTAFOSB PEAKS, A FINDING CONSISTENT WITH EARLIER STUDIES OF DELTAFOSB'S INTERACTING PROTEINS. CHRONIC COCAINE USE INDUCES BROAD CHANGES IN DELTAFOSB BINDING IN BOTH D1 AND D2 NUCLEUS ACCUMBENS MEDIUM SPINY NEURONS OF MALE AND FEMALE MICE. IN ADDITION, IN SILICO ANALYSES PREDICT THAT DELTAFOSB COOPERATIVELY REGULATES GENE EXPRESSION WITH HOMEOBOX AND T-BOX TRANSCRIPTION FACTORS. CONCLUSIONS: THESE NOVEL FINDINGS UNCOVER KEY ELEMENTS OF DELTAFOSB'S MOLECULAR MECHANISMS IN TRANSCRIPTIONAL REGULATION AT BASELINE AND IN RESPONSE TO CHRONIC COCAINE EXPOSURE. FURTHER CHARACTERIZATION OF DELTAFOSB'S COLLABORATIVE TRANSCRIPTIONAL AND CHROMATIN PARTNERS SPECIFICALLY IN D1 AND D2 MEDIUM SPINY NEURONS WILL REVEAL A BROADER PICTURE OF THE FUNCTION OF DELTAFOSB AND THE MOLECULAR BASIS OF DRUG ADDICTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                  
17  1727  32 DYSREGULATION OF LONG NON-CODING RNAS IN MOUSE MODELS OF LOCALIZATION-RELATED EPILEPSY. GENOME-WIDE PROFILING HAS REVEALED THAT EUKARYOTIC GENOMES ARE TRANSCRIBED INTO NUMEROUS NON-CODING RNAS. IN PARTICULAR, LONG NON-CODING RNAS (LNCRNAS) HAVE BEEN IMPLICATED IN VARIOUS HUMAN DISEASES DUE TO THEIR BIOCHEMICAL AND FUNCTIONAL DIVERSITY. EPILEPTIC DISORDERS HAVE BEEN CHARACTERIZED BY DYSREGULATION OF EPIGENETIC REGULATORY MECHANISMS, AND RECENT STUDIES HAVE IDENTIFIED SEVERAL LNCRNAS INVOLVED IN NEURAL DEVELOPMENT AND NETWORK FUNCTION. HOWEVER, COMPREHENSIVE PROFILING OF LNCRNAS IMPLICATED IN CHRONIC EPILEPSY HAS BEEN LACKING. IN THIS STUDY, MICROARRAY ANALYSIS WAS PERFORMED TO OBTAIN THE EXPRESSION PROFILE OF LNCRNAS DYSREGULATED IN PILOCARPINE AND KAINATE MODELS, TWO MODELS OF TEMPORAL LOBE EPILEPSY COMMONLY USED FOR STUDYING EPILEPTIC MECHANISMS. TOTAL OF 4622 LNCRNAS WERE ANALYZED: 384 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN PILOCARPINE MODEL, AND 279 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN KAINATE MODEL COMPARED WITH CONTROL MICE (>/=3.0-FOLD, P < 0.05). AMONG THESE, 54 AND 14 LNCRNAS, RESPECTIVELY, HAD ADJACENT PROTEIN-CODING GENES WHOSE EXPRESSIONS WERE ALSO SIGNIFICANTLY DYSREGULATED (>/=2.0-FOLD, P < 0.05). MAJORITY OF THESE PAIRS OF LNCRNAS AND ADJACENT GENES SHARED THE SAME DIRECTION OF DYSREGULATION. FOR THE SELECTED ADJACENT GENE-LNCRNA PAIRS, SIGNIFICANT GENE ONTOLOGY TERMS WERE EMBRYONIC APPENDAGE MORPHOGENESIS AND NEURON DIFFERENTIATION. THIS WAS THE FIRST STUDY TO COMPREHENSIVELY IDENTIFY DYSREGULATED LNCRNAS IN TWO DIFFERENT MODELS OF CHRONIC EPILEPSY AND WILL LIKELY PROVIDE A NOVEL INSIGHT INTO DEVELOPING LNCRNA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  1218  28 CRISPR INTERFERENCE OF A CLONALLY VARIANT GC-RICH NONCODING RNA FAMILY LEADS TO GENERAL REPRESSION OF VAR GENES IN PLASMODIUM FALCIPARUM. THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM USES MUTUALLY EXCLUSIVE EXPRESSION OF THE PFEMP1-ENCODING VAR GENE FAMILY TO