1 4583 68 N6-METHYLADENINE RNA METHYLATION EPIGENETIC MODIFICATION AND KIDNEY DISEASES. RNA METHYLATION MODIFICATION IS A RAPIDLY DEVELOPING FIELD IN EPIGENETICS. N6-METHYLADENSINE (M(6)A) IS THE MOST COMMON INTERNAL MODIFICATION IN EUKARYOTIC MRNA. M(6)A GROUP REGULATES RNA SPLICING, STABILITY, TRANSLOCATION, AND TRANSLATION. ENZYMES CATALYZING THIS PROCESS WERE TERMED AS WRITERS, ERASERS, AND READERS. RECENT STUDIES HAVE FOCUSED ON EXPLORING THE ROLE OF RNA METHYLATION IN HUMAN DISEASES. RNA METHYLATION MODIFICATIONS, PARTICULARLY M(6)A, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF KIDNEY DISEASES. IN THIS REVIEW, WE PROVIDE A BRIEF DESCRIPTION OF M(6)A AND SUMMARIZE THE IMPACT OF M(6)A ON ACUTE AND CHRONIC KIDNEY DISEASE (CKD) AND POSSIBLE FUTURE STUDY DIRECTIONS FOR THIS RESEARCH. 2023 2 1720 37 DYSREGULATED N6-METHYLADENOSINE (M(6)A) PROCESSING IN HEPATOCELLULAR CARCINOMA. N6-METHYLADENOSINE (M(6)A) IS THE MOST THOROUGHLY STUDIED TYPE OF INTERNAL RNA MODIFICATION, AS THIS EPIGENETIC MODIFICATION IS THE MOST ABUNDANT IN EUKARYOTIC RNAS TO DATE. THIS MODIFICATION OCCURS IN VARIOUS TYPES OF RNAS AND PLAYS SIGNIFICANT ROLES IN DOMINANT RNA-RELATED PROCESSES, SUCH AS TRANSLATION, SPLICING, EXPORT AND DEGRADATION. THESE PROCESSES ARE CATALYZED BY THREE TYPES OF PROMINENT ENZYMES: WRITERS, ERASERS AND READERS. INCREASING EVIDENCE HAS SHOWN THAT M(6)A MODIFICATION IS VITAL FOR THE REGULATION OF GENE EXPRESSION, CARCINOGENESIS, TUMOR PROGRESSION AND OTHER ABNORMAL CHANGES, AND RECENT STUDIES HAVE SHOWN THAT M(6)A IS IMPORTANT IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HEREIN, WE SUMMARIZE THE NATURE AND REGULATORY MECHANISMS OF M(6)A MODIFICATION, INCLUDING ITS ROLE IN THE PATHOGENESIS OF HCC AND RELATED CHRONIC LIVER DISEASES. WE ALSO HIGHLIGHT THE CLINICAL SIGNIFICANCE AND FUTURE STRATEGIES INVOLVING RNA M(6)A MODIFICATIONS IN HCC. 2021 3 6766 20 ZINC METALLOPROTEINS IN EPIGENETICS AND THEIR CROSSTALK. MORE THAN HALF A CENTURY AGO, ZINC WAS ESTABLISHED AS AN ESSENTIAL MICRONUTRIENT FOR NORMAL HUMAN PHYSIOLOGY. IN SILICO DATA SUGGEST THAT ABOUT 10% OF THE HUMAN PROTEOME POTENTIALLY BINDS ZINC. MANY PROTEINS WITH ZINC-BINDING DOMAINS (ZBDS) ARE INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, WHICH REGULATE TRANSCRIPTION IN PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. ZINC METALLOPROTEINS IN EPIGENETICS ARE MAINLY ZINC METALLOENZYMES AND ZINC FINGER PROTEINS (ZFPS), WHICH ARE CLASSIFIED INTO WRITERS, ERASERS, READERS, EDITORS, AND FEEDERS. ALTOGETHER, THESE CLASSES OF PROTEINS ENGAGE