1  2041 129 EPIGENETIC CHANGES WITHIN THE ANNULUS FIBROSUS BY DNA METHYLATION IN RAT INTERVERTEBRAL DISC DEGENERATION MODEL. INTERVERTEBRAL DISC DEGENERATION (IDD) IS AN AGE-DEPENDENT PROGRESSIVE SPINAL DISEASE THAT CAUSES CHRONIC BACK OR NECK PAIN. ALTHOUGH AGING HAS LONG BEEN PRESENTED AS THE MAIN RISK FACTOR, THE EXACT CAUSE IS NOT FULLY KNOWN. DNA METHYLATION IS ASSOCIATED WITH CHRONIC PAIN, SUGGESTING THAT EPIGENETIC MODULATION MAY AMELIORATE DISC DEGENERATION. WE EXAMINED HISTOLOGICAL CHANGES IN THE DNA METHYLATION WITHIN THE DISCS AND THEIR ASSOCIATION WITH PAIN-RELATED TRANSIENT RECEPTOR POTENTIAL VANILLOID SUBTYPE 1 (TRPV1) EXPRESSION IN RATS SUBJECTED TO IDD. EPIGENETIC MARKERS (5-HYDROXYMETHYLCYTOSINE (5HMC), 5-METHYLCYTOSINE (5MC)), DNA METHYLTRANSFERASES (DNMTS), AND TEN-ELEVEN TRANSLOCATIONS (TETS) WERE ANALYZED USING IMMUNOHISTOCHEMISTRY, REAL-TIME PCR, AND DNA DOT-BLOT FOLLOWING IDD. RESULTS REVEALED HIGH 5MC LEVELS IN THE ANNULUS FIBROSUS (AF) REGION WITHIN THE DISC AFTER IDD AND AN ASSOCIATION WITH TRPV1 EXPRESSION. DNMT1 IS MAINLY INVOLVED IN 5MC CONVERSION IN DEGENERATED DISCS. HOWEVER, 5HMC LEVELS DID NOT DIFFER BETWEEN GROUPS. A DEGENERATED DISC CAN LEAD TO LOCOMOTOR DEFECTS AS ASSESSED BY LADDER AND TAIL SUSPENSION TESTS, NO PAIN SIGNALS IN THE VON FREY TEST, UPREGULATED MATRIX METALLOPROTEINASE-3, AND DOWNREGULATED AGGRECAN LEVELS WITHIN THE DISC. THUS, WE FOUND THAT THE DNA METHYLATION STATUS IN THE AF REGION OF THE DISC WAS MAINLY CHANGED AFTER IDD AND ASSOCIATED WITH ABERRANT TRPV1 EXPRESSION IN DEGENERATED DISCS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  2229  27 EPIGENETIC MODIFICATIONS OF INFLAMMATION IN INTERVERTEBRAL DISC DEGENERATION. INTERVERTEBRAL DISC DEGENERATION (IDD) IS A COMMON CAUSE OF JOINT-RELATED CHRONIC DISABILITY IN ELDERLY INDIVIDUALS WORLDWIDE. IT SERIOUSLY IMPACTS THE QUALITY OF LIFE AND INFLICTS A SUBSTANTIAL SOCIAL AND ECONOMIC BURDEN. THE PATHOLOGICAL MECHANISMS UNDERLYING IDD HAVE NOT BEEN FULLY REVEALED, LEADING TO LESS SATISFACTORY CLINICAL TREATMENT OUTCOMES. MORE STUDIES ARE URGENTLY NEEDED TO REVEAL ITS PRECISE PATHOLOGICAL MECHANISMS. NUMEROUS STUDIES HAVE REVEALED THAT INFLAMMATION IS CLOSELY RELATED TO VARIOUS PATHOLOGICAL PROCESSES OF IDD, INCLUDING THE CONTINUOUS LOSS OF EXTRACELLULAR MATRIX, CELL APOPTOSIS, AND SENESCENCE, INDICATING THE IMPORTANT ROLE OF INFLAMMATION IN THE PATHOLOGICAL MECHANISM OF IDD. EPIGENETIC MODIFICATIONS AFFECT THE FUNCTIONS AND CHARACTERISTICS OF GENES MAINLY THROUGH DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA REGULATION, AND OTHER MECHANISMS, THUS HAVING A MAJOR EFFECT ON THE SURVIVAL STATE OF THE BODY. RECENTLY, THE ROLE OF EPIGENETIC MODIFICATIONS IN INFLAMMATION DURING IDD HAS BEEN ATTRACTING RESEARCH INTEREST. IN THIS REVIEW, WE SUMMARIZE THE ROLES OF DIFFERENT TYPES OF EPIGENETIC MODIFICATIONS IN INFLAMMATION DURING IDD IN RECENT YEARS, TO IMPROVE OUR UNDERSTANDING OF THE ETIOLOGY OF IDD AND TO TRANSFORM BASIC RESEARCH STRATEGY INTO A CLINICALLY EFFECTIVE TREATMENT FOR JOINT-RELATED CHRONIC DISABILITY IN ELDERLY INDIVIDUALS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  2284  15 EPIGENETIC REGULATION IN INTERVERTEBRAL DISC DEGENERATION. INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH HAS A STRIKING IMPACT ON NUMEROUS PATIENTS. THEREFORE, COMPREHENSIVELY ILLUMINATING THE REGULATORY MECHANISMS OF IVD DEGENERATION IS OF GREAT SIGNIFICANCE. HERE, WE DISCUSS THE LATEST ADVANCES IN UNDERSTANDING THE MAIN EPIGENETIC MECHANISMS REGULATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  5973  32 TET-CATALYZED 5-HYDROXYMETHYLATION PRECEDES HNF4A PROMOTER CHOICE DURING DIFFERENTIATION OF BIPOTENT LIVER PROGENITORS. UNDERSTANDING THE PROCESSES THAT GOVERN LIVER PROGENITOR CELL DIFFERENTIATION HAS IMPORTANT IMPLICATIONS FOR THE DESIGN OF STRATEGIES TARGETING CHRONIC LIVER DISEASES, WHEREBY REGENERATION OF LIVER TISSUE IS CRITICAL. ALTHOUGH DNA METHYLATION (5MC) AND HYDROXYMETHYLATION (5HMC) ARE HIGHLY DYNAMIC DURING EARLY EMBRYONIC DEVELOPMENT, LESS IS KNOWN ABOUT THEIR ROLES AT LATER STAGES OF DIFFERENTIATION. USING AN IN VITRO MODEL OF HEPATOCYTE DIFFERENTIATION, WE SHOW HERE THAT 5HMC PRECEDES THE EXPRESSION OF PROMOTER 1 (P1)-DEPENDENT ISOFORMS OF HNF4A, A MASTER TRANSCRIPTION FACTOR OF HEPATOCYTE IDENTITY. 5HMC AND HNF4A EXPRESSION FROM P1 ARE DEPENDENT ON TEN-ELEVEN TRANSLOCATION (TET) DIOXYGENASES. IN TURN, THE LIVER PIONEER FACTOR FOXA2 IS NECESSARY FOR TET1 BINDING TO THE P1 LOCUS. BOTH FOXA2 AND TETS ARE REQUIRED FOR THE 5HMC-RELATED SWITCH IN HNF4A EXPRESSION. THE EPIGENETIC EVENT IDENTIFIED HERE MAY BE A KEY STEP FOR THE ESTABLISHMENT OF THE HEPATOCYTE PROGRAM BY HNF4A.