1 6855 111 [NEW APPROACH TO THE INVESTIGATION OF DOHAD USING X-INACTIVATION GENE EXPRESSION SYSTEM]. X-CHROMOSOME INACTIVATION (XCI) OCCURS DURING THE GESTATION PERIOD TO COMPENSATE FOR THE DOSAGE OF X-LINKED GENES IN FEMALE MAMMALS. XIST RNA IS A LONG NONCODING RNA WITH A GLOBAL EPIGENETIC FUNCTION AND IS INDISPENSABLE FOR XCI FROM THE INITIATION TO ESTABLISHMENT AND MAINTENANCE PHASES. THE X CHROMOSOME CONTAINS OVER 1,000 GENES THAT ARE ESSENTIAL FOR PROPER DEVELOPMENT, ESPECIALLY THAT OF THE BRAIN, IMMUNE SYSTEM, METABOLISM AND REPRODUCTIVE FUNCTIONS. WE FOUND THAT EXPOSURE TO BISPHENOL A OR FOLATE DEFICIENCY DURING THE FETAL PERIOD CHANGES THE EXPRESSIONS OF XIST, TSIX (THE ANTISENSE REPRESSOR OF XIST), AND MANY X CHROMOSOME LINKED GENES WIDELY IN NEWBORN MICE. THIS FINDING SUGGESTS THAT THIS X-CHROMOSOME MEDIATED EFFECT IS CONSIDERED ONE OF THE MECHANISMS OF VARIOUS PROBLEMS ENCOUNTERED IN THE FETAL ENVIRONMENT. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) HYPOTHESIS STATES THAT NUTRITION AND OTHER ENVIRONMENTAL STIMULI DURING CRITICAL PERIODS AFFECT DEVELOPMENTAL PATHWAYS WITH EPIGENETICS AND INDUCE METABOLISM AND CHRONIC DISEASE SUSCEPTIBILITY. THE XCI PROCESS HAS SOME SIMILARITIES TO THIS HYPOTHESIS AND IT MAY BECOME ONE OF THE APPROACHES TO REVEAL THE DOHAD MECHANISMS. 2018 2 635 45 BIOLOGICAL FUNCTION OF LONG NON-CODING RNA (LNCRNA) XIST. LONG NON-CODING RNAS (LNCRNAS) REGULATE GENE EXPRESSION IN A VARIETY OF WAYS AT EPIGENETIC, CHROMATIN REMODELING, TRANSCRIPTIONAL, AND TRANSLATIONAL LEVELS. ACCUMULATING EVIDENCE SUGGESTS THAT LNCRNA X-INACTIVE SPECIFIC TRANSCRIPT (LNCRNA XIST) SERVES AS AN IMPORTANT REGULATOR OF CELL GROWTH AND DEVELOPMENT. DESPITES ITS ORIGINAL ROLES IN X-CHROMOSOME DOSAGE COMPENSATION, LNCRNA XIST ALSO PARTICIPATES IN THE DEVELOPMENT OF TUMOR AND OTHER HUMAN DISEASES BY FUNCTIONING AS A COMPETING ENDOGENOUS RNA (CERNA). IN THIS REVIEW, WE COMPREHENSIVELY SUMMARIZED RECENT PROGRESS IN UNDERSTANDING THE CELLULAR FUNCTIONS OF LNCRNA XIST IN MAMMALIAN CELLS AND DISCUSSED CURRENT KNOWLEDGE REGARDING THE CERNA NETWORK OF LNCRNA XIST IN VARIOUS DISEASES. LONG NON-CODING RNAS (LNCRNAS) ARE TRANSCRIPTS THAT ARE MORE THAN 200 NT IN LENGTH AND WITHOUT AN APPARENT PROTEIN-CODING CAPACITY (FURLAN AND ROUGEULLE, 2016; MADURO ET AL., 2016). THESE RNAS ARE BELIEVED TO BE TRANSCRIBED BY THE APPROXIMATELY 98-99% NON-CODING REGIONS OF THE HUMAN GENOME (DERRIEN ET AL., 2012; FU, 2014; MONTALBANO ET AL., 2017; SLACK AND CHINNAIYAN, 2019), AS WELL AS A LARGE VARIETY OF GENOMIC REGIONS, SUCH AS EXONIC, TRONIC, AND INTERGENIC REGIONS. HENCE, LNCRNAS ARE ALSO DIVIDED INTO EIGHT CATEGORIES: INTERGENIC