IN CROSSTALK THAT FUNDAMENTALLY MAINTAINS THE EPIGENOME'S MODUS OPERANDI. CHANGES IN THE EXPRESSION OR FUNCTION OF THESE PROTEINS INDUCED BY ZINC DEFICIENCY OR LOSS OF FUNCTION MUTATIONS IN THEIR ZBDS MAY LEAD TO ABERRANT EPIGENETIC REPROGRAMMING, WHICH MAY WORSEN THE RISK OF NON-COMMUNICABLE CHRONIC DISEASES. THIS REVIEW ATTEMPTS TO ADDRESS ZINC'S ROLE AND ITS PROTEINS IN NATURAL EPIGENETIC PROGRAMMING AND ARTIFICIAL REPROGRAMMING AND BRIEFLY DISCUSSES HOW THE ZBDS IN THESE PROTEINS INTERACT WITH THE CHROMATIN. 2021 4 760 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 5 1728 23 DYSREGULATION OF MICRORNAS IN HYPERTROPHY AND OSSIFICATION OF LIGAMENTUM FLAVUM: NEW ADVANCES, CHALLENGES, AND POTENTIAL DIRECTIONS. PATHOLOGICAL CHANGES IN THE LIGAMENTUM FLAVUM (LF) CAN BE DEFINED AS A PROCESS OF CHRONIC PROGRESSIVE ABERRATIONS IN THE NATURE AND STRUCTURE OF LIGAMENTOUS TISSUES CHARACTERIZED BY INCREASED THICKNESS, REDUCED ELASTICITY, LOCAL CALCIFICATION, OR AGGRAVATED OSSIFICATION, WHICH MAY CAUSE SEVERE MYELOPATHY, RADICULOPATHY, OR BOTH. HYPERTROPHY OF LIGAMENTUM FLAVUM (HLF) AND OSSIFICATION OF LIGAMENTUM FLAVUM (OLF) ARE CLINICALLY COMMON ENTITIES. THOUGH ACCUMULATED EVIDENCE HAS INDICATED BOTH GENETIC AND ENVIRONMENTAL FACTORS COULD CONTRIBUTE TO THE INITIATION AND PROGRESSION OF HLF/OLF, THE DEFINITE PATHOGENESIS REMAINS FULLY UNCLEAR. MICRORNAS (MIRNAS), ONE OF THE IMPORTANT EPIGENETIC MODIFICATIONS, ARE SHORT SINGLE-STRANDED RNA MOLECULES THAT REGULATE PROTEIN-CODING GENE EXPRESSION AT POSTTRANSCRIPTIONAL LEVEL, WHICH CAN DISCLOSE THE MECHANISM UNDERLYING DISEASES, IDENTIFY VALUABLE BIOMARKERS, AND EXPLORE POTENTIAL THERAPEUTIC TARGETS. CONSIDERING THAT MIRNAS PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION, WE SUMMARIZED CURRENT STUDIES FROM THE POINT OF VIEW OF MIRNA-RELATED MOLECULAR REGULATION NETWORKS IN HLF/OLF. EXPLORATORY STUDIES REVEALED A VARIETY OF MIRNA EXPRESSION PROFILES AND IDENTIFIED A BATTERY OF UPREGULATED AND DOWNREGULATED MIRNAS IN OLF/HLF PATIENTS THROUGH MICROARRAY DATASETS OR TRANSCRIPTOME SEQUENCING. EXPERIMENTAL STUDIES VALIDATED THE ROLES OF SPECIFIC MIRNAS (E.G., MIR-132-3P, MIR-199B-5P IN OLF, MIR-155, AND MIR-21 IN HLF) IN REGULATING FIBROSIS OR OSTEOGENESIS DIFFERENTIATION OF LF CELLS AND RELATED TARGET GENES OR MOLECULAR SIGNALING PATHWAYS. FINALLY, WE DISCUSSED THE PERSPECTIVES AND CHALLENGES OF MIRNA-BASED MOLECULAR MECHANISM, DIAGNOSTIC BIOMARKERS, AND THERAPEUTIC TARGETS OF HLF/OLF. 2021 6 460 23 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE. 2021 7 