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  1807  26 EFFECTIVE MODULATION OF INFLAMMATION AND OXIDATIVE STRESS FOR ENHANCED REGENERATION OF INTERVERTEBRAL DISCS USING 3D POROUS HYBRID PROTEIN NANOSCAFFOLD. DEGENERATION OF FIBROCARTILAGINOUS TISSUES IS OFTEN ASSOCIATED WITH COMPLEX PRO-INFLAMMATORY FACTORS. THESE INCLUDE REACTIVE OXYGEN SPECIES (ROS), CELL-FREE NUCLEIC ACIDS (CF-NAS), AND EPIGENETIC CHANGES IN IMMUNE CELLS. TO EFFECTIVELY CONTROL THIS COMPLEX INFLAMMATORY SIGNALING, IT DEVELOPED AN ALL-IN-ONE NANOSCAFFOLD-BASED 3D POROUS HYBRID PROTEIN (3D-PHP) SELF-THERAPEUTIC STRATEGY FOR TREATING INTERVERTEBRAL DISC (IVD) DEGENERATION. THE 3D-PHP NANOSCAFFOLD IS SYNTHESIZED BY INTRODUCING A NOVEL NANOMATERIAL-TEMPLATED PROTEIN ASSEMBLY (NTPA) STRATEGY. 3D-PHP NANOSCAFFOLDS THAT AVOID COVALENT MODIFICATION OF PROTEINS DEMONSTRATE INFLAMMATORY STIMULI-RESPONSIVE DRUG RELEASE, DISC-MIMETIC STIFFNESS, AND EXCELLENT BIODEGRADABILITY. ENZYME-LIKE 2D NANOSHEETS INCORPORATED INTO NANOSCAFFOLDS FURTHER ENABLED ROBUST SCAVENGING OF ROS AND CF-NAS, REDUCING INFLAMMATION AND ENHANCING THE SURVIVAL OF DISC CELLS UNDER INFLAMMATORY STRESS IN VITRO. IMPLANTATION OF 3D-PHP NANOSCAFFOLDS LOADED WITH BROMODOMAIN EXTRATERMINAL INHIBITOR (BETI) INTO A RAT NUCLEOTOMY DISC INJURY MODEL EFFECTIVELY SUPPRESSED INFLAMMATION IN VIVO, THUS PROMOTING RESTORATION OF THE EXTRACELLULAR MATRIX (ECM). THE RESULTING REGENERATION OF DISC TISSUE FACILITATED LONG-TERM PAIN REDUCTION. THEREFORE, SELF-THERAPEUTIC AND EPIGENETIC MODULATOR-ENCAPSULATED HYBRID PROTEIN NANOSCAFFOLD SHOWS GREAT PROMISE AS A NOVEL APPROACH TO RESTORE DYSREGULATED INFLAMMATORY SIGNALING AND TREAT DEGENERATIVE FIBROCARTILAGINOUS DISEASES, INCLUDING DISC INJURIES, PROVIDING HOPE AND RELIEF TO PATIENTS WORLDWIDE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6   277  33 AGE-RELATED EPIGENOME-WIDE DNA METHYLATION AND HYDROXYMETHYLATION IN LONGITUDINAL MOUSE BLOOD. DNA METHYLATION AT CYTOSINE-PHOSPHATE-GUANINE (CPG) DINUCLEOTIDES CHANGES AS A FUNCTION OF AGE IN HUMANS AND ANIMAL MODELS, A PROCESS THAT MAY CONTRIBUTE TO CHRONIC DISEASE DEVELOPMENT. RECENT STUDIES HAVE INVESTIGATED THE ROLE OF AN OXIDIZED FORM OF DNA METHYLATION - 5-HYDROXYMETHYLCYTOSINE (5HMC) - IN THE EPIGENOME, BUT ITS CONTRIBUTION TO AGE-RELATED DNA METHYLATION REMAINS UNCLEAR. WE TESTED THE HYPOTHESIS THAT 5HMC CHANGES WITH AGE, BUT IN A DIRECTION OPPOSITE TO 5-METHYLCYTOSINE (5MC), POTENTIALLY PLAYING A DISTINCT ROLE IN AGING. TO CHARACTERIZE EPIGENETIC AGING, GENOME-WIDE 5MC AND 5HMC WERE MEASURED IN LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OF AGE) FROM ISOGENIC MICE USING TWO SEQUENCING METHODS - ENHANCED REDUCED REPRESENTATION BISULFITE SEQUENCING AND HYDROXYMETHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. EXAMINING THE EPIGENOME BY AGE, WE IDENTIFIED 28,196 UNIQUE DIFFERENTIALLY METHYLATED CPGS (DMCS) AND 8,613 DIFFERENTIALLY HYDROXYMETHYLATED REGIONS (DHMRS). MOUSE BLOOD SHOWED A GENERAL PATTERN OF EPIGENOME-WIDE HYPERMETHYLATION AND HYPO-HYDROXYMETHYLATION WITH AGE. COMPARING AGE-RELATED DMCS AND DHMRS, 1,854 ANNOTATED GENES SHOWED BOTH DIFFERENTIAL 5MC AND 5HMC, INCLUDING ONE GENE - NFIC - AT FIVE CPGS IN THE SAME 250 BP CHROMOSOMAL REGION. AT THIS REGION, 5MC AND 5HMC LEVELS BOTH DECREASED WITH AGE. REFLECTING THESE AGE-RELATED EPIGENETIC CHANGES, NFIC RNA EXPRESSION IN BLOOD DECREASED WITH AGE, SUGGESTING THAT AGE-RELATED REGULATION OF THIS GENE MAY BE DRIVEN BY 5HMC, NOT CANONICAL DNA METHYLATION. COMBINED, OUR GENOME-WIDE RESULTS SHOW AGE-RELATED DIFFERENTIAL 5MC AND 5HMC, AS WELL AS SOME EVIDENCE THAT CHANGES IN 5HMC MAY DRIVE AGE-RELATED DNA METHYLATION AND GENE EXPRESSION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  4033  36 M6A HYPOMETHYLATION OF DNMT3B REGULATED BY ALKBH5 PROMOTES INTERVERTEBRAL DISC DEGENERATION VIA E4F1 DEFICIENCY. BACKGROUND: THE INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH ACCOUNTS FOR A MAIN CAUSE OF DISABILITY. N6-METHYLADENOSINE (M6A) IS THE MOST ABUNDANT INTERNAL MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS INVOLVED IN VARIOUS DISEASES AND CELLULAR PROCESSES BY MODULATING MRNA FATE. HOWEVER, THE CRITICAL ROLE OF M6A REGULATION IN IVD DEGENERATION REMAINS UNCLEAR. NUCLEUS PULPOSUS CELL (NPC) SENESCENCE IS CRITICAL FOR THE PROGRESSION OF IVD