LNCRNAS, INTRONIC LNCRNAS, ENHANCER LNCRNAS, PROMOTER LNCRNAS, NATURAL ANTISENSE/SENSE LNCRNAS, SMALL NUCLEOLAR RNA-ENDED LNCRNAS (SNO-LNCRNAS), BIDIRECTIONAL LNCRNAS, AND NON-POLY(A) LNCRNAS (MA ET AL., 2013; DEVAUX ET AL., 2015; ST LAURENT ET AL., 2015; CHEN, 2016; QUINN AND CHANG, 2016; RICHARD AND EICHHORN, 2018; CONNERTY ET AL., 2020). A RANGE OF EVIDENCE HAS SUGGESTED THAT LNCRNAS FUNCTION AS KEY REGULATORS IN CRUCIAL CELLULAR FUNCTIONS, INCLUDING PROLIFERATION, DIFFERENTIATION, APOPTOSIS, MIGRATION, AND INVASION, BY REGULATING THE EXPRESSION LEVEL OF TARGET GENES VIA EPIGENOMIC, TRANSCRIPTIONAL, OR POST-TRANSCRIPTIONAL APPROACHES (CAO ET AL., 2018). MOREOVER, LNCRNAS DETECTED IN BODY FLUIDS WERE ALSO BELIEVED TO SERVE AS POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, AND ACT AS NOVEL AND POTENTIAL DRUG TARGETS FOR THERAPEUTIC EXPLOITATION IN HUMAN DISEASE (JIANG W. ET AL., 2018; ZHOU ET AL., 2019A). LONG NON-CODING RNA X-INACTIVE SPECIFIC TRANSCRIPT (LNCRNA XIST) ARE A SET OF 15,000-20,000 NT SEQUENCES LOCALIZED IN THE X CHROMOSOME INACTIVATION CENTER (XIC) OF CHROMOSOME XQ13.2 (BROWN ET AL., 1992; DEBRAND ET AL., 1998; KAY, 1998; LEE ET AL., 2013; DA ROCHA AND HEARD, 2017; YANG Z. ET AL., 2018; BROCKDORFF, 2019). PREVIOUS STUDIES HAVE INDICATED THAT LNCRNA XIST REGULATE X CHROMOSOME INACTIVATION (XCI), RESULTING IN THE INHERITABLE SILENCING OF ONE OF THE X-CHROMOSOMES DURING FEMALE CELL DEVELOPMENT. ALSO, IT SERVES A VITAL REGULATORY FUNCTION IN THE WHOLE SPECTRUM OF HUMAN DISEASE (NOTABLY CANCER) AND CAN BE USED AS A NOVEL DIAGNOSTIC AND PROGNOSTIC BIOMARKER AND AS A POTENTIAL THERAPEUTIC TARGET FOR HUMAN DISEASE IN THE CLINIC (LIU ET AL., 2018B; DENG ET AL., 2019; DINESCU ET AL., 2019; MUTZEL AND SCHULZ, 2020; PATRAT ET AL., 2020; WANG ET AL., 2020A). IN PARTICULAR, LNCRNA XIST HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE DEVELOPMENT OF MULTIPLE TYPES OF TUMORS INCLUDING BRAIN TUMOR, LEUKEMIA, LUNG CANCER, BREAST CANCER, AND LIVER CANCER, WITH THE PROMINENT EXAMPLES OUTLINED IN TABLE 1. IT WAS ALSO BELIEVED THAT LNCRNA XIST (CHALIGNE AND HEARD, 2014; YANG Z. ET AL., 2018) CONTRIBUTED TO OTHER DISEASES, SUCH AS PULMONARY FIBROSIS, INFLAMMATION, NEUROPATHIC PAIN, CARDIOMYOCYTE HYPERTROPHY, AND OSTEOARTHRITIS CHONDROCYTES, AND MORE SPECIFIC DETAILS CAN BE FOUND IN TABLE 2. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ON THE REGULATORY MECHANISMS OF LNCRNA XIST ON BOTH CHROMOSOME DOSAGE COMPENSATION AND PATHOGENESIS (ESPECIALLY CANCER) PROCESSES, WITH A FOCUS ON THE REGULATORY NETWORK OF LNCRNA XIST IN HUMAN DISEASE. 2021 3 5723 30 SJOGREN'S SYNDROME X-CHROMOSOME DOSE EFFECT: AN EPIGENETIC PERSPECTIVE. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING EXOCRINE GLANDS LEADING TO MOUTH AND EYES DRYNESS. THE EXTENT TO WHICH EPIGENETIC DNA METHYLATION CHANGES ARE RESPONSIBLE FOR AN X-CHROMOSOME DOSE EFFECT HAS YET TO BE DETERMINED. OUR OBJECTIVES WERE TO (I) DESCRIBE HOW EPIGENETIC DNA METHYLATION CHANGES COULD EXPLAIN AN X-CHROMOSOME DOSE EFFECT IN SS FOR WOMEN WITH NORMAL 46,XX GENOTYPE AND (II) DETERMINE THE RELEVANT RELATIONSHIPS TO THIS DOSE EFFECT, BETWEEN X-LINKED GENES, GENES CONTROLLING X-CHROMOSOME INACTIVATION (XCI) AND GENES ENCODING ASSOCIATED TRANSCRIPTION FACTORS, ALL OF WHICH ARE DIFFERENTIALLY EXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN THE SALIVARY GLANDS OF PATIENTS WITH SS. WE IDENTIFIED 58 UPREGULATED X-CHROMOSOME GENES, INCLUDING 22 GENES PREVIOUSLY SHOWN TO ESCAPE XCI, BASED ON THE ANALYSIS OF SS PATIENT SALIVARY GLAND GEO2R GENE EXPRESSION DATASETS. MOREOVER, WE FOUND XIST AND ITS CIS REGULATORS RLIM, FTX, AND CHIC1, AND POLYCOMB REPRESSOR GENES OF THE PRC1/2 COMPLEXES TO BE UPREGULATED. MANY OF THE X-CHROMOSOME GENES IMPLICATED IN SS PATHOGENESIS CAN BE REGULATED BY TRANSCRIPTION FACTORS WHICH WE FOUND TO BE OVEREXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN PATIENTS WITH SS. DETERMINATION OF THE MECHANISMS UNDERLYING METHYLATION-DEPENDENT GENE EXPRESSION AND IMPAIRED XCI IS NEEDED TO FURTHER ELUCIDATE THE ETIOPATHOGENESIS OF SS. 2019 4 2326 19 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY. 2018 5 2205 33 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES. 2006 6 4015 38 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS. 2017 7 329 26 ALPHA-OXOGLUTARATE INHIBITS THE PROLIFERATION OF IMMORTALIZED NORMAL BLADDER EPITHELIAL CELLS VIA AN EPIGENETIC SWITCH INVOLVING ARID1A. INTERSTITIAL CYSTITIS (IC) IS A CHRONIC URINARY TRACT DISEASE THAT IS CHARACTERIZED BY UNPLEASANT SENSATIONS, SUCH AS PERSISTENT PELVIC PAIN, IN THE ABSENCE OF INFECTION OR OTHER IDENTIFIABLE CAUSES. WE PREVIOUSLY PERFORMED COMPREHENSIVE METABOLOMICS PROFILING OF URINE SAMPLES FROM IC PATIENTS USING NUCLEAR MAGNETIC RESONANCE AND GAS-CHROMATOGRAPHY/MASS SPECTROMETRY AND FOUND THAT URINARY ALPHA-OXOGLUTARATE (ALPHA-OG), WAS SIGNIFICANTLY ELEVATED. ALPHA-OG, A TRICARBOXYLIC ACID (TCA) CYCLE INTERMEDIATE, REPORTEDLY FUNCTIONS TO SUPPRESS THE PROLIFERATION OF IMMORTALIZED NORMAL HUMAN BLADDER EPITHELIAL CELLS. HERE, WE IDENTIFIED AT-RICH INTERACTIVE DOMAIN 1 A (ARID1A), A KEY CHROMATIN REMODELER, AS BEING HYPOMETHYLATED AND UPREGULATED BY ALPHA-OG TREATMENT. THIS WAS DONE THROUGH EPIC DNA METHYLATION PROFILING AND SUBSEQUENT BIOCHEMICAL APPROACHES, INCLUDING