35 13 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES. 2014 8 5298 17 PROTEIN ARGININE METHYLTRANSFERASE 5 SUPPRESSES THE TRANSCRIPTION OF THE RB FAMILY OF TUMOR SUPPRESSORS IN LEUKEMIA AND LYMPHOMA CELLS. THE PROPER EPIGENETIC MODIFICATION OF CHROMATIN BY PROTEIN ARGININE METHYLTRANSFERASES (PRMTS) IS CRUCIAL FOR NORMAL CELL GROWTH AND HEALTH. THE HUMAN SWI/SNF-ASSOCIATED PRMT5 IS INVOLVED IN THE TRANSCRIPTIONAL REPRESSION OF TARGET GENES BY DIRECTLY METHYLATING H3R8 AND H4R3. TO FURTHER UNDERSTAND THE IMPACT OF PRMT5-MEDIATED HISTONE METHYLATION ON CANCER, WE ANALYZED ITS EXPRESSION IN NORMAL AND TRANSFORMED HUMAN B LYMPHOCYTES. OUR FINDINGS REVEAL THAT PRMT5 PROTEIN LEVELS ARE ENHANCED IN VARIOUS HUMAN LYMPHOID CANCER CELLS, INCLUDING TRANSFORMED CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) CELL LINES. PRMT5 OVEREXPRESSION IS CAUSED BY THE ALTERED EXPRESSION OF THE PRMT5-SPECIFIC MICRORNAS 19A, 25, 32, 92, 92B, AND 96 AND RESULTS IN THE INCREASED GLOBAL SYMMETRIC METHYLATION OF H3R8 AND H4R3. AN EVALUATION OF BOTH EPIGENETIC MARKS AT PRMT5 TARGET GENES SUCH AS RB1 (P105), RBL1 (P107), AND RBL2 (P130) SHOWED THAT PROMOTERS H3R8 AND H4R3 ARE HYPERMETHYLATED, WHICH IN TURN TRIGGERS POCKET PROTEIN TRANSCRIPTIONAL REPRESSION. FURTHERMORE, REDUCING PRMT5 EXPRESSION IN WAC3CD5 B-CLL CELLS ABOLISHES H3R8 AND H4R3 HYPERMETHYLATION, RESTORES RBL2 EXPRESSION, AND INHIBITS CANCER CELL PROLIFERATION. THESE RESULTS INDICATE THAT PRMT5 OVEREXPRESSION EPIGENETICALLY ALTERS THE TRANSCRIPTION OF KEY TUMOR SUPPRESSOR GENES AND SUGGEST A CAUSAL ROLE OF THE ELEVATED SYMMETRIC METHYLATION OF H3R8 AND H4R3 AT THE RBL2 PROMOTER IN TRANSFORMED B-LYMPHOCYTE PATHOLOGY. 2008 9 2640 17 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 10 3353 19 HISTONE DEMETHYLASES REGULATE ADIPOCYTE THERMOGENESIS. ADIPOCYTES PLAY A PIVOTAL ROLE IN THE REGULATION OF ENERGY METABOLISM. WHILE WHITE ADIPOCYTE STORES ENERGY, BROWN ADIPOCYTE DISSIPATES ENERGY BY PRODUCING HEAT. IN ADDITION, ANOTHER TYPE OF HEAT-PRODUCING ADIPOCYTE, BEIGE ADIPOCYTE, EMERGES IN WHITE ADIPOSE TISSUE IN RESPONSE TO CHRONIC COLDNESS. THIS PHENOTYPIC ADAPTATION TO THE COLD ENVIRONMENT IS CONSIDERED TO BE ATTRIBUTED TO THE EPIGENETIC MODIFICATIONS. HISTONE METHYLATION IS A CHEMICALLY STABLE EPIGENETIC MODIFICATION AND THUS A PROPER MECHANISM FOR LONG-LASTING CELLULAR MEMORY. SEVERAL HISTONE METHYL-MODIFYING ENZYMES SUCH AS EHMT1, JMJD1A, JMJD3, AND LSD1 ARE REPORTED TO BE INVOLVED IN THE BEIGE ADIPOSE CELL FATE DETERMINATION. AMONG THESE, A HISTONE DEMETHYLASE