DEGENERATION. HERE, WE UNCOVERED THE ROLE AND EXPLORED THE REGULATORY MECHANISM OF M6A IN NPC SENESCENCE DURING IVD DEGENERATION. METHODS: IDENTIFICATION OF NPC SENESCENCE DURING IVD DEGENERATION WAS BASED ON THE ANALYSIS OF TISSUE SAMPLES AND THE CELLULAR MODEL. ALKBH5 UPREGULATION INDUCING CELLULAR SENESCENCE WAS CONFIRMED BY FUNCTIONAL EXPERIMENTS IN VIVO AND IN VITRO. CHIP-QPCR AND DNA-PULLDOWN WERE USED TO REVEAL INCREASED ALKBH5 WAS REGULATED BY KDM4A-MEDIATED H3K9ME3. FURTHERMORE, ME-RIP-SEQ WAS PERFORMED TO IDENTIFY M6A HYPOMETHYLATION OF DNMT3B TRANSCRIPTS IN SENESCENT NPCS. STABILITY ANALYSIS SHOWED THAT DNMT3B EXPRESSION WAS ENHANCED FOR LESS YTHDF2 RECOGNITION AND INCREASED DNMT3B PROMOTED NPC SENESCENCE AND IVD DEGENERATION VIA E4F1 METHYLATION BY IN VIVO AND IN VITRO ANALYSES. RESULTS: EXPRESSION OF ALKBH5 IS ENHANCED DURING IVD DEGENERATION AND NPC SENESCENCE, DUE TO DECREASED KDM4A-MEDIATED H3K9ME3 MODIFICATION. FUNCTIONALLY, ALKBH5 CAUSES NPC SENESCENCE BY DEMETHYLATING DNMT3B TRANSCRIPTS AND IN TURN PROMOTING ITS EXPRESSION VIA LESS YTHDF2 RECOGNITION AND FOLLOWING DEGRADATION DUE TO TRANSCRIPT HYPOMETHYLATION IN VITRO AND IN VIVO. INCREASED DNMT3B PROMOTES THE DEVELOPMENT OF IVD DEGENERATION AND NPC SENESCENCE, MECHANISTICALLY BY METHYLATING CPG ISLANDS OF E4F1 AT THE PROMOTER REGION AND THUS RESTRAINING ITS TRANSCRIPTION AND EXPRESSION. CONCLUSIONS: COLLECTIVELY, OUR FINDINGS REVEAL AN EPIGENETIC INTERPLAY MECHANISM IN NPC SENESCENCE AND IVD DEGENERATION, PRESENTING A CRITICAL PRO-SENESCENCE ROLE OF ALKBH5 AND M6A HYPOMETHYLATION, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF TARGETING THE M6A/DNMT3B/E4F1 AXIS FOR TREATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8   328  29 ALPHA-KETOGLUTARIC ACID AMELIORATES INTERVERTEBRAL DISC DEGENERATION BY BLOCKING THE IL-6/JAK2/STAT3 PATHWAY. INTERVERTEBRAL DISC DEGENERATION (IVDD) IS THE MAJOR CAUSE OF LOW BACK PAIN. ALPHA-KETOGLUTARIC ACID (ALPHA-KG), AN IMPORTANT INTERMEDIATE IN ENERGY METABOLISM, HAS VARIOUS FUNCTIONS, INCLUDING EPIGENETIC REGULATION, MAINTENANCE OF REDOX HOMEOSTASIS, AND ANTI-AGING, BUT WHETHER IT CAN AMELIORATE IVDD HAS NOT BEEN REPORTED. HERE, WE EXAMINED THE IMPACTS OF LONG-TERM ADMINISTRATION OF A-KG ON AGING-ASSOCIATED IVDD IN ADULT RATS. IN VIVO AND IN VITRO EXPERIMENTS SHOWED THAT ALPHA-KG SUPPLEMENTATION EFFECTIVELY AMELIORATED IVDD IN RATS AND THE SENESCENCE OF NUCLEUS PULPOSUS CELLS (NPCS). ALPHA-KG SUPPLEMENTATION SIGNIFICANTLY ATTENUATED SENESCENCE, APOPTOSIS AND MMP-13 PROTEIN EXPRESSION, AND IT INCREASED THE SYNTHESIS OF AGGRECAN AND COLLAGEN II IN IL-1BETA-TREATED NPCS. IN ADDITION, ALPHA-KG SUPPLEMENTATION REDUCED THE LEVELS OF IL-6, PHOSPHORYLATED JAK2 AND STAT3, AND THE NUCLEAR TRANSLOCATION OF P-STAT3 IN IL-1BETA-INDUCED DEGENERATING NPCS. THE EFFECTS OF ALPHA-KG WERE ENHANCED BY AG490 IN NPCS. THE UNDERLYING MECHANISM MAY INVOLVE THE INHIBITION OF JAK2/STAT3 PHOSPHORYLATION AND THE REDUCTION OF IL-6 EXPRESSION. OUR FINDINGS MAY HELP IN THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES FOR IVDD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  5297  37 PROTEIN ARGININE METHYLTRANSFERASE 5 CONTRIBUTES TO PACLITAXEL-INDUCED NEUROPATHIC PAIN BY ACTIVATING TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 EPIGENETIC MODIFICATION IN DORSAL ROOT GANGLION. BACKGROUND: PACLITAXEL (PTX), WHICH IS A FIRST-LINE CHEMOTHERAPY DRUG USED TO TREAT VARIOUS TYPES OF CANCERS, EXHIBITS PERIPHERAL NEUROPATHY AS A COMMON SIDE EFFECT THAT IS DIFFICULT TO TREAT. PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT 5) IS A KEY REGULATOR OF THE CHEMOTHERAPY RESPONSE, AS CHEMOTHERAPY DRUGS INDUCE PRMT5 EXPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PRMT5-MEDIATED EPIGENETIC MECHANISMS INVOLVED IN PTX-INDUCED NEUROPATHIC ALLODYNIA. METHODS: SPRAGUE-DAWLEY RATS WERE INTRAPERITONEALLY GIVEN PTX TO INDUCE NEUROPATHIC PAIN. BIOCHEMICAL ANALYSES WERE CONDUCTED TO MEASURE THE PROTEIN EXPRESSION LEVELS IN THE DORSAL ROOT GANGLION (DRG) OF THE ANIMALS. THE VON FREY TEST AND HOT PLATE TEST WERE USED TO EVALUATE NOCICEPTIVE BEHAVIORS. RESULTS: PTX INCREASED THE PRMT5 (MEAN DIFFERENCE [MD]: 0.68, 95% CONFIDENCE INTERVAL [CI], 0.88-0.48; P < .001 FOR VEHICLE)-MEDIATED DEPOSITION OF HISTONE H3R2 DIMETHYL SYMMETRIC (H3R2ME2S) AT THE TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1) PROMOTER IN THE DRG. PRMT5-INDUCED H3R2ME2S RECRUITED WD REPEAT DOMAIN 5 (WDR5) TO INCREASE TRIMETHYLATION OF LYSINE 4 ON HISTONE H3 (H3K4ME3) AT TRPV1 