QUANTITATIVE RT-PCR AND WESTERN BLOT ANALYSES. FURTHERMORE, WE FOUND THAT ALPHA-OG ALMOST COMPLETELY SUPPRESSES TEN-ELEVEN TRANSLOCATION (TET) ACTIVITY, BUT DOES NOT AFFECT DNA METHYLTRANSFERASE (DNMT) ACTIVITY. ALTOGETHER, OUR STUDIES REVEAL THE POTENTIAL ROLE OF ALPHA-OG IN EPIGENETIC REMODELING THROUGH ITS EFFECTS ON ARID1A AND TET EXPRESSION IN THE BLADDER. THIS MAY PROVIDE A NEW POSSIBLE THERAPEUTIC STRATEGY IN TREATING IC. 2018 8 2684 29 EVALUATION OF X CHROMOSOME INACTIVATION WITH RESPECT TO HLA GENETIC SUSCEPTIBILITY IN RHEUMATOID ARTHRITIS AND SYSTEMIC SCLEROSIS. BACKGROUND: AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA) AND SYSTEMIC SCLEROSIS (SSC) ARE CHARACTERIZED BY A STRONG GENETIC SUSCEPTIBILITY FROM THE HUMAN LEUCOCYTE ANTIGEN (HLA) LOCUS. ADDITIONALLY, DISORDERS OF EPIGENETIC PROCESSES, IN PARTICULAR NON-RANDOM X CHROMOSOME INACTIVATION (XCI), HAVE BEEN REPORTED IN MANY FEMALE-PREDOMINANT AUTOIMMUNE DISEASES. HERE WE TEST THE HYPOTHESIS THAT WOMEN WITH RA OR SSC WHO ARE STRONGLY GENETICALLY PREDISPOSED ARE LESS SUSCEPTIBLE TO XCI BIAS. METHODS: USING METHYLATION SENSITIVE GENOTYPING OF THE ANDROGEN RECEPTOR (AR) GENE, XCI PROFILES WERE PERFORMED IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 161 WOMEN WITH RA, 96 WOMEN WITH SSC AND 100 HEALTHY WOMEN. HLA-DRB1 AND DQB1 WERE GENOTYPED. PRESENCE OF SPECIFIC AUTOANTIBODIES WAS DOCUMENTED FOR PATIENTS. XCI SKEWING WAS DEFINED AS HAVING A RATIO >/= 80:20 OF CELLS INACTIVATING THE SAME X CHROMOSOME. RESULTS: 110 WOMEN WITH RA, 68 WOMEN WITH SSC, AND 69 CONTROLS WERE INFORMATIVE FOR THE AR POLYMORPHISM. AMONG THEM 40.9% OF RA PATIENTS AND 36.8% OF SSC PATIENTS HAD SKEWED XCI COMPARED TO 17.4% OF HEALTHY WOMEN (P = 0.002 AND 0.018, RESPECTIVELY). PRESENCE OF RA-SUSCEPTIBILITY ALLELES CODING FOR THE "SHARED EPITOPE" CORRELATED WITH HIGHER SKEWING AMONG RA PATIENTS (P = 0.002) AND SUCH CORRELATION WAS NOT OBSERVED IN OTHER WOMEN, HEALTHY OR WITH SSC. PRESENCE OF SSC-SUSCEPTIBILITY ALLELES DID NOT CORRELATE WITH XCI PATTERNS AMONG SSC PATIENTS. CONCLUSION: DATA DEMONSTRATE XCI SKEWING IN BOTH RA AND SSC COMPARED TO HEALTHY WOMEN. UNEXPECTEDLY, SKEWED XCI OCCURS MORE OFTEN IN WOMEN WITH RA CARRYING THE SHARED EPITOPE, WHICH USUALLY REFLECTS SEVERE DISEASE. THIS REINFORCES THE VIEW THAT LOSS OF MOSAICISM IN PERIPHERAL BLOOD MAY BE A CONSEQUENCE OF CHRONIC AUTOIMMUNITY. 