JMJD1A SENSES COLD ENVIRONMENT BY BEING PHOSPHORYLATED AT S265 IN RESPONSE TO BETA-ADRENERGIC RECEPTOR STIMULATION. PHOSPHORYLATED JMJD1A REGULATES BOTH ACUTE AND COLD THERMOGENESIS. UNDER ACUTE COLDNESS, PHOSPHORYLATED JMJD1A FORMS A COMPLEX WITH CHROMATIN REMODELER SWI/SNF AND DNA-BOUND PPARGAMMA, WHICH RECRUITS JMJD1A TO THE TARGET GENOMIC REGIONS IN BROWN ADIPOCYTE. THIS COMPLEX FORMATION, IN TURN, INDUCES THE EXPRESSION OF TARGET GENES BY BRINGING THE ENHANCER AND THE PROMOTER INTO CLOSE PROXIMITY. DURING CHRONIC COLDNESS, PHOSPHORYLATED JMJD1A REGULATES BEIGE ADIPOGENESIS THROUGH A TWO-STEP MECHANISM. IN THE FIRST STEP, PHOSPHORYLATED JMJD1A IS RECRUITED TO THE REGULATORY REGIONS OF TARGET GENES BY FORMING A COMPLEX WITH PRDM16, PGC1ALPHA, AND DNA-BOUND PPARGAMMA. IN THE SECOND STEP, JMJD1A DEMETHYLATES HISTONE H3K9ME2 AND INDUCES STABLE EXPRESSION OF BEIGE-SELECTIVE GENES. THE PHENOTYPIC ANALYSES OF JMJD1A-NULL MICE AND NON-PHOSPHORYLATED MUTANT S265A JMJD1A KNOCK-IN MICE INDICATE THAT JMJD1A IS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF OBESITY-RELATED DISEASES INCLUDING METABOLIC SYNDROME AND TYPE 2 DIABETES. 2018 11 1130 27 COMPREHENSIVE ANALYSIS OF TRANSCRIPTOME-WIDE M(6)A METHYLOME IN THE LUNG TISSUES OF MICE WITH ACUTE PARTICULATE MATTER EXPOSURE. PARTICULATE MATTER (PM) EXPOSURE IS IDENTIFIED AS A CRITICAL RISK FACTOR FOR CHRONIC AIRWAY DISEASES, BUT THE BIOLOGICAL MECHANISM OF PM-INDUCED LUNG DAMAGE WAS NOT FULLY ELUCIDATED. THE M(6)A METHYLATION, AS THE MAIN MEMBER OF EPIGENETIC MODIFICATIONS, HAS BEEN FOUND TO PLAY AN IMPORTANT ROLE IN DIFFERENT PULMONARY DISEASES, BUT ITS REGULATORY EFFECT ON PM-INDUCED LUNG DAMAGE REMAINS UNKNOWN. THIS STUDY FIRSTLY USED THE METHYLATED RNA IMMUNOPRECIPITATION SEQUENCING (MERIP-SEQ) TO REVEAL THE M(6)A METHYLOME PROFILES IN THE LUNG TISSUES OF MICE WITH ACUTE PM EXPOSURE. COMPARED WITH THE NORMAL CONTROL, A TOTAL OF 2210 DIFFERENTIALLY HYPERMETHYLATED M(6)A PEAKS WITHIN 1879 GENES AND 1278 DIFFERENTIALLY HYPOMETHYLATED M(6)A PEAKS WITHIN 1153 GENES WERE IDENTIFIED IN THE PM-EXPOSED GROUP. CONJOINT ANALYSIS OF MERIP-SEQ AND HIGH-THROUGHPUT SEQUENCING FOR RNA (RNA-SEQ) DATA PREDICATED SEVERAL POTENTIAL PATHWAYS INCLUDING MAPK SIGNALING PATHWAY, CELL SENESCENCE, AND CELL CYCLE. FOUR M(6)A-MODIFIED DIFFERENTIALLY EXPRESSED GENES (IL-1A, IL-1B, ADAM-8, AND HMOX-1) WERE SELECTED FOR VALIDATION USING MERIP-QPCR. FURTHERMORE, THE M(6)A-MODIFIED IL-1A PROMOTED PM-INDUCED INFLAMMATION VIA REGULATING MAPK SIGNALING PATHWAY. THESE RESULTS PROVIDE A NEW INSIGHT INTO THE BIOLOGICAL MECHANISM OF PM-INDUCED LUNG DAMAGE, AND HELP US TO DEVELOP NEW METHODS TO PREVENT AND TREAT PM-INDUCED ADVERSE HEALTH EFFECTS. 