PROMOTERS, THUS RESULTING IN TRPV1 TRANSCRIPTIONAL ACTIVATION (MD: 0.65, 95% CI, 0.82-0.49; P < .001 FOR VEHICLE) IN DRG IN PTX-INDUCED NEUROPATHIC PAIN. MOREOVER, PTX INCREASED THE ACTIVITY OF NADPH OXIDASE 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 FOR VEHICLE), PRMT5-INDUCED H3R2ME2S, AND WDR5-MEDIATED H3K4ME3 IN THE DRG IN PTX-INDUCED NEUROPATHIC PAIN. PHARMACOLOGICAL ANTAGONISM AND THE SELECTIVE KNOCKDOWN OF PRMT5 IN DRG NEURONS COMPLETELY BLOCKED PRMT5-MEDIATED H3R2ME2S, WDR5-MEDIATED H3K4ME3, OR TRPV1 EXPRESSION AND NEUROPATHIC PAIN DEVELOPMENT AFTER PTX INJECTION. REMARKABLY, NOX4 INHIBITION NOT ONLY ATTENUATED ALLODYNIA BEHAVIOR AND REVERSED THE ABOVE-MENTIONED SIGNALING BUT ALSO REVERSED NOX4 UPREGULATION VIA PTX. CONCLUSIONS: THUS, THE NOX4/PRMT5-ASSOCIATED EPIGENETIC MECHANISM IN DRG HAS A DOMINANT FUNCTION IN THE TRANSCRIPTIONAL ACTIVATION OF TRPV1 IN PTX-INDUCED NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10    21  23 5-HYDROXYMETHYLCYTOSINE (5HMC) AND TEN-ELEVEN TRANSLOCATION 1-3 (TET1-3) PROTEINS IN THE DORSAL ROOT GANGLIA OF MOUSE: EXPRESSION AND DYNAMIC REGULATION IN NEUROPATHIC PAIN. EPIGENETIC MECHANISMS ARE INCREASINGLY IMPLICATED IN CHRONIC PAIN PATHOLOGY. IN THIS STUDY, WE DEMONSTRATE THAT THE NOVEL EPIGENETIC MARK 5-HYDROXYMETHYLCYTOSINE (5HMC) IS PRESENT IN DORSAL ROOT GANGLIA (DRG) NEURONS AND GLIA, AND ITS LEVELS INCREASE FOLLOWING NERVE INJURY. FURTHERMORE, WE SHOW THAT THE 5HMC-GENERATING TEN-ELEVEN TRANSLOCATION 1-3 (TET1-3) PROTEINS ARE EXPRESSED IN A CELL-TYPE SPECIFIC MANNER IN THE DRG, WITH TET3 DISPLAYING DIFFERENTIAL UPREGULATION AFTER INJURY, SUGGESTING A POTENTIAL ROLE IN NEUROPATHIC PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  1492  30 DNA HYDROXYMETHYLATION BY TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 AND 3 REGULATES NOCICEPTIVE SENSITIZATION IN A CHRONIC INFLAMMATORY PAIN MODEL. BACKGROUND: TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE CONVERTS 5-METHYLCYTOSINE IN DNA TO 5-HYDROXYMETHYLCYTOSINE, WHICH PLAYS AN IMPORTANT ROLE IN GENE TRANSCRIPTION. ALTHOUGH 5-HYDROXYMETHYLCYTOSINE IS ENRICHED IN MAMMALIAN NEURONS, ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING IS UNKNOWN. METHODS: THE GLOBAL LEVELS OF 5-HYDROXYMETHYLCYTOSINE AND TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE WERE MEASURED IN SPINAL CORDS IN MICE TREATED WITH COMPLETE FREUND'S ADJUVANT. IMMUNOBLOTTING, IMMUNOHISTOCHEMISTRY, AND BEHAVIORAL TESTS WERE USED TO EXPLORE THE DOWNSTREAM TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-DEPENDENT SIGNALING PATHWAY. RESULTS: COMPLETE FREUND'S ADJUVANT-INDUCED NOCICEPTION INCREASED THE MEAN LEVELS (+/- SD) OF SPINAL 5-HYDROXYMETHYLCYTOSINE (178 +/- 34 VS. 100 +/- 21; P = 0.0019), TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-1 (0.52 +/- 0.11 VS. 0.36 +/- 0.064; P = 0.0088), AND TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-3 (0.61 +/- 0.13 VS. 0.39 +/- 0.08; P = 0.0083) COMPARED WITH LEVELS IN CONTROL MICE (N = 6/GROUP). THE KNOCKDOWN OF TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-1 OR TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-3 ALLEVIATED THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA, WHEREAS OVEREXPRESSION CYTOSINETHEM IN NAIVE MICE (N = 6/GROUP). DOWN-REGULATION OF SPINAL TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-1 AND TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-3 ALSO REVERSED THE INCREASES IN FOS EXPRESSION (123 +/- 26 VS. 294 +/- 6; P = 0.0031; AND 140 +/- 21 VS. 294 +/- 60; P = 0.0043, RESPECTIVELY; N = 6/GROUP), 5-HYDROXYMETHYLCYTOSINE LEVELS IN THE STAT3 PROMOTER (75 +/- 16.1 VS. 156 +/- 28.9; P = 0.0043; AND 91 +/- 19.1 VS. 156 +/- 28.9; P = 0.0066, RESPECTIVELY; N = 5/GROUP), AND CONSEQUENT STAT3 EXPRESSION (93 +/- 19.6 VS. 137 +/- 27.5; P = 0.035; AND 72 +/- 15.2 VS. 137 +/- 27.5; P = 0.0028, RESPECTIVELY; N = 5/GROUP) IN COMPLETE FREUND'S ADJUVANT-TREATED MICE. CONCLUSIONS: THIS STUDY REVEALS A NOVEL EPIGENETIC MECHANISM FOR TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-1 AND TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE-3 IN THE MODULATION OF SPINAL NOCICEPTIVE INFORMATION VIA TARGETING OF STAT3.