EVADE THE HOST IMMUNE SYSTEM. DESPITE PROGRESS IN THE MOLECULAR UNDERSTANDING OF THE DEFAULT SILENCING MECHANISM, THE ACTIVATION MECHANISM OF THE UNIQUELY EXPRESSED VAR MEMBER REMAINS ELUSIVE. A GC-RICH NONCODING RNA (NCRNA) GENE FAMILY HAS COEVOLVED WITH PLASMODIUM SPECIES THAT EXPRESS VAR GENES. HERE, WE SHOW THAT THIS NCRNA FAMILY IS TRANSCRIBED IN A CLONALLY VARIANT MANNER, WITH PREDOMINANT TRANSCRIPTION OF A SINGLE MEMBER OCCURRING WHEN THE NCRNA IS LOCATED ADJACENT TO AND UPSTREAM OF AN ACTIVE VAR GENE. WE DEVELOPED A SPECIFIC CRISPR INTERFERENCE (CRISPRI) STRATEGY THAT ALLOWED FOR THE TRANSCRIPTIONAL REPRESSION OF ALL GC-RICH MEMBERS. A LACK OF GC-RICH NCRNA TRANSCRIPTION LED TO THE DOWNREGULATION OF THE ENTIRE VAR GENE FAMILY IN RING-STAGE PARASITES. STRIKINGLY, IN MATURE BLOOD-STAGE PARASITES, THE GC-RICH NCRNA CRISPRI AFFECTED THE TRANSCRIPTION PATTERNS OF OTHER CLONALLY VARIANT GENE FAMILIES, INCLUDING THE DOWNREGULATION OF ALL PFMC-2TM MEMBERS. WE PROVIDE EVIDENCE FOR THE KEY ROLE OF GC-RICH NCRNA TRANSCRIPTION IN VAR GENE ACTIVATION AND DISCOVERED A MOLECULAR LINK BETWEEN THE TRANSCRIPTIONAL CONTROL OF VARIOUS CLONALLY VARIANT MULTIGENE FAMILIES INVOLVED IN PARASITE VIRULENCE. THIS WORK OPENS NEW AVENUES FOR ELUCIDATING THE MOLECULAR PROCESSES THAT CONTROL IMMUNE EVASION AND PATHOGENESIS IN P. FALCIPARUMIMPORTANCEPLASMODIUM FALCIPARUM IS THE DEADLIEST MALARIA PARASITE SPECIES, ACCOUNTING FOR THE VAST MAJORITY OF DISEASE CASES AND DEATHS. THE VIRULENCE OF THIS PARASITE IS RELIANT UPON THE MUTUALLY EXCLUSIVE EXPRESSION OF CYTOADHERENCE PROTEINS ENCODED BY THE 60-MEMBER VAR GENE FAMILY. ANTIGENIC VARIATION OF THIS MULTIGENE FAMILY SERVES AS AN IMMUNE EVASION MECHANISM, ULTIMATELY LEADING TO CHRONIC INFECTION AND PATHOGENESIS. UNDERSTANDING THE REGULATION MECHANISM OF ANTIGENIC VARIATION IS KEY TO DEVELOPING NEW THERAPEUTIC AND CONTROL STRATEGIES. OUR STUDY UNCOVERS A NOVEL LAYER IN THE EPIGENETIC REGULATION OF TRANSCRIPTION OF THIS FAMILY OF VIRULENCE GENES BY MEANS OF A MULTIGENE-TARGETING CRISPR INTERFERENCE APPROACH.	2020	

19  2352  37 EPIGENETIC REGULATION OF NRF2/KEAP1 BY PHYTOCHEMICALS. EPIGENETICS HAS PROVIDED A NEW DIMENSION TO OUR UNDERSTANDING OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (HUMAN NRF2/KEAP1 AND MURINE NRF2/KEAP1) SIGNALING. UNLIKE THE GENETIC CHANGES AFFECTING DNA SEQUENCE, THE REVERSIBLE NATURE OF EPIGENETIC ALTERATIONS PROVIDES AN ATTRACTIVE AVENUE FOR CANCER INTERCEPTION. THUS, TARGETING EPIGENETIC MECHANISMS IN THE CORRESPONDING SIGNALING NETWORKS REPRESENTS AN ENTICING STRATEGY FOR THERAPEUTIC INTERVENTION WITH DIETARY PHYTOCHEMICALS ACTING AT TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. THIS REGULATION INVOLVES THE INTERPLAY OF HISTONE MODIFICATIONS AND DNA METHYLATION STATES IN THE HUMAN NFE2L2/KEAP1 AND MURINE NFE2L2/KEAP1 GENES, ACETYLATION OF LYSINE RESIDUES IN NRF2 AND NRF2, INTERACTION