2022 12 4034 21 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021 13 5972 16 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 14 4048 16 MAINTENANCE AND PHARMACOLOGIC TARGETING OF ROR1 PROTEIN LEVELS VIA UHRF1 IN T(1;19) PRE-B-ALL. EXPRESSION OF THE TRANSMEMBRANE PSEUDOKINASE ROR1 IS REQUIRED FOR SURVIVAL OF T(1;19)-PRE-B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T(1;19) PRE-B-ALL), CHRONIC LYMPHOCYTIC LEUKEMIA, AND MANY SOLID TUMORS. HOWEVER, TARGETING ROR1 WITH SMALL-MOLECULES HAS BEEN CHALLENGING DUE TO THE ABSENCE OF ROR1 KINASE ACTIVITY. TO IDENTIFY GENES THAT REGULATE ROR1 EXPRESSION AND MAY, THEREFORE, SERVE AS SURROGATE DRUG TARGETS, WE EMPLOYED AN SIRNA SCREENING APPROACH AND DETERMINED THAT THE EPIGENETIC REGULATOR AND E3 UBIQUITIN LIGASE, UHRF1, IS REQUIRED FOR T(1;19) PRE-B-ALL CELL VIABILITY IN A ROR1-DEPENDENT MANNER. UPON UHRF1 SILENCING, ROR1 PROTEIN IS REDUCED WITHOUT ALTERING ROR1 MRNA, AND ECTOPICALLY EXPRESSED UHRF1 IS SUFFICIENT TO INCREASE ROR1 LEVELS. ADDITIONALLY, PROTEASOME INHIBITION RESCUES LOSS OF ROR1 PROTEIN AFTER UHRF1 SILENCING, SUGGESTING A ROLE FOR THE PROTEASOME IN THE UHRF1-ROR1 AXIS. FINALLY, WE SHOW THAT ROR1-POSITIVE CELLS ARE TWICE AS SENSITIVE TO THE UHRF1-TARGETING DRUG, NAPHTHAZARIN, AND UNDERGO INCREASED APOPTOSIS COMPARED TO ROR1-NEGATIVE CELLS. NAPHTHAZARIN ELICITS REDUCED EXPRESSION OF UHRF1 AND ROR1, AND COMBINATION OF NAPHTHAZARIN WITH INHIBITORS OF PRE-B CELL RECEPTOR SIGNALING RESULTS IN FURTHER REDUCTION OF CELL SURVIVAL COMPARED WITH EITHER INHIBITOR ALONE. THEREFORE, OUR WORK REVEALS A MECHANISM BY WHICH UHRF1 STABILIZES ROR1, SUGGESTING A POTENTIAL TARGETING STRATEGY TO INHIBIT ROR1 IN T(1;19) PRE-B-ALL AND OTHER MALIGNANCIES. 2018 15 4443 18 MOLECULAR INSIGHTS INTO SPINDLIN1-HBX INTERPLAY AND ITS IMPACT ON HBV TRANSCRIPTION FROM CCCDNA MINICHROMOSOME. MOLECULAR INTERPLAY BETWEEN HOST EPIGENETIC FACTORS AND VIRAL PROTEINS CONSTITUTES AN INTRIGUING MECHANISM FOR SUSTAINING HEPATITIS B VIRUS (HBV) LIFE CYCLE AND ITS CHRONIC INFECTION. HBV ENCODES A REGULATORY PROTEIN, HBX, WHICH ACTIVATES TRANSCRIPTION AND REPLICATION OF HBV GENOME ORGANIZED AS COVALENTLY CLOSED CIRCULAR (CCC) DNA MINICHROMOSOME. HERE WE ILLUSTRATE HOW HBX ACCOMPLISHES ITS TASK BY HIJACKING SPINDLIN1, AN EPIGENETIC READER COMPRISING THREE CONSECUTIVE TUDOR DOMAINS. OUR BIOCHEMICAL AND STRUCTURAL STUDIES HAVE REVEALED THAT THE HIGHLY