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  6430  25 THE USE OF MEDICAL OZONE IN CHRONIC INTERVERTEBRAL DISC DEGENERATION CAN BE AN ETIOLOGICAL AND CONSERVATIVE TREATMENT. DEGENERATION OF THE INTERVERTEBRAL DISC IS ONE OF THE MOST FREQUENT CAUSES OF LUMBAR PAIN, AND IT PUTS AN EXTREME STRAIN ON WORLDWIDE HEALTHCARE SYSTEMS. FINDING A SOLUTION FOR THIS DISEASE IS AN IMPORTANT CHALLENGE AS CURRENT SURGICAL AND CONSERVATIVE TREATMENTS FAIL TO BRING A SHORT-TERM OR LONG-TERM SOLUTION TO THE PROBLEM. MEDICAL OZONE HAS YIELDED EXCELLENT RESULTS IN INTERVERTEBRAL DISC PATHOLOGY. WHEN IT COMES TO EXTRUDED DISC HERNIATION, OZONE IS THE ONLY ETIOLOGICAL TREATMENT BECAUSE IT STIMULATES THE IMMUNE SYSTEM TO ABSORB THE HERNIATED PORTION OF THE NUCLEUS PULPOSUS, THUS RESOLVING DISCAL EXTRUSION. THIS WORK AIMS TO EXAMINE THE BIOMOLECULAR MECHANISMS THAT LEAD TO INTERVERTEBRAL DISC DEGENERATION WHILE HIGHLIGHTING THE SIGNIFICANCE OF OXIDATIVE STRESS AND CHRONIC INFLAMMATION. CONSIDERING THAT OZONE IS A REGULATOR OF OXIDATIVE STRESS AND, THEREFORE, OF INFLAMMATION, WE ASSERT THAT MEDICAL OZONE COULD MODULATE THIS PROCESS AND OBTAIN INFLAMMATORY STAGE MACROPHAGES (M1) TO SWITCH TO THE REPAIR PHASE (M2). CONSEQUENTLY, THE OZONE WOULD BE A THERAPEUTIC RESOURCE THAT WOULD WORK ON THE ETIOLOGY OF THE DISEASE AS AN EPIGENETIC REGULATOR THAT WOULD HELP REPAIR THE INTERVERTEBRAL SPACE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  3724  35 INHIBITION OF EZH2 AMELIORATES CARTILAGE ENDPLATE DEGENERATION AND ATTENUATES THE PROGRESSION OF INTERVERTEBRAL DISC DEGENERATION VIA DEMETHYLATION OF SOX-9. BACKGROUND: CARTILAGINOUS ENDPLATE (CEP) DEGENERATION IS CONSIDERED AS ONE OF THE MAJOR CAUSES OF INTERVERTEBRAL DISC DEGENERATION (IVDD) WHICH CAUSES LOW BACK PAIN. RECENT STUDIES HAVE PROVED THAT EPIGENETIC ALTERATION IS INVOLVED IN A VARIETY OF DISEASES. THIS WORK EXPLORED THE ROLE OF HISTONE METHYLTRANSFERASE ENHANCER OF ZESTE HOMOLOGUE 2 (EZH2) IN CEP DEGENERATION, AS WELL AS ITS UNDERLYING EPIGENETIC MECHANISMS, AND CONFIRMED THE EFFECT OF EZH2 KNOCKDOWN ON DELAYING IVDD DEVELOPMENT. METHODS: WESTERN BLOTTING, IMMUNOFLUORESCENCE STAINING, AND CHIP ASSAY WERE APPLIED TO DEMONSTRATE THE MOLECULAR MECHANISM OF EZH2 IN CEP TISSUE. THE THERAPEUTIC POTENTIAL OF EZH2 WAS INVESTIGATED USING PUNCTURE-INDUCED RAT MODELS. FINDINGS: THE EZH2 EXPRESSION WAS UPREGULATED IN HUMAN AND RAT CEP TISSUE. IT WAS ALSO FOUND THAT THE OVEREXPRESSION OF EZH2 SUPPRESSED THE EXPRESSION OF COLLAGEN II, AGGRECAN AND SOX-9, AND PROMOTED THE EXPRESSION OF ADTAMTS5 AND MMP13 IN RAT ENDPLATE CHONDROCYTES (EPCS), WHICH COULD BE REVERSED BY EZH2 SILENCING. THE CORRELATION BETWEEN EZH2 AND SOX-9 WAS FURTHER EXPLORED, WHILE OVEREXPRESSION OF SOX-9 COULD REVERSE THE EFFECT OF EZH2 IN RAT EPCS. MOREOVER, INHIBITION OF EZH2 UPREGULATED THE LEVEL OF SOX-9 BY DEMETHYLATING H3K27ME3 AT SOX-9 PROMOTER SITES, REVEALING THE REGULATORY MECHANISM OF EZH2 ON SOX-9. MEANWHILE, PUNCTURE-INDUCED RAT MODELS SHOWED THAT EZH2 KNOCKDOWN EXERTED A PROTECTIVE EFFECT ON CEP AND DISC DEGENERATION. INTERPRETATION: THIS STUDY REVEALS THAT EZH2 INHIBITION IS A PROMISING STRATEGY FOR MITIGATING THE SYMPTOMS AND PROGRESSION OF IVDD. FUNDING: THIS STUDY WAS FUNDED BY THE NATURAL SCIENCE FOUNDATION OF ZHEJIANG PROVINCE (Y16H060034). AUTHORS DECLARE THAT THE FUNDERS HAD NO INVOLVEMENT IN THE STUDY DESIGN, DATA ANALYSIS AND INTERPRETATION OF THE RESULTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  5062  36 PHOSPHATE NIMA-RELATED KINASE 2-DEPENDENT EPIGENETIC PATHWAYS IN DORSAL ROOT GANGLION NEURONS MEDIATES PACLITAXEL-INDUCED NEUROPATHIC PAIN. BACKGROUND: THE MICROTUBULE-STABILIZING DRUG PACLITAXEL (PTX) IS AN IMPORTANT CHEMOTHERAPEUTIC AGENT FOR CANCER TREATMENT AND CAUSES PERIPHERAL NEUROPATHY AS A COMMON SIDE EFFECT THAT SUBSTANTIALLY IMPACTS THE FUNCTIONAL STATUS AND QUALITY OF LIFE OF PATIENTS. THE MECHANISTIC ROLE FOR NIMA-RELATED KINASE 2 (NEK2) IN THE PROGRESSION OF PTX-INDUCED NEUROPATHIC PAIN HAS NOT BEEN ESTABLISHED. METHODS: ADULT MALE SPRAGUE-DAWLEY RATS INTRAPERITONEALLY RECEIVED PTX TO INDUCE NEUROPATHIC PAIN. THE PROTEIN EXPRESSION LEVELS IN THE DORSAL ROOT GANGLION (DRG) OF ANIMALS WERE MEASURED BY BIOCHEMICAL ANALYSES. NOCICEPTIVE BEHAVIORS WERE EVALUATED BY VON FREY TESTS AND HOT PLATE TESTS. RESULTS: PTX INCREASED PHOSPHORYLATION OF THE IMPORTANT MICROTUBULE DYNAMICS REGULATOR NEK2 IN DRG NEURONS AND INDUCED PROFOUND NEUROPATHIC ALLODYNIA. PTX-ACTIVATED PHOSPHORYLATED NEK2 (PNEK2) INCREASED JUMONJI DOMAIN-CONTAINING 3 (JMJD3) PROTEIN, A HISTONE DEMETHYLASE PROTEIN, TO SPECIFICALLY CATALYZE THE DEMETHYLATION OF THE REPRESSIVE HISTONE MARK H3 LYSINE 27 TRIMETHYLATION (H3K27ME3) AT THE TRPV1 GENE, THEREBY ENHANCING TRANSIENT RECEPTOR POTENTIAL VANILLOID SUBTYPE-1 (TRPV1) EXPRESSION IN DRG NEURONS. MOREOVER, THE PNEK2-DEPENDENT PTX RESPONSE PROGRAM IS REGULATED BY ENHANCING P90 RIBOSOMAL S6 KINASE 2 (RSK2) PHOSPHORYLATION. CONVERSELY, INTRATHECAL INJECTIONS OF KAEMPFEROL (A SELECTIVE RSK2 ACTIVATION ANTAGONIST), NCL 00017509 (A SELECTIVE NEK2 INHIBITOR), NEK2-TARGETED SIRNA, GSK-J4 (A SELECTIVE JMJD3 INHIBITOR), OR CAPSAZEPINE (AN ANTAGONIST OF TRPV1 RECEPTOR) INTO PTX-TREATED RATS REVERSED NEUROPATHIC ALLODYNIA AND RESTORED SILENCING OF THE TRPV1 GENE, SUGGESTING THE HIERARCHY AND INTERACTION AMONG PHOSPHORYLATED RSK2 (PRSK2), PNEK2, JMJD3, H3K27ME3, AND TRPV1 IN THE DRG NEURONS IN PTX-INDUCED NEUROPATHIC PAIN. CONCLUSIONS: PRSK2/JMJD3/H3K27ME3/TRPV1 SIGNALING IN THE DRG NEURONS PLAYS AS A KEY REGULATOR FOR PTX THERAPEUTIC APPROACHES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  2706  49 EXERCISE ATTENUATES LOW BACK PAIN AND ALTERS EPIGENETIC REGULATION IN INTERVERTEBRAL DISCS IN A MOUSE MODEL. BACKGROUND CONTEXT: CHRONIC LOW BACK PAIN (LBP) IS A MULTIFACTORIAL DISORDER WITH COMPLEX UNDERLYING MECHANISMS, INCLUDING ASSOCIATIONS WITH INTERVERTEBRAL DISC (IVD) DEGENERATION IN SOME INDIVIDUALS. IT HAS BEEN DEMONSTRATED THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE PATHOLOGY OF IVD DEGENERATION. EPIGENETICS REFERS TO SEVERAL MECHANISMS, INCLUDING DNA METHYLATION, THAT HAVE THE ABILITY TO CHANGE GENE EXPRESSION WITHOUT INDUCING ANY CHANGE IN THE UNDERLYING DNA SEQUENCE. DNA METHYLATION CAN ALTER THE ENTIRE STATE OF A TISSUE FOR AN EXTENDED PERIOD OF TIME AND THUS COULD POTENTIALLY BE HARNESSED FOR LONG-TERM PAIN RELIEF. LIFESTYLE FACTORS, SUCH AS PHYSICAL ACTIVITY, HAVE A STRONG INFLUENCE ON EPIGENETIC REGULATION. EXERCISE IS A COMMONLY PRESCRIBED TREATMENT FOR CHRONIC LBP, AND SEX-SPECIFIC EPIGENETIC ADAPTATIONS IN RESPONSE TO ENDURANCE EXERCISE HAVE BEEN REPORTED. HOWEVER, WHETHER EXERCISE INTERVENTIONS THAT ATTENUATE LBP ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS IN DEGENERATING IVDS HAS NOT BEEN EVALUATED. PURPOSE: WE HYPOTHESIZE THAT THE THERAPEUTIC EFFICACY OF PHYSICAL ACTIVITY IS MEDIATED, AT LEAST IN PART, AT THE EPIGENETIC LEVEL. THE PURPOSE OF THIS STUDY WAS TO USE THE SPARC-NULL MOUSE MODEL OF LBP ASSOCIATED WITH IVD DEGENERATION TO CLARIFY (1) IF IVD DEGENERATION IS ASSOCIATED WITH ALTERED EXPRESSION OF EPIGENETIC REGULATORY GENES IN THE IVDS, (2) IF EPIGENETIC REGULATORY MACHINERY IS SENSITIVE TO THERAPEUTIC ENVIRONMENTAL INTERVENTION, AND (3) IF THERE ARE SEX-SPECIFIC DIFFERENCES IN (1) AND/OR (2). STUDY DESIGN: EIGHT-MONTH-OLD MALE AND FEMALE SPARC-NULL AND AGE-MATCHED CONTROL (WT) MICE (N=108) WERE ASSIGNED TO EXERCISE (N=56) OR SEDENTARY (N=52) GROUPS. DELETION OF SPARC IS ASSOCIATED WITH PROGRESSIVE IVD DEGENERATION AND BEHAVIORAL SIGNS OF LBP. THE EXERCISE GROUP RECEIVED A CIRCULAR PLASTIC HOME CAGE RUNNING WHEEL ON WHICH THEY COULD RUN FREELY. THE SEDENTARY GROUP RECEIVED AN IDENTICAL WHEEL SECURED IN PLACE TO PREVENT ROTATION. AFTER 6 MONTHS, THE RESULTS OBTAINED IN EACH GROUP WERE COMPARED. METHODS: AFTER 6 MONTHS OF EXERCISE, LBP-RELATED BEHAVIORAL INDICES WERE DETERMINED, AND GLOBAL DNA METHYLATION (5-METHYLCYTOSINE) AND EPIGENETIC REGULATORY GENE MRNA EXPRESSION IN IVDS WERE ASSESSED. THIS PROJECT WAS SUPPORTED BY THE CANADIAN INSTITUTES FOR HEALTH RESEARCH. THE AUTHORS HAVE NO CONFLICTS OF INTEREST. RESULTS: LUMBAR IVDS FROM WT SEDENTARY AND SPARC-NULL SEDENTARY MICE HAD SIMILAR LEVELS OF GLOBAL DNA METHYLATION (%5-MC) AND COMPARABLE MRNA EXPRESSION OF EPIGENETIC REGULATORY GENES (DNMT1,3A,B, MECP2, MBD2A,B, TET1-3) IN BOTH SEXES. EXERCISE ATTENUATED LBP-RELATED BEHAVIORS, DECREASED GLOBAL DNA METHYLATION IN BOTH WT (P<.05) AND SPARC-NULL MICE (P<.01) AND REDUCED MRNA EXPRESSION OF MECP2 IN SPARC-NULL MICE (P<.05). SEX-SPECIFIC EFFECTS OF EXERCISE ON EXPRESSION OF MRNA WERE ALSO OBSERVED. CONCLUSIONS: EXERCISE ALLEVIATES LBP IN A MOUSE MODEL. THIS MAY BE MEDIATED, IN PART, BY CHANGES IN THE EPIGENETIC REGULATORY MACHINERY IN DEGENERATING IVDS. EPIGENETIC ALTERATIONS DUE TO A LIFESTYLE CHANGE COULD HAVE A LONG-LASTING THERAPEUTIC IMPACT BY CHANGING TISSUE HOMEOSTASIS IN IVDS. CLINICAL SIGNIFICANCE: THIS STUDY CONFIRMED THE THERAPEUTIC BENEFITS OF EXERCISE ON LBP AND SUGGESTS THAT EXERCISE RESULTS IN SEX-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION IN IVDS. ELUCIDATING THE EFFECTS OF EXERCISE ON EPIGENETIC REGULATION MAY ENABLE THE DISCOVERY OF NOVEL GENE TARGETS OR NEW STRATEGIES TO IMPROVE THE TREATMENT OF CHRONIC LBP.	2021	

