1 2117 120 EPIGENETIC HISTONE METHYLATION MODULATES FIBROTIC GENE EXPRESSION. TGF-BETA1-INDUCED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) GENES PLAYS A MAJOR ROLE IN THE DEVELOPMENT OF CHRONIC RENAL DISEASES SUCH AS DIABETIC NEPHROPATHY. ALTHOUGH MANY KEY TRANSCRIPTION FACTORS ARE KNOWN, MECHANISMS INVOLVING THE NUCLEAR CHROMATIN THAT MODULATE ECM GENE EXPRESSION REMAIN UNCLEAR. HERE, WE EXAMINED THE ROLE OF EPIGENETIC CHROMATIN MARKS SUCH AS HISTONE H3 LYSINE METHYLATION (H3KME) IN TGF-BETA1-INDUCED GENE EXPRESSION IN RAT MESANGIAL CELLS UNDER NORMAL AND HIGH-GLUCOSE (HG) CONDITIONS. TGF-BETA1 INCREASED THE EXPRESSION OF THE ECM-ASSOCIATED GENES CONNECTIVE TISSUE GROWTH FACTOR, COLLAGEN-ALPHA1[IOTA], AND PLASMINOGEN ACTIVATOR INHIBITOR-1. INCREASED LEVELS OF CHROMATIN MARKS ASSOCIATED WITH ACTIVE GENES (H3K4ME1, H3K4ME2, AND H3K4ME3), AND DECREASED LEVELS OF REPRESSIVE MARKS (H3K9ME2 AND H3K9ME3) AT THESE GENE PROMOTERS ACCOMPANIED THESE CHANGES IN EXPRESSION. TGF-BETA1 ALSO INCREASED EXPRESSION OF THE H3K4 METHYLTRANSFERASE SET7/9 AND RECRUITMENT TO THESE PROMOTERS. SET7/9 GENE SILENCING WITH SIRNAS SIGNIFICANTLY ATTENUATED TGF-BETA1-INDUCED ECM GENE EXPRESSION. FURTHERMORE, A TGF-BETA1 ANTIBODY NOT ONLY BLOCKED HG-INDUCED ECM GENE EXPRESSION BUT ALSO REVERSED HG-INDUCED CHANGES IN PROMOTER H3KME LEVELS AND SET7/9 OCCUPANCY. TAKEN TOGETHER, THESE RESULTS SHOW THE FUNCTIONAL ROLE OF EPIGENETIC CHROMATIN HISTONE H3KME IN TGF-BETA1-MEDIATED ECM GENE EXPRESSION IN MESANGIAL CELLS UNDER NORMAL AND HG CONDITIONS. PHARMACOLOGIC AND OTHER THERAPIES THAT REVERSE THESE MODIFICATIONS COULD HAVE POTENTIAL RENOPROTECTIVE EFFECTS FOR DIABETIC NEPHROPATHY. 2010 2 6431 32 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION. 2018 3 141 35 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 4 172 38 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 5 6321 32 THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN KIDNEY DISEASES. METHYLATION CAN OCCUR IN BOTH HISTONES AND NON-HISTONES. KEY LYSINE AND ARGININE METHYLTRANSFERASES UNDER INVESTIGATION FOR RENAL DISEASE TREATMENT INCLUDE ENHANCER OF ZESTE HOMOLOG 2 (EZH2), G9A, DISRUPTOR OF TELOMERIC SILENCING 1-LIKE PROTEIN (DOT1L), AND PROTEIN ARGININE METHYLTRANSFERASES (PRMT) 1 AND 5. RECENT STUDIES HAVE SHOWN THAT METHYLTRANSFERASES EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY(AKI), OBSTRUCTIVE NEPHROPATHY, DIABETIC NEPHROPATHY AND LUPUS NEPHRITIS. THE INHIBITION OF MOST METHYLTRANSFERASES CAN ATTENUATE KIDNEY INJURY, WHILE THE ROLE OF METHYLTRANSFERASE IN DIFFERENT ANIMAL MODELS REMAINS CONTROVERSIAL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN VARIOUS KIDNEY DISEASES AND HIGHLIGHT METHYLTRANSFERASE AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2022 6 5279 32 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 7 476 45 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 8 4497 40 MORPHINE LEADS TO GLOBAL GENOME CHANGES IN H3K27ME3 LEVELS VIA A POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) SELF-REGULATORY MECHANISM IN MESCS. BACKGROUND: ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES CAN LEAD TO HEALTH PROBLEMS OR DISEASE, BUT THE MECHANISMS INVOLVED REMAIN UNCLEAR. MORPHINE CAN PASS THROUGH THE PLACENTAL BARRIER LEADING TO ABNORMAL EMBRYO DEVELOPMENT. HOWEVER, THE MECHANISM BY WHICH MORPHINE CAUSES THESE EFFECTS AND HOW THEY SOMETIMES PERSIST INTO ADULTHOOD IS NOT WELL KNOWN. TO UNRAVEL THE MORPHINE-INDUCED CHROMATIN ALTERATIONS INVOLVED IN ABERRANT EMBRYO DEVELOPMENT, WE EXPLORED THE ROLE OF THE H3K27ME3/PRC2 REPRESSIVE COMPLEX IN GENE EXPRESSION AND ITS TRANSMISSION ACROSS CELLULAR GENERATIONS IN RESPONSE TO MORPHINE. RESULTS: USING MOUSE EMBRYONIC STEM CELLS AS A MODEL SYSTEM, WE FOUND THAT CHRONIC MORPHINE TREATMENT INDUCES A GLOBAL DOWNREGULATION OF THE HISTONE MODIFICATION H3K27ME3. CONVERSELY, CHIP-SEQ SHOWED A REMARKABLE INCREASE IN H3K27ME3 LEVELS AT SPECIFIC GENOMIC SITES, PARTICULARLY PROMOTERS, DISRUPTING SELECTIVE TARGET GENES RELATED TO EMBRYO DEVELOPMENT, CELL CYCLE AND METABOLISM. THROUGH A SELF-REGULATORY MECHANISM, MORPHINE DOWNREGULATED THE TRANSCRIPTION OF PRC2 COMPONENTS RESPONSIBLE FOR H3K27ME3 BY ENRICHING HIGH H3K27ME3 LEVELS AT THE PROMOTER REGION. DOWNREGULATION OF PRC2 COMPONENTS PERSISTED FOR AT LEAST 48 H (4 CELL CYCLES) FOLLOWING MORPHINE REMOVAL, THOUGH PROMOTER H3K27ME3 LEVELS RETURNED TO CONTROL LEVELS. CONCLUSIONS: MORPHINE INDUCES TARGETING OF THE PRC2 COMPLEX TO SELECTED PROMOTERS, INCLUDING THOSE OF PRC2 COMPONENTS, LEADING TO CHARACTERISTIC CHANGES IN GENE EXPRESSION AND A GLOBAL REDUCTION IN H3K27ME3. FOLLOWING MORPHINE REMOVAL, ENHANCED PROMOTER H3K27ME3 LEVELS REVERT TO NORMAL SOONER THAN GLOBAL H3K27ME3 OR PRC2 COMPONENT TRANSCRIPT LEVELS. WE SUGGEST THAT H3K27ME3 IS INVOLVED IN INITIATING MORPHINE-INDUCED CHANGES IN GENE EXPRESSION, BUT NOT IN THEIR MAINTENANCE. MODEL OF POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) AND H3K27ME3 ALTERATIONS INDUCED BY CHRONIC MORPHINE EXPOSURE. MORPHINE INDUCES H3K27ME3 ENRICHMENT AT PROMOTERS OF GENES ENCODING CORE MEMBERS OF THE PRC2 COMPLEX AND IS ASSOCIATED WITH THEIR TRANSCRIPTIONAL DOWNREGULATION. 