CONSERVED N-TERMINAL 2-21 SEGMENT OF HBX (HBX(2-21)) ASSOCIATES INTIMATELY WITH TUDOR 3 OF SPINDLIN1, ENHANCING HISTONE H3 "K4ME3-K9ME3" READOUT BY TUDORS 2 AND 1. FUNCTIONALLY, SPINDLIN1-HBX ENGAGEMENT PROMOTES GENE EXPRESSION FROM THE CHROMATINIZED CCCDNA, ACCOMPANIED BY AN EPIGENETIC SWITCH FROM AN H3K9ME3-ENRICHED REPRESSIVE STATE TO AN H3K4ME3-MARKED ACTIVE STATE, AS WELL AS A CONFORMATIONAL SWITCH OF HBX THAT MAY OCCUR IN COORDINATION WITH OTHER HBX-BINDING FACTORS, SUCH AS DDB1. DESPITE A PROPOSED TRANSREPRESSION ACTIVITY OF HBX(2-21), OUR STUDY REVEALS A KEY ROLE OF SPINDLIN1 IN DEREPRESSING THIS CONSERVED MOTIF, THEREBY PROMOTING HBV TRANSCRIPTION FROM ITS CHROMATINIZED GENOME. 2023 16 3962 19 LONG NONCODING RNA LEENE PROMOTES ANGIOGENESIS AND ISCHEMIC RECOVERY IN DIABETES MODELS. IMPAIRED ANGIOGENESIS IN DIABETES IS A KEY PROCESS CONTRIBUTING TO ISCHEMIC DISEASES SUCH AS PERIPHERAL ARTERIAL DISEASE. EPIGENETIC MECHANISMS, INCLUDING THOSE MEDIATED BY LONG NONCODING RNAS (LNCRNAS), ARE CRUCIAL LINKS CONNECTING DIABETES AND THE RELATED CHRONIC TISSUE ISCHEMIA. HERE WE IDENTIFY THE LNCRNA THAT ENHANCES ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) EXPRESSION (LEENE) AS A REGULATOR OF ANGIOGENESIS AND ISCHEMIC RESPONSE. LEENE EXPRESSION WAS DECREASED IN DIABETIC CONDITIONS IN CULTURED ENDOTHELIAL CELLS (ECS), MOUSE HIND LIMB MUSCLES, AND HUMAN ARTERIES. INHIBITION OF LEENE IN HUMAN MICROVASCULAR ECS REDUCED THEIR ANGIOGENIC CAPACITY WITH A DYSREGULATED ANGIOGENIC GENE PROGRAM. DIABETIC MICE DEFICIENT IN LEENE DEMONSTRATED IMPAIRED ANGIOGENESIS AND PERFUSION FOLLOWING HIND LIMB ISCHEMIA. IMPORTANTLY, OVEREXPRESSION OF HUMAN LEENE RESCUED THE IMPAIRED ISCHEMIC RESPONSE IN LEENE-KNOCKOUT MICE AT TISSUE FUNCTIONAL AND SINGLE-CELL TRANSCRIPTOMIC LEVELS. MECHANISTICALLY, LEENE RNA PROMOTED TRANSCRIPTION OF PROANGIOGENIC GENES IN ECS, SUCH AS KDR (ENCODING VEGFR2) AND NOS3 (ENCODING ENOS), POTENTIALLY BY INTERACTING WITH LEO1, A KEY COMPONENT OF THE RNA POLYMERASE II-ASSOCIATED FACTOR COMPLEX AND MYC, A CRUCIAL TRANSCRIPTION FACTOR FOR ANGIOGENESIS. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE AN ESSENTIAL ROLE FOR LEENE IN THE REGULATION OF ANGIOGENESIS AND TISSUE PERFUSION. FUNCTIONAL ENHANCEMENT OF LEENE TO RESTORE ANGIOGENESIS FOR TISSUE REPAIR AND REGENERATION MAY REPRESENT A POTENTIAL STRATEGY TO TACKLE ISCHEMIC VASCULAR DISEASES. 