16  3729  39 INHIBITION OF TET1 PREVENTS THE DEVELOPMENT OF OSTEOARTHRITIS AND REVEALS THE 5HMC LANDSCAPE THAT ORCHESTRATES PATHOGENESIS. OSTEOARTHRITIS (OA) IS A DEGENERATIVE DISEASE OF THE JOINT, WHICH RESULTS IN PAIN, LOSS OF MOBILITY, AND, EVENTUALLY, JOINT REPLACEMENT. CURRENTLY, NO DISEASE-MODIFYING DRUGS EXIST, PARTLY BECAUSE OF THE MULTIPLE LEVELS AT WHICH CARTILAGE HOMEOSTASIS IS DISRUPTED. RECENT STUDIES HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC DYSREGULATION IN OA, SPARKING INTEREST IN THE EPIGENETIC MODULATION FOR THIS DISEASE. IN OUR PREVIOUS WORK, WE CHARACTERIZED A FIVEFOLD INCREASE IN CYTOSINE HYDROXYMETHYLATION (5HMC), AN OXIDIZED DERIVATIVE OF CYTOSINE METHYLATION (5MC) ASSOCIATED WITH GENE ACTIVATION, ACCUMULATING AT OA-ASSOCIATED GENES. TO TEST THE ROLE OF 5HMC IN OA, HERE, WE USED A MOUSE MODEL OF SURGICALLY INDUCED OA AND FOUND THAT OA ONSET WAS ACCOMPANIED BY A GAIN OF ~40,000 DIFFERENTIALLY HYDROXYMETHYLATED SITES BEFORE THE NOTABLE HISTOLOGICAL APPEARANCE OF DISEASE. WE DEMONSTRATED THAT TEN-ELEVEN-TRANSLOCATION ENZYME 1 (TET1) MEDIATES THE 5HMC DEPOSITION BECAUSE 98% OF SITES ENRICHED FOR 5HMC IN OA WERE LOST IN TET1(-/-) MICE. LOSS OF TET1-MEDIATED 5HMC PROTECTED THE TET1(-/-) MICE FROM OA DEVELOPMENT, INCLUDING DEGENERATION OF THE CARTILAGE SURFACE AND OSTEOPHYTE FORMATION, BY DIRECTLY PREVENTING THE ACTIVATION OF MULTIPLE OA PATHWAYS. LOSS OF TET1 IN HUMAN OA CHONDROCYTES REDUCED THE EXPRESSION OF THE MATRIX METALLOPROTEINASES MMP3 AND MMP13 AND MULTIPLE INFLAMMATORY CYTOKINES. INTRA-ARTICULAR INJECTIONS OF A DIOXYGENASES INHIBITOR, 2-HYDROXYGLUTARATE, ON MICE AFTER SURGICAL INDUCTION OF OA STALLED DISEASE PROGRESSION. TREATMENT OF HUMAN OA CHONDROCYTES WITH THE SAME INHIBITOR ALSO PHENOCOPIED TET1 LOSS. COLLECTIVELY, THESE DATA DEMONSTRATE THAT TET1-MEDIATED 5HMC DEPOSITION REGULATES MULTIPLE OA PATHWAYS AND CAN BE MODULATED FOR THERAPEUTIC INTERVENTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   895  33 CHRONIC ETHANOL-MEDIATED HEPATOCYTE APOPTOSIS LINKS TO DECREASED TET1 AND 5-HYDROXYMETHYLCYTOSINE FORMATION. THE 5-HYDROXYMETHYLCYTOSINE (5HMC) IS A NEWLY IDENTIFIED EPIGENETIC MODIFICATION THOUGHT TO BE REGULATED BY THE TET FAMILY OF PROTEINS. LITTLE INFORMATION IS AVAILABLE ABOUT HOW ETHANOL CONSUMPTION MAY MODULATE 5HMC FORMATION AND ALCOHOLIC LIVER DISEASE (ALD) PROGRESSION. A RAT ALD MODEL WAS USED TO STUDY 5HMC IN RELATIONSHIP TO HEPATOCYTE APOPTOSIS. HUMAN ALD LIVER SAMPLES WERE ALSO USED TO VALIDATE THESE FINDINGS. IT WAS FOUND THAT CHRONIC ETHANOL FEEDING SIGNIFICANTLY REDUCED 5HMC FORMATION IN A RAT ALD MODEL. THERE WERE NO SIGNIFICANT CHANGES IN TET2 AND TET3 BETWEEN THE CONTROL- AND ETHANOL-FED ANIMALS. IN CONTRAST, METHYLCYTOSINE DIOXYGENASE TET1 (TET1) EXPRESSION WAS SUBSTANTIALLY REDUCED IN THE ETHANOL-FED RATS AND WAS ACCOMPANIED BY INCREASED HEPATOCYTE APOPTOSIS. SIMILARLY, KNOCKDOWN OF TET1 IN HUMAN HEPATOCYTE-LIKE CELLS ALSO SIGNIFICANTLY PROMOTED APOPTOSIS. DOWN-REGULATION OF TET1 RESULTED IN ELEVATED EXPRESSION OF THE DNA DAMAGE MARKER, SUGGESTING A ROLE FOR 5HMC IN HEPATOCYTE DNA DAMAGE AS WELL. MECHANISTIC STUDIES REVEALED THAT INHIBITION OF TET1 PROMOTED APOPTOTIC GENE EXPRESSION. SIMILARLY, TARGETING TET1 ACTIVITY BY REMOVING COSUBSTRATE PROMOTED APOPTOSIS AND DNA DAMAGE. FURTHERMORE, TREATMENT WITH 5-AZACITIDINE SIGNIFICANTLY MIMICS THESE EFFECTS, SUGGESTING THAT CHRONIC ETHANOL CONSUMPTION PROMOTES HEPATOCYTE APOPTOSIS AND DNA DAMAGE BY DIMINISHING TET1-MEDIATED 5HMC FORMATION AND DNA METHYLATION. IN SUMMARY, THE CURRENT STUDY PROVIDES A NOVEL MOLECULAR INSIGHT THAT TET1-MEDIATED 5HMC IS INVOLVED IN HEPATOCYTE APOPTOSIS IN ALD PROGRESSION.-JI, C., NAGAOKA, K., ZOU, J., CASULLI, S., LU, S., CAO, K. Y., ZHANG, H., IWAGAMI, Y., CARLSON, R. I., BROOKS, K., LAWRENCE, J., MUELLER, W., WANDS, J. R., HUANG, C.-K. CHRONIC ETHANOL-MEDIATED HEPATOCYTE APOPTOSIS LINKS TO DECREASED TET1 AND 5-HYDROXYMETHYLCYTOSINE FORMATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  2762  37 EXPRESSION OF TET2 ENZYME INDICATES ENHANCED EPIGENETIC MODIFICATION OF CELLS IN PERIODONTITIS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC MECHANISM INVOLVED IN THE REGULATION OF GENE EXPRESSION, AND A REDUCTION IN DNA METHYLATION INFLUENCES CELL-CYCLE PROGRESSION AND CELL DIFFERENTIATION IN INFLAMMATORY CELLS. THE AIM OF THE PRESENT STUDY WAS TO ANALYZE THE DNA-METHYLATION PATTERN AT LOCAL AND GLOBAL/SYSTEMIC LEVELS IN PATIENTS WITH PERIODONTITIS AND GINGIVITIS. TWENTY-ONE SUBJECTS WITH GENERALIZED, SEVERE