2016 9 4573 21 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 10 124 28 A SYSTEMS APPROACH DELIVERS A FUNCTIONAL MICRORNA CATALOG AND EXPANDED TARGETS FOR SEIZURE SUPPRESSION IN TEMPORAL LOBE EPILEPSY. TEMPORAL LOBE EPILEPSY IS THE MOST COMMON DRUG-RESISTANT FORM OF EPILEPSY IN ADULTS. THE REORGANIZATION OF NEURAL NETWORKS AND THE GENE EXPRESSION LANDSCAPE UNDERLYING PATHOPHYSIOLOGIC NETWORK BEHAVIOR IN BRAIN STRUCTURES SUCH AS THE HIPPOCAMPUS HAS BEEN SUGGESTED TO BE CONTROLLED, IN PART, BY MICRORNAS. TO SYSTEMATICALLY ASSESS THEIR SIGNIFICANCE, WE SEQUENCED ARGONAUTE-LOADED MICRORNAS TO DEFINE FUNCTIONALLY ENGAGED MICRORNAS IN THE HIPPOCAMPUS OF THREE DIFFERENT ANIMAL MODELS IN TWO SPECIES AND AT SIX TIME POINTS BETWEEN THE INITIAL PRECIPITATING INSULT THROUGH TO THE ESTABLISHMENT OF CHRONIC EPILEPSY. WE THEN SELECTED COMMONLY UP-REGULATED MICRORNAS FOR A FUNCTIONAL IN VIVO THERAPEUTIC SCREEN USING OLIGONUCLEOTIDE INHIBITORS. ARGONAUTE SEQUENCING GENERATED 1.44 BILLION SMALL RNA READS OF WHICH UP TO 82% WERE MICRORNAS, WITH OVER 400 UNIQUE MICRORNAS DETECTED PER MODEL. APPROXIMATELY HALF OF THE DETECTED MICRORNAS WERE DYSREGULATED IN EACH EPILEPSY MODEL. WE PRIORITIZED COMMONLY UP-REGULATED MICRORNAS THAT WERE FULLY CONSERVED IN HUMANS AND DESIGNED CUSTOM ANTISENSE OLIGONUCLEOTIDES FOR THESE CANDIDATE TARGETS. ANTISEIZURE PHENOTYPES WERE OBSERVED UPON KNOCKDOWN OF MIR-10A-5P, MIR-21A-5P, AND MIR-142A-5P AND ELECTROPHYSIOLOGICAL ANALYSES INDICATED BROAD SAFETY OF THIS APPROACH. COMBINED INHIBITION OF THESE THREE MICRORNAS REDUCED SPONTANEOUS SEIZURES IN EPILEPTIC MICE. PROTEOMIC DATA, RNA SEQUENCING, AND PATHWAY ANALYSIS ON PREDICTED AND VALIDATED TARGETS OF THESE MICRORNAS IMPLICATED DEREPRESSED TGF-BETA SIGNALING AS A SHARED SEIZURE-MODIFYING MECHANISM. CORRESPONDINGLY, INHIBITION OF TGF-BETA SIGNALING OCCLUDED THE ANTISEIZURE EFFECTS OF THE ANTAGOMIRS. TOGETHER, THESE RESULTS IDENTIFY SHARED, DYSREGULATED, AND FUNCTIONALLY ACTIVE MICRORNAS DURING THE PATHOGENESIS OF EPILEPSY WHICH REPRESENT THERAPEUTIC ANTISEIZURE TARGETS. 2020 11 6231 18 THE LONG NONCODING RNA MEG3 AND ITS TARGET MIR-147 REGULATE JAK/STAT PATHWAY IN ADVANCED CHRONIC MYELOID LEUKEMIA. BACKGROUND: LONG NON-CODING (LNC) RNAS PLAYS AN IMPORTANT ROLE IN CHRONIC MYELOID LEUKEMIA (CML). IN THIS STUDY, WE AIMED TO UNCOVER THE MECHANISM OF THE LNCRNA MATERNALLY EXPRESSED 3 (MEG3) AND ITS TARGET MICRORNA-147 (MIR-147) IN CML. METHODS: SIXTY CML PATIENTS AND 10 HEALTHY DONORS WERE INCLUDED IN THE STUDY. THE METHYLATION OF MEG3 AND MIR-147 PROMOTER WAS DETERMINED BY METHYLATION-SPECIFIC PCR. THE RELATIONSHIP OF MEG3 AND MIR-147 WAS EXPLORED BY LUCIFERASE ASSAY. THE INTERACTIONS OF PROTEINS WERE STUDIED BY RNA PULL-DOWN ASSAY, RNA IMMUNOPRECIPITATION AND CO-IMMUNOPRECIPITATION. FINDINGS: PATIENTS IN ACCELERATED PHASE CML (CML-AP) AND BLAST PHASE CML (CML-BP) SHOWED LOWER EXPRESSIONS OF MEG3 AND MIR-147 AND