WITH BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) ACETYL "READER" PROTEINS, AND NON-CODING RNAS SUCH AS MICRORNA (MIRNA) AND LONG NON-CODING RNA (LNCRNA). PHYTOCHEMICALS DOCUMENTED TO MODULATE NRF2 SIGNALING ACT BY REVERSING HYPERMETHYLATED STATES IN THE CPG ISLANDS OF NFE2L2 OR NFE2L2, VIA THE INHIBITION OF DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), THROUGH THE INDUCTION OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES, OR BY INDUCING MIRNA TO TARGET THE 3'-UTR OF THE CORRESPONDING MRNA TRANSCRIPTS. TO DATE, FEWER THAN TWENTY PHYTOCHEMICALS HAVE BEEN REPORTED AS NRF2 EPIGENETIC MODIFIERS, INCLUDING CURCUMIN, SULFORAPHANE, RESVERATROL, RESERPINE, AND URSOLIC ACID. THIS OPENS AVENUES FOR EXPLORING ADDITIONAL DIETARY PHYTOCHEMICALS THAT REGULATE THE HUMAN EPIGENOME, AND THE POTENTIAL FOR NOVEL STRATEGIES TO TARGET NRF2 SIGNALING WITH A VIEW TO BENEFICIAL INTERCEPTION OF CANCER AND OTHER CHRONIC DISEASES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  3946  34 LNCRNA MALAT1 BINDS CHROMATIN REMODELING SUBUNIT BRG1 TO EPIGENETICALLY PROMOTE INFLAMMATION-RELATED HEPATOCELLULAR CARCINOMA PROGRESSION. HEPATOCELLULAR CARCINOMA (HCC) IS ONE TYPE OF CANCERS WHOSE CARCINOGENESIS AND PROGRESSION ARE CLOSELY RELATED TO CHRONIC INFLAMMATION. IDENTIFYING THE MOLECULAR MECHANISMS FOR INFLAMMATION-RELATED HCC PROGRESSION WILL CONTRIBUTE TO IMPROVE THE EFFICACY OF CURRENT THERAPEUTICS FOR HCC PATIENTS. MANY KINDS OF EPIGENETIC FACTORS, INCLUDING LONG NON-CODING RNAS (LNCRNAS), HAVE BEEN DISCOVERED TO BE IMPORTANT IN HCC GROWTH AND METASTASIS. HOWEVER, HOW THE LNCRNAS PROMOTE HCC PROGRESSION AND WHAT'S THE APPLICATION OF LNCRNA SILENCING IN VIVO IN SUPPRESSING HCC REMAIN TO BE FURTHER INVESTIGATED. HERE, WE FOUND THAT LNCRNA METASTASIS ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT1 (MALAT1) WAS UPREGULATED IN HCC TUMOR TISSUES, AND KNOCKDOWN OF MALAT1 SUPPRESSED PROLIFERATION, CELL CYCLE AND INVASION OF HCC CELLS IN RESPONSE TO LIPOPOLYSACCHARIDE (LPS) STIMULATION. KNOCKDOWN OF MALAT1 SIGNIFICANTLY INHIBITED LPS-INDUCED PRO-INFLAMMATORY MEDIATORS IL-6 AND CXCL8 EXPRESSION IN HCC CELLS, WHICH COULD BE RESTORED BY OVEREXPRESSING MALAT1. MECHANISTICALLY, MALAT1 RECRUITED BRAHMA-RELATED GENE 1 (BRG1), A CATALYTIC SUBUNIT OF CHROMATIN REMODELING COMPLEX SWITCHING/SUCROSE NON-FERMENTABLE (SWI/SNF), TO THE PROMOTER REGION OF IL-6 AND CXCL8, AND THUS FACILITATED NF-KAPPAB TO INDUCE THE EXPRESSION OF THESE INFLAMMATORY FACTORS. IMPORTANTLY, IN VIVO SILENCING OF MALAT1 IN HCC TISSUES INHIBITED GROWTH OF HCC XENOGRAFTS, AND ALSO SUPPRESSED THE EXPRESSION OF PRO-INFLAMMATORY FACTORS IN HCC TISSUES ACCORDINGLY. OUR RESULTS DEMONSTRATE THAT MALAT1 PROMOTES HCC PROGRESSION BY BINDING BRG1 TO EPIGENETICALLY ENHANCE INFLAMMATORY RESPONSE IN HCC TISSUES, AND SILENCING OF MALAT1 MAY BE A POTENTIAL APPROACH TO THE TREATMENT OF HCC.	2019