PERIODONTITIS AND 17 SUBJECTS WITH GINGIVAL INFLAMMATION BUT NO ATTACHMENT LOSS WERE RECRUITED. GINGIVAL BIOPSIES AND PERIPHERAL BLOOD SAMPLES WERE COLLECTED AND PREPARED FOR IMMUNOHISTOCHEMICAL ANALYSIS OF 5-METHYLCYTOSINE (5MC), 5-HYDROXYMETHYLCYTOSINE (5HMC), TEN-ELEVEN TRANSLOCATION 2 (TET2), AND DNA METHYLTRANSFERASE 1 (DNMT1). WHILST A SIMILAR PATTERN FOR 5MC AND 5HMC DNA METHYLATION WAS FOUND IN BOTH TYPES OF LESIONS, A SIGNIFICANTLY LARGER PROPORTION OF TET2-POSITIVE CELLS WAS FOUND IN PERIODONTITIS LESIONS THAN IN GINGIVITIS LESIONS. QUANTITATIVE REAL-TIME PCR ANALYSIS SHOWED NO DIFFERENCES BETWEEN GINGIVITIS AND PERIODONTITIS LESIONS REGARDING EXPRESSION OF TET2 AND ISOCITRATE DEHYDROGENASE (IDH) GENES, WHILE THE GLOBAL LEVEL OF 5HMC WAS SIGNIFICANTLY HIGHER IN BLOOD THAN IN TISSUE IN PATIENTS WITH PERIODONTITIS. IT IS SUGGESTED THAT EPIGENETIC CHANGES ARE MORE COMMON IN PERIODONTITIS LESIONS THAN IN GINGIVITIS LESIONS AND THAT SUCH CHANGES ARE TISSUE SPECIFIC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19   337  31 ALTERATIONS IN DNA METHYLATION/DEMETHYLATION INTERMEDIATES PREDICT CLINICAL OUTCOME IN CHRONIC LYMPHOCYTIC LEUKEMIA. CYTOSINE DERIVATIVE DYSREGULATIONS REPRESENT IMPORTANT EPIGENETIC MODIFICATIONS WHOSE IMPACT ON THE CLINICAL OUTCOME IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS INCOMPLETELY UNDERSTOOD. HENCE, GLOBAL LEVELS OF 5-METHYLCYTOSINE (5-MCYT), 5-HYDROXYMETHYLCYTOSINE (5-HMCYT), 5-CARBOXYLCYTOSINE (5-CACYT) AND 5-HYDROXYMETHYLURACIL WERE TESTED IN PURIFIED B CELLS FROM CLL PATIENTS (N = 55) AND CONTROLS (N = 17). THE DNA METHYLATION 'WRITERS' (DNA METHYLTRANSFERASES [DNMT1/3A/3B]), 'READERS' (METHYL-CPG-BINDING DOMAIN [MBD2/4]), 'EDITORS' (TEN-ELEVEN TRANSLOCATION [TET1/2/3]) AND 'MODULATORS' (SAT1) WERE ALSO EVALUATED. ACCORDINGLY, PATIENTS WERE STRATIFIED INTO THREE SUBGROUPS. FIRST, A SUBGROUP WITH A GLOBAL DEFICIT IN CYTOSINE DERIVATIVES CHARACTERIZED BY HYPERLYMPHOCYTOSIS, REDUCED MEDIAN PROGRESSION FREE SURVIVAL (PFS = 52 MONTHS) AND SHORTER TREATMENT FREE SURVIVAL (TFS = 112 MONTHS) WAS IDENTIFIED. IN THIS SUBGROUP, MAJOR EPIGENETIC MODIFICATIONS WERE HIGHLIGHTED INCLUDING A REDUCTION OF 5-MCYT, 5-HMCYT, 5-CACYT ASSOCIATED WITH DNMT3A, MBD2/4 AND TET1/2 DOWNREGULATION. SECOND, THE CYTOSINE DERIVATIVE ANALYSIS REVEALED A SUBGROUP WITH A PARTIAL DEFICIT (PFS = 84, TFS = 120 MONTHS), MAINLY AFFECTING DNA DEMETHYLATION (5-HMCYT REDUCTION, SAT1 INDUCTION). THIRD, A SUBGROUP EPIGENETICALLY SIMILAR TO CONTROLS WAS IDENTIFIED (PFS AND TFS > 120 MONTHS). THE PROGNOSTIC IMPACT OF STRATIFYING CLL PATIENTS WITHIN THREE EPIGENETIC SUBGROUPS WAS CONFIRMED IN A VALIDATION COHORT. IN CONCLUSION, OUR RESULTS SUGGEST THAT DYSREGULATIONS OF CYTOSINE DERIVATIVE REGULATORS REPRESENT MAJOR EVENTS ACQUIRED DURING CLL PROGRESSION AND ARE INDEPENDENT FROM IGHV MUTATIONAL STATUS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  5740  32 SMOKING AND TETRAMER TRYPTASE ACCELERATE INTERVERTEBRAL DISC DEGENERATION BY INDUCING METTL14-MEDIATED DIXDC1 M(6) MODIFICATION. ALTHOUGH CIGARETTE SMOKING (CS) AND LOW BACK PAIN (LBP) ARE COMMON WORLDWIDE, THEIR CORRELATIONS AND THE MECHANISMS OF ACTION REMAIN UNCLEAR. WE HAVE SHOWN THAT EXCESSIVE ACTIVATION OF MAST CELLS (MCS) AND THEIR PROTEASES PLAY KEY ROLES IN CS-ASSOCIATED DISEASES, LIKE ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BLOOD COAGULATION, AND LUNG CANCER. PREVIOUS STUDIES HAVE ALSO SHOWN THAT MCS AND THEIR PROTEASES INDUCE DEGENERATIVE MUSCULOSKELETAL DISEASE. BY USING A CUSTOM-DESIGNED SMOKE-EXPOSURE MOUSE SYSTEM, WE DEMONSTRATED THAT CS RESULTS IN INTERVERTEBRAL DISC (IVD) DEGENERATION AND RELEASE OF MC-RESTRICTED TETRAMER TRYPTASES (TTS) IN THE IVDS. TTS WERE FOUND TO REGULATE THE EXPRESSION OF METHYLTRANSFERASE 14 (METTL14) AT THE EPIGENETIC LEVEL BY INDUCING N6-METHYLADENOSINE (M(6)A) DEPOSITION IN THE 3' UNTRANSLATED REGION (UTR) OF THE TRANSCRIPT THAT ENCODES DISHEVELLED-AXIN (DIX) DOMAIN-CONTAINING 1 (DIXDC1). THAT REACTION INCREASES THE MRNA STABILITY AND EXPRESSION OF DIXDC1. DIXDC1 FUNCTIONALLY INTERACTS WITH DISRUPTED IN SCHIZOPHRENIA 1 (DISC1) TO ACCELERATE THE DEGENERATION AND SENESCENCE OF NUCLEUS PULPOSUS (NP) CELLS BY ACTIVATING A CANONICAL WNT PATHWAY. OUR STUDY DEMONSTRATES THE ASSOCIATION BETWEEN CS, MC-DERIVED TTS, AND LBP. THESE FINDINGS RAISE THE POSSIBILITY THAT METTL14-MEDICATED DIXDC1 M(6)A MODIFICATION COULD SERVE AS A POTENTIAL THERAPEUTIC TARGET TO BLOCK THE DEVELOPMENT OF DEGENERATION OF THE NP IN LBP PATIENTS.	2023