HIGHER EXPRESSIONS OF DNMT1, DNMT3B, MBD2, MECP2 AND HDAC1 COMPARED TO THE CONTROLS. THESE PATIENTS ALSO SHOWED A HIGHER DEGREE OF METHYLATION OF MEG3 AND MIR-147 WHILE THERE WAS A REDUCTION AFTER CHIDAMIDE TREATMENT. FURTHERMORE, THE OVEREXPRESSION OF MEG3 AND MIR-147 INHIBITED CELL PROLIFERATION BOTH IN VIVO AND IN VITRO, PROMOTED APOPTOSIS AND DECREASED THE EXPRESSIONS OF DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 AND MECP2. WE ALSO FOUND MEG3 INTERACTED WITH DNMT1, JAK2, STAT3, HDAC1, AND TYK2, AND JAK2 WAS BOUND TO STAT3, STAT5 AND MYC. MORE INTERESTINGLY, JAK2 WAS BOUND TO TYK2 BY THE BRIDGE OF MEG3. INTERPRETATION: LNCRNA MEG3 AND ITS TARGET MIR-147 MAY SERVE AS A NOVEL THERAPEUTIC TARGET FOR CML BLAST CRISIS, AND CHIDAMIDE MIGHT HAVE A POTENTIAL CLINICAL APPLICATION IN TREATING CML BLAST CRISIS. 2018 12 4304 25 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 13 3064 26 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15. 2019 14 207 28 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS. 2010 15 6687 16 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 16 4338 19 MICROVASCULAR BARRIER PROTECTION BY MICRORNA-183 VIA FOXO1 REPRESSION: A PATHWAY DISTURBED IN NEUROPATHY AND COMPLEX REGIONAL PAIN SYNDROME. BLOOD NERVE BARRIER DISRUPTION AND EDEMA ARE COMMON IN NEUROPATHIC PAIN AS WELL AS IN COMPLEX REGIONAL PAIN SYNDROME (CRPS). MICRORNAS (MIRNA) ARE EPIGENETIC MULTITARGET SWITCHES CONTROLLING NEURONAL AND NON-NEURONAL CELLS IN PAIN. THE MIR-183 COMPLEX ATTENUATES HYPEREXCITABILITY IN NOCICEPTORS, BUT ADDITIONAL NON-NEURONAL EFFECTS VIA TRANSCRIPTION FACTORS COULD CONTRIBUTE AS WELL. THIS STUDY EXPLORED EXOSOMAL MIR-183 IN CRPS AND MURINE NEUROPATHY, ITS EFFECT ON THE MICROVASCULAR BARRIER VIA TRANSCRIPTION FACTOR FOXO1 AND TIGHT JUNCTION PROTEIN CLAUDIN-5, AND ITS ANTIHYPERALGESIC POTENTIAL. SCIATIC MIR-183 DECREASED AFTER CCI. SUBSTITUTION WITH PERINEURAL MIR-183 MIMIC ATTENUATED MECHANICAL HYPERSENSITIVITY AND RESTORED BLOOD NERVE BARRIER FUNCTION. IN VITRO, SERUM FROM CCI MICE UND CRPS PATIENTS WEAKENED THE MICROVASCULAR BARRIER OF MURINE CEREBELLAR ENDOTHELIAL CELLS, INCREASED ACTIVE FOXO1 AND REDUCED CLAUDIN-5, CONCOMITANT WITH A LACK OF EXOSOMAL MIR-183 IN CRPS PATIENTS. CELLULAR STRESS ALSO COMPROMISED THE MICROVASCULAR BARRIER WHICH WAS RESCUED EITHER BY MIR-183 MIMIC VIA FOXO1 REPRESSION OR BY PRIOR SILENCING OF FOXO1. PERSPECTIVE: LOW MIR-183 LEADING TO BARRIER IMPAIRMENT VIA FOXO1 AND SUBSEQUENT CLAUDIN-5 SUPPRESSION IS A NEW ASPECT IN THE PATHOPHYSIOLOGY OF CRPS AND NEUROPATHIC PAIN. THIS PATHWAY MIGHT HELP UNTANGLE THE WIDE SYMPTOMATIC RANGE OF CRPS AND NURTURE FURTHER RESEARCH INTO MIRNA MIMICS OR FOXO1 INHIBITORS. 