2023 17 481 23 ARSENIC-INDUCED SUMOYLATION OF MUS81 IS INVOLVED IN REGULATING GENOMIC STABILITY. CHRONIC ENVIRONMENTAL EXPOSURE TO METAL TOXICANTS SUCH AS CHROMIUM AND ARSENIC IS CLOSELY RELATED TO THE DEVELOPMENT OF SEVERAL TYPES OF COMMON CANCERS. GENETIC AND EPIGENETIC STUDIES IN THE PAST DECADE REVEAL THAT POST-TRANSLATIONAL MODIFICATIONS OF HISTONES PLAY A ROLE IN METAL CARCINOGENESIS. HOWEVER, EXACT MOLECULAR MECHANISMS OF METAL CARCINOGENESIS REMAIN TO BE ELUCIDATED. IN THIS STUDY WE FOUND THAT AS(2)O(3), AN ENVIRONMENTAL METAL TOXICANT, UPREGULATED OVERALL MODIFICATIONS OF MANY CELLULAR PROTEINS BY SUMO2/3. SUMOYLATED PROTEINS FROM ARSENIC-TREATED CELLS CONSTITUTIVELY EXPRESSING HIS(6)-SUMO2 WERE PULLED DOWN BY NI-IDA RESIN UNDER DENATURING CONDITIONS. MASS SPECTROMETRIC ANALYSIS REVEALED OVER 100 PROTEINS THAT WERE POTENTIALLY MODIFIED BY SUMOYLATION. MUS81, A DNA ENDONUCLEASE INVOLVED IN HOMOLOGOUS RECOMBINATION REPAIR, WAS AMONG THE IDENTIFIED PROTEINS WHOSE SUMOYLATION WAS INCREASED AFTER TREATMENT WITH AS(2)O(3.) WE FURTHER SHOWED THAT K10 AND K524 WERE 2 LYSINE RESIDUES ESSENTIAL FOR MUS81 SUMOYLATION. MOREOVER, WE DEMONSTRATED THAT MUS81 SUMOYLATION IS IMPORTANT FOR NORMAL MITOTIC CHROMOSOME CONGRESSION AND THAT CELLS EXPRESSING SUMO-RESISTANT MUS81 MUTANTS DISPLAYED COMPROMISED DNA DAMAGE RESPONSES AFTER EXPOSURE TO METAL TOXINS SUCH AS CR(VI) AND ARSENIC. 2017 18 6888 15 [ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF ABDOMINAL AORTIC ANEURYSM AND POTENTIAL THERAPEUTIC TARGETS]. ABDOMINAL AORTIC ANEURYSM(AAA)IS A COMMON AORTIC DEGENERATIVE DISEASE IN THE ELDERLY,AND ITS INCIDENCE IS GRADUALLY INCREASING WITH THE AGING OF THE POPULATION.THERE ARE NO SPECIFIC DRUGS AVAILABLE TO DELAY THE EXPANSION OF AAA.ONCE THE ANEURYSM RUPTURES,THE MORTALITY WILL EXCEED 90%,WHICH SERIOUSLY THREATENS THE LIFE OF PATIENTS.GIVEN THE HIGH INCIDENCE OF AAA IN THE ELDERLY,THIS REVIEW DISCUSSES THE ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF AAA,INVOLVING CHRONIC INFLAMMATION,OXIDATIVE STRESS,MITOCHONDRIAL DYSFUNCTION,PROTEIN HOMEOSTASIS IMBALANCE,INCREASED APOPTOSIS AND NECROSIS,EXTRACELLULAR MATRIX REMODELING,NUTRITIONAL SENSING DISORDERS,EPIGENETIC CHANGES,AND INCREASED PRO-AGING FACTORS.MEANWHILE,SEVERAL POTENTIAL AGING-RELATED DRUG TARGETS OF AAA ARE LISTED.THIS REVIEW PROVIDES NEW IDEAS FOR BASIC AND TRANSLATIONAL MEDICAL RESEARCH OF AAA. 2021 19 3157 17 GLYCEMIC MEMORY. PURPOSE OF REVIEW: THE MISTAKE OF PREDICTING THE FUTURE IS PERHAPS NOT TENDING TO REPRESSED OR PAST MEMORIES. HAMLET'S 17TH-CENTURY SOLILOQUY 'THE HEARTACHE AND THE THOUSAND NATURAL SHOCKS, THAT FLESH IS HEIR TO', (3.1. 7-8) IS A TALE THAT LOOKS BEYOND THE PRESENT BY LINKING THE PAST WITH THE FUTURE. THE PRESENT ARTICLE EXAMINES THE RESURGENCE IN THE FIELD TO UNDERSTAND GENE-REGULATING EPIGENETIC CHANGES CONFERRING GLYCEMIC MEMORY. RECENT FINDINGS: CHROMATIN MODIFICATIONS ARE CRITICAL IN REGULATING GENOME STRUCTURE AND FUNCTION AND DESPITE THE SIGNIFICANT ADVANCES OF RECENT YEARS IN IDENTIFYING THE ENZYMES-MEDIATING CHEMICAL CHANGES TO HISTONE TAILS AND THE DNA TEMPLATE, THE PRECISE REGULATION OF GENE EXPRESSION REMAINS INCOMPLETE IN MODELS OF HEALTH AND DIABETIC COMPLICATIONS. SUMMARY: DISPELLING THE MYTH THAT ALL GENOMES ARE DRIVEN AND RESPOND EQUALLY, EXPERIMENTAL RESEARCH IS NOW UNCOVERING THE FUNCTION OF ENZYMES CONFERRING CHROMATIN MODIFICATIONS. WHATEVER THE ROLE OF THE EPIGENOME, SHOWING ITS INVOLVEMENT IN GLYCEMIC SIGNALING IS THE FIRST STEP TO NEW STRATEGIES AND TARGETS TO DEVELOP THERAPIES THAT PREVENT, RETARD OR REVERSE THE LONG-TERM DELETERIOUS END-ORGAN EFFECTS OF CHRONIC, INTERMITTENT AND PRIOR HYPERGLYCEMIA. 2012 20 5504 18 RHEIN REVERSAL OF DNA HYPERMETHYLATION-ASSOCIATED KLOTHO SUPPRESSION AMELIORATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS THE HALLMARK OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS. RHEIN, A PLANT-DERIVED ANTHRAQUINONE, DISPLAYS STRONG ANTI-FIBROSIS PROPERTIES, BUT ITS PROTECTIVE MODE OF ACTION REMAINS INCOMPLETELY UNDERSTOOD. HERE WE EXPLORE THE MECHANISM OF RHEIN ANTI-RENAL FIBROSIS BY INVESTIGATING ITS REGULATION OF KLOTHO, A KNOWN RENAL ANTI-FIBROTIC PROTEIN WHOSE SUPPRESSION AFTER RENAL INJURY REPORTEDLY INVOLVES ABERRANT DNA METHYLATION. WE REPORT THAT RHEIN IS AN IMPRESSIVE UP-REGULATOR OF KLOTHO AND IT MARKEDLY REVERSED KLOTHO DOWN-REGULATION IN UNILATERAL URETERAL OCCLUSION-INDUCED FIBROTIC KIDNEY. FURTHER EXAMINATIONS REVEALED THAT KLOTHO LOSS IN FIBROTIC KIDNEY IS ASSOCIATED WITH KLOTHO PROMOTER HYPERMETHYLATION DUE TO ABERRANT METHYLTRANSFERASE 1 AND 3A EXPRESSIONS. HOWEVER, RHEIN SIGNIFICANTLY CORRECTED ALL THESE EPIGENETIC ALTERATIONS AND SUBSEQUENTLY ALLEVIATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS, WHEREAS KLOTHO KNOCKDOWN VIA RNA INTERFERENCES LARGELY ABROGATED THE ANTI-RENAL FIBROTIC EFFECTS OF RHEIN, SUGGESTING THAT RHEIN EPIGENETIC REVERSAL OF KLOTHO LOSS REPRESENTS A CRITICAL MODE OF ACTION THAT CONFERS RHEIN'S ANTI- RENAL FIBROTIC FUNCTIONS. ALTOGETHER OUR STUDIES UNCOVER A NOVEL HYPOMETHYLATING CHARACTER OF RHEIN IN PREVENTING KLOTHO LOSS AND RENAL FIBROSIS, AND DEMONSTRATE THE EFFICACY OF KLOTHO-TARGETED EPIGENETIC INTERVENTION IN POTENTIAL TREATMENT OF RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. 2016