2020 9 3795 33 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 10 3367 37 HISTONE METHYLTRANSFERASE EZH2: A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A HISTONE-LYSINE N-METHYLTRANSFERASE ENZYME THAT CATALYZES THE ADDITION OF METHYL GROUPS TO HISTONE H3 AT LYSINE 27, LEADING TO GENE SILENCING. MUTATION OR OVER-EXPRESSION OF EZH2 HAS BEEN LINKED TO MANY CANCERS INCLUDING RENAL CARCINOMA. RECENT STUDIES HAVE SHOWN THAT EZH2 EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY (AKI), RENAL FIBROSIS, DIABETIC NEPHROPATHY, LUPUS NEPHRITIS (LN), AND RENAL TRANSPLANTATION REJECTION. THE PHARMACOLOGICAL AND/OR GENETIC INHIBITION OF EZH2 CAN ALLEVIATE AKI, RENAL FIBROSIS, AND LN, BUT POTENTIATE PODOCYTE INJURY IN ANIMAL MODELS, SUGGESTING THAT THE FUNCTIONAL ROLE OF EZH2 VARIES WITH RENAL CELL TYPE AND DISEASE MODEL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE OF EZH2 IN THE PATHOLOGY OF RENAL INJURY AND RELEVANT MECHANISMS AND HIGHLIGHT EZH2 AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2021 11 2493 37 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 12 5995 34 TGFBETA-INDUCED FIBROBLAST ACTIVATION REQUIRES PERSISTENT AND TARGETED HDAC-MEDIATED GENE REPRESSION. TISSUE FIBROSIS IS A CHRONIC DISEASE DRIVEN BY PERSISTENT FIBROBLAST ACTIVATION THAT HAS RECENTLY BEEN LINKED TO EPIGENETIC MODIFICATIONS. HERE, WE SCREENED A SMALL LIBRARY OF EPIGENETIC SMALL-MOLECULE MODULATORS TO IDENTIFY COMPOUNDS CAPABLE OF INHIBITING OR REVERSING TGFBETA-MEDIATED FIBROBLAST ACTIVATION. WE IDENTIFIED PRACINOSTAT, AN HDAC INHIBITOR, AS A POTENT ATTENUATOR OF LUNG FIBROBLAST ACTIVATION AND CONFIRMED ITS EFFICACY IN PATIENT-DERIVED FIBROBLASTS ISOLATED FROM FIBROTIC LUNG TISSUE. MECHANISTICALLY, WE FOUND THAT HDAC-DEPENDENT TRANSCRIPTIONAL REPRESSION WAS AN EARLY AND ESSENTIAL EVENT IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION. TREATMENT OF LUNG FIBROBLASTS WITH PRACINOSTAT BROADLY ATTENUATED TGFBETA-MEDIATED EPIGENETIC REPRESSION AND PROMOTED FIBROBLAST QUIESCENCE. WE CONFIRMED A SPECIFIC ROLE FOR HDAC-DEPENDENT HISTONE DEACETYLATION IN THE PROMOTER REGION OF THE ANTI-FIBROTIC GENE PPARGC1A (PGC1ALPHA) IN RESPONSE TO TGFBETA STIMULATION. FINALLY, WE IDENTIFIED HDAC7 AS A KEY FACTOR WHOSE SIRNA-MEDIATED KNOCKDOWN ATTENUATES FIBROBLAST ACTIVATION WITHOUT ALTERING GLOBAL HISTONE ACETYLATION. TOGETHER, THESE RESULTS PROVIDE NOVEL MECHANISTIC INSIGHT INTO THE ESSENTIAL ROLE HDACS PLAY IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION VIA TARGETED GENE REPRESSION. 