2022 17 1484 28 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS. 2021 18 66 23 A KEY ROLE FOR EZH2 IN EPIGENETIC SILENCING OF HOX GENES IN MANTLE CELL LYMPHOMA. THE CHROMATIN MODIFIER EZH2 IS OVEREXPRESSED AND ASSOCIATED WITH INFERIOR OUTCOME IN MANTLE CELL LYMPHOMA (MCL). RECENTLY, WE DEMONSTRATED PREFERENTIAL DNA METHYLATION OF HOX GENES IN MCL COMPARED WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DESPITE THESE GENES NOT BEING EXPRESSED IN EITHER ENTITY. SINCE EZH2 HAS BEEN SHOWN TO REGULATE HOX GENE EXPRESSION, TO GAIN FURTHER INSIGHT INTO ITS POSSIBLE ROLE IN DIFFERENTIAL SILENCING OF HOX GENES IN MCL VS. CLL, WE PERFORMED DETAILED EPIGENETIC CHARACTERIZATION USING REPRESENTATIVE CELL LINES AND PRIMARY SAMPLES. WE OBSERVED SIGNIFICANT OVEREXPRESSION OF EZH2 IN MCL VS. CLL. CHROMATIN IMMUNE PRECIPITATION (CHIP) ASSAYS REVEALED THAT EZH2 CATALYZED REPRESSIVE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3), WHICH WAS SUFFICIENT TO SILENCE HOX GENES IN CLL, WHEREAS IN MCL H3K27ME3 IS ACCOMPANIED BY DNA METHYLATION FOR A MORE STABLE REPRESSION. MORE IMPORTANTLY, HYPERMETHYLATION OF THE HOX GENES IN MCL RESULTED FROM EZH2 OVEREXPRESSION AND SUBSEQUENT RECRUITMENT OF THE DNA METHYLATION MACHINERY ONTO HOX GENE PROMOTERS. THE IMPORTANCE OF EZH2 UPREGULATION IN THIS PROCESS WAS FURTHER UNDERSCORED BY SIRNA TRANSFECTION AND EZH2 INHIBITOR EXPERIMENTS. ALTOGETHER, THESE OBSERVATIONS IMPLICATE EZH2 IN THE LONG-TERM SILENCING OF HOX GENES IN MCL, AND ALLUDE TO ITS POTENTIAL AS A THERAPEUTIC TARGET WITH CLINICAL IMPACT. 2013 19 701 20 BROWN FAT DNMT3B DEFICIENCY AMELIORATES OBESITY IN FEMALE MICE. OBESITY RESULTS FROM A CHRONIC ENERGY IMBALANCE DUE TO ENERGY INTAKE EXCEEDING ENERGY EXPENDITURE. ACTIVATION OF BROWN FAT THERMOGENESIS HAS BEEN SHOWN TO COMBAT OBESITY. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HAS EMERGED AS A KEY REGULATOR OF BROWN FAT THERMOGENIC FUNCTION. HERE WE AIMED TO STUDY THE ROLE OF DNMT3B, A DNA METHYLTRANSFERASE INVOLVED IN DE NOVO DNA METHYLATION, IN THE REGULATION OF BROWN FAT THERMOGENESIS AND OBESITY. WE FOUND THAT THE SPECIFIC DELETION OF DNMT3B IN BROWN FAT PROMOTES THE THERMOGENIC AND MITOCHONDRIAL PROGRAM IN BROWN FAT, ENHANCES ENERGY EXPENDITURE, AND DECREASES ADIPOSITY IN FEMALE MICE FED A REGULAR CHOW DIET. WITH A LEAN PHENOTYPE, THE FEMALE KNOCKOUT MICE ALSO EXHIBIT INCREASED INSULIN SENSITIVITY. IN ADDITION, DNMT3B DEFICIENCY IN BROWN FAT ALSO PREVENTS DIET-INDUCED OBESITY AND INSULIN RESISTANCE IN FEMALE MICE. INTERESTINGLY, OUR RNA-SEQ ANALYSIS REVEALED AN UPREGULATION OF THE PI3K-AKT PATHWAY IN THE BROWN FAT OF FEMALE DNMT3B KNOCKOUT MICE. HOWEVER, MALE DNMT3B KNOCKOUT MICE HAVE NO CHANGE IN THEIR BODY WEIGHT, SUGGESTING THE EXISTENCE OF SEXUAL DIMORPHISM IN THE BROWN FAT DNMT3B KNOCKOUT MODEL. OUR DATA DEMONSTRATE THAT DNMT3B PLAYS AN IMPORTANT ROLE IN THE REGULATION OF BROWN FAT FUNCTION, ENERGY METABOLISM AND OBESITY IN FEMALE MICE. 2021 20 2768 26 EXPRESSIONS OF SERUM LNCRNAS IN DIABETIC RETINOPATHY - A POTENTIAL DIAGNOSTIC TOOL. WITH INCREASING INCIDENCE OF DIABETES WORLDWIDE, THERE IS AN EVER-EXPANDING NUMBER OF PATIENTS WITH CHRONIC DIABETIC COMPLICATIONS SUCH AS DIABETIC RETINOPATHY (DR), ONE OF THE LEADING CAUSES OF BLINDNESS IN THE WORKING AGE POPULATION. EARLY SCREENING FOR THE ONSET AND SEVERITY OF DR IS ESSENTIAL FOR TIMELY INTERVENTION. WITH RECENT ADVANCEMENTS IN GENOMIC TECHNOLOGIES, EPIGENETIC ALTERATIONS IN DR ARE BEGINNING TO UNRAVEL. LONG NON-CODING RNAS (LNCRNAS), WHICH ARE KEY EPIGENETIC MEDIATORS, HAVE DEMONSTRATED IMPLICATIONS IN SEVERAL (DR) RELATED PROCESSES. BASED ON THE PREVIOUS RESEARCH, WE HAVE DEVELOPED A SERUM-BASED, MULTI-PANEL PCR TEST USING 9 LNCRNAS (ANRIL, MALAT1, WISPER, ZFAS1, H19, HOTAIR, HULC, MEG3, AND MIAT) TO IDENTIFY AND VALIDATE WHETHER THIS PANEL COULD BE USED AS A DIAGNOSTIC AND PROGNOSTIC TOOL FOR DR. WE INITIALLY USED A CELL CULTURE MODEL (HUMAN RETINAL ENDOTHELIAL CELLS) AND CONFIRMED THAT 25 MM GLUCOSE INDUCES UPREGULATIONS OF ANRIL, HOTAIR, HULC, MALAT1, AND ZFAS1, AND DOWNREGULATION OF H19 COMPARED TO 5 MM GLUCOSE CONTROLS. THEN AS AN INITIAL PROOF-OF-CONCEPT, WE TESTED VITREOUS HUMOR AND SERUM SAMPLES FROM A SMALL COHORT OF NON-DIABETIC (N=10) AND DIABETIC PATIENTS WITH PROLIFERATIVE RETINOPATHY (PDR, N=11) AND MEASURED THE LEVELS OF THE 9 LNCRNAS. DIFFERENTIAL EXPRESSIONS OF LNCRNAS WERE FOUND IN THE VITREOUS AND SERUM OF PATIENTS AND SHOWED SIGNIFICANT CORRELATIONS. WE EXPANDED OUR APPROACH AND ASSESSED THE SAME LNCRNAS USING SAMPLES FROM A LARGER COHORT OF DIABETIC (N= 59; M/F:44/15) AND NON-DIABETIC PATIENTS (N= 11; M/F:4/7). SIGNIFICANT INCREASED LNCRNA EXPRESSIONS OF ANRIL, H19, HOTAIR, HULC, MIAT, WISPER AND ZFAS1 WERE OBSERVED IN THE SERUM OF DIABETIC PATIENTS (WITH VARYING STAGES OF DR) COMPARED TO NON-DIABETICS. NO SIGNIFICANT CORRELATIONS WERE DEMONSTRATED BETWEEN LNCRNA EXPRESSIONS AND CREATININE OR GLYCATED HEMOGLOBIN (HBA1C) LEVELS. USING ROC AND FURTHER ANALYSES, WE IDENTIFIED DISTINCT LNCRNA PHENOTYPE COMBINATIONS, WHICH MAY BE USED TO IDENTIFY PATIENTS WITH DR. DATA FROM THIS STUDY INDICATE THAT A PANEL OF SERUM LNCRNAS MAY BE USED FOR A POTENTIAL SCREENING TEST FOR DR. FURTHER LARGE-SCALE STUDIES ARE NEEDED TO VALIDATE THIS NOTION. 2022