2019 13 4574 39 MYOCARDIN-RELATED TRANSCRIPTION FACTOR A EPIGENETICALLY REGULATES RENAL FIBROSIS IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY (DN) IS ONE OF THE MOST COMMON COMPLICATIONS ASSOCIATED WITH DIABETES AND CHARACTERIZED BY RENAL MICROVASCULAR INJURY ALONG WITH ACCELERATED SYNTHESIS OF EXTRACELLULAR MATRIX PROTEINS CAUSING TUBULOINTERSTITIAL FIBROSIS. PRODUCTION OF TYPE I COLLAGEN, THE MAJOR COMPONENT OF EXTRACELLULAR MATRIX, IS AUGMENTED DURING RENAL FIBROSIS AFTER CHRONIC EXPOSURE TO HYPERGLYCEMIA. HOWEVER, THE TRANSCRIPTIONAL MODULATOR RESPONSIBLE FOR THE EPIGENETIC MANIPULATION LEADING TO INDUCTION OF TYPE I COLLAGEN GENES IS NOT CLEARLY DEFINED. WE SHOW HERE THAT TUBULOINTERSTITIAL FIBROSIS AS A RESULT OF DN WAS DIMINISHED IN MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A) -DEFICIENT MICE. IN CULTURED RENAL TUBULAR EPITHELIAL CELLS AND THE KIDNEYS OF MICE WITH DN, MRTF-A WAS INDUCED BY GLUCOSE AND SYNERGIZED WITH GLUCOSE TO ACTIVATE COLLAGEN TRANSCRIPTION. NOTABLY, MRTF-A SILENCING LED TO THE DISAPPEARANCE OF PROMINENT HISTONE MODIFICATIONS INDICATIVE OF TRANSCRIPTIONAL ACTIVATION, INCLUDING ACETYLATED HISTONE H3K18/K27 AND TRIMETHYLATED HISTONE H3K4. DETAILED ANALYSIS REVEALED THAT MRTF-A RECRUITED P300, A HISTONE ACETYLTRANSFERASE, AND WD REPEAT-CONTAINING PROTEIN 5 (WDR5), A KEY COMPONENT OF THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX, TO THE COLLAGEN PROMOTERS AND ENGAGED THESE PROTEINS IN TRANSCRIPTIONAL ACTIVATION. ESTRADIOL SUPPRESSED COLLAGEN PRODUCTION BY DAMPENING THE EXPRESSION AND BINDING ACTIVITY OF MRTF-A AND INTERFERING WITH THE INTERACTION BETWEEN P300 AND WDR5 IN RENAL EPITHELIAL CELLS. THEREFORE, TARGETING THE MRTF-A-ASSOCIATED EPIGENETIC MACHINERY MIGHT YIELD INTERVENTIONAL STRATEGIES AGAINST DN-ASSOCIATED RENAL FIBROSIS. 2015 14 4900 34 OXIDATIVE STRESS-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH MALIGNANT TRANSFORMATION OF HUMAN KIDNEY EPITHELIAL CELLS. RENAL CELL CARCINOMA (RCC) IN HUMANS IS POSITIVELY INFLUENCED BY OXIDATIVE STRESS STATUS IN KIDNEYS. WE RECENTLY REPORTED THAT ADAPTIVE RESPONSE TO LOW LEVEL OF CHRONIC OXIDATIVE STRESS INDUCES MALIGNANT TRANSFORMATION OF IMMORTALIZED HUMAN RENAL TUBULAR EPITHELIAL CELLS. EPIGENETIC ALTERATIONS IN HUMAN RCC ARE WELL DOCUMENTED, BUT ITS ROLE IN OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION OF KIDNEY CELLS IS NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE POTENTIAL ROLE OF EPIGENETIC CHANGES IN CHRONIC OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION OF HK-2, HUMAN RENAL TUBULAR EPITHELIAL CELLS. THE RESULTS REVEALED ABERRANT EXPRESSION OF EPIGENETIC REGULATORY GENES INVOLVED IN DNA METHYLATION (DNMT1, DNMT3A AND MBD4) AND HISTONE MODIFICATIONS (HDAC1, HMT1 AND HAT1) IN HK-2 CELLS MALIGNANTLY TRANSFORMED BY CHRONIC OXIDATIVE STRESS. ADDITIONALLY, BOTH IN VITRO SOFT AGAR ASSAY AND IN VIVO NUDE MICE STUDY SHOWING DECREASED TUMORIGENIC POTENTIAL OF MALIGNANTLY TRANSFORMED HK-2 CELLS FOLLOWING TREATMENT WITH DNA DE-METHYLATING AGENT 5-AZA 2' DC FURTHER CONFIRMED THE CRUCIAL ROLE OF DNA HYPERMETHYALTION IN OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION. CHANGES OBSERVED IN GLOBAL HISTONE H3 ACETYLATION (H3K9, H3K18, H3K27 AND H3K14) AND DECREASE IN PHOSPHO-H2AX (SER139) ALSO SUGGEST POTENTIAL ROLE OF HISTONE MODIFICATIONS IN INCREASED SURVIVAL AND MALIGNANT TRANSFORMATION OF HK-2 CELLS BY OXIDATIVE STRESS. IN SUMMARY, THE RESULTS OF THIS STUDY SUGGEST THAT EPIGENETIC REPROGRAMMING INDUCED BY LOW LEVELS OF OXIDATIVE STRESS ACT AS DRIVER FOR MALIGNANT TRANSFORMATION OF KIDNEY EPITHELIAL CELLS. FINDINGS OF THIS STUDY ARE HIGHLY RELEVANT IN POTENTIAL CLINICAL APPLICATION OF EPIGENETIC-BASED THERAPEUTICS FOR TREATMENTS OF KIDNEY CANCERS. 2017 15 3527 27 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 16 4215 33 METHYL DEFICIENCY, ALTERATIONS IN GLOBAL HISTONE MODIFICATIONS, AND CARCINOGENESIS. THE METHYL-DEFICIENT MODEL OF ENDOGENOUS HEPATOCARCINOGENESIS IN RODENTS IS UNIQUE IN THAT DIETARY OMISSION RATHER THAN THE ADDITION OF CHEMICAL CARCINOGENS LEADS TO TUMOR FORMATION. THUS, THE BIOCHEMICAL AND MOLECULAR EVENTS PREDISPOSING TO CANCER IN THIS MODEL RESULT FROM CHRONIC METABOLIC STRESS AND PROVIDE AN IDEAL MODEL SYSTEM TO STUDY PROGRESSIVE ALTERATIONS THAT OCCUR DURING CARCINOGENESIS. MOREOVER, EPIGENETIC ALTERATIONS IMPOSED BY THIS DIET ARE BELIEVED TO BE 1 OF THE MAIN MECHANISMS RESPONSIBLE FOR MALIGNANT TRANSFORMATION OF RAT LIVER CELLS. IN THIS STUDY WE EXAMINED THE CHANGES IN GLOBAL HISTONE MODIFICATION PATTERNS IN LIVER DURING HEPATOCARCINOGENESIS INDUCED BY METHYL DEFICIENCY. FEEDING ANIMALS THE METHYL-DEFICIENT DIET (MDD) LED TO PROGRESSIVE LOSS OF HISTONE H4 LYSINE 20 TRIMETHYLATION (H4K20ME3), H3 LYSINE 9 TRIMETHYLATION (H3K9ME3), AND HISTONE H3 LYSINE 9 (H3K9AC) AND HISTONE H4 LYSINE 16 (H4K16AC) ACETYLATION. A CONSIDERABLE DECREASE OF H4K20ME3 AND H3K9AC WAS ALSO DETECTED IN LIVER TUMORS INDUCED BY MDD. IN CONTRAST, LIVER TUMORS DISPLAYED AN INCREASE IN H3K9ME3 AND H4K16AC. TO DETERMINE THE POSSIBLE MECHANISM OF ALTERATIONS OF HISTONE MODIFICATIONS, WE ANALYZED THE EXPRESSION OF HISTONE-MODIFYING ENZYMES IN LIVER DURING HEPATOCARCINOGENESIS. THE EXPRESSION OF SUV4-20H2 AND RIZ1 HISTONE METHYLTRANSFERASES (HMTS) STEADILY DECREASED ALONG WITH THE DEVELOPMENT OF LIVER TUMORS AND REACHED ITS LOWEST LEVEL IN TUMOR TISSUE, WHEREAS THE EXPRESSION OF SUV39-H1 HMT AND HISTONE ACETYLTRANSFERASE 1 (HAT1) SUBSTANTIALLY INCREASED IN TUMORS. THESE RESULTS ILLUSTRATE THE COMPLEXITY AND IMPORTANCE OF HISTONE MODIFICATION CHANGES IN THE ETIOLOGY OF HEPATOCARCINOGENESIS INDUCED BY MDD. 2007 17 3341 26 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 18 2280 40 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 19 808 32 CHANGED HISTONE ACETYLATION PATTERNS IN NORMAL-APPEARING WHITE MATTER AND EARLY MULTIPLE SCLEROSIS LESIONS. THE EPIGENETIC IDENTITY OF OLIGODENDROCYTES IS MODULATED BY POSTTRANSLATIONAL MODIFICATIONS OF HISTONES. ACETYLATION OF HISTONE H3 RESULTS FROM THE BALANCE BETWEEN THE ACTIVITY OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES AND MODULATES TRANSCRIPTIONAL ACTIVATION. WE HAVE PREVIOUSLY SHOWN THAT, IN RODENTS, HISTONE DEACETYLATION FAVORS OLIGODENDROCYTE DIFFERENTIATION, WHEREAS ACETYLATION IS ASSOCIATED WITH INCREASED LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION. HERE, WE REPORT, IN HUMANS BRAINS, A SHIFT TOWARD HISTONE ACETYLATION IN THE WHITE MATTER OF THE FRONTAL LOBES OF AGED SUBJECTS AND IN PATIENTS WITH CHRONIC MULTIPLE SCLEROSIS (MS). INCREASED IMMUNOREACTIVITY FOR ACETYLATED HISTONE H3 WAS OBSERVED IN THE NUCLEI OF NOGOA+ OLIGODENDROCYTES IN A SUBSET OF MS SAMPLES. THESE CHANGES WERE ASSOCIATED WITH HIGH LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION (I.E., TCF7L2, ID2, AND SOX2) AND HIGHER HAT TRANSCRIPT LEVELS (I.E., CBP, P300) IN FEMALE MS PATIENTS COMPARED WITH NON-NEUROLOGICAL CONTROLS AND CORRELATED WITH DISEASE DURATION. CHROMATIN IMMUNOPRECIPITATION FROM SAMPLES OF MS PATIENTS REVEALED ENRICHMENT OF ACETYL-HISTONE H3 AT THE PROMOTER OF THE INCREASED TARGET GENES (I.E., TCF7L2). THE DATA IN CHRONIC LESIONS CONTRASTED WITH FINDINGS IN EARLY MS LESIONS, WHERE A MARKED OLIGODENDROGLIAL HISTONE DEACETYLATION WAS OBSERVED. TOGETHER, THESE DATA SUGGEST THAT HISTONE DEACETYLATION IS A PROCESS THAT OCCURS AT THE EARLY STAGES OF THE DISEASE AND WHOSE EFFICIENCY DECREASES WITH DISEASE DURATION. 2011 20 356 36 ALTERING A HISTONE H3K4 METHYLATION PATHWAY IN GLOMERULAR PODOCYTES PROMOTES A CHRONIC DISEASE PHENOTYPE. METHYLATION OF SPECIFIC LYSINE RESIDUES IN CORE HISTONE PROTEINS IS ESSENTIAL FOR EMBRYONIC DEVELOPMENT AND CAN IMPART ACTIVE AND INACTIVE EPIGENETIC MARKS ON CHROMATIN DOMAINS. THE UBIQUITOUS NUCLEAR PROTEIN PTIP IS ENCODED BY THE PAXIP1 GENE AND IS AN ESSENTIAL COMPONENT OF A HISTONE H3 LYSINE 4 (H3K4) METHYLTRANSFERASE COMPLEX CONSERVED IN METAZOANS. IN ORDER TO DETERMINE IF PTIP AND ITS ASSOCIATED COMPLEXES ARE NECESSARY FOR MAINTAINING STABLE GENE EXPRESSION PATTERNS IN A TERMINALLY DIFFERENTIATED, NON-DIVIDING CELL, WE CONDITIONALLY DELETED PTIP IN GLOMERULAR PODOCYTES IN MICE. RENAL DEVELOPMENT AND FUNCTION WERE NOT IMPAIRED IN YOUNG MICE. HOWEVER, OLDER ANIMALS PROGRESSIVELY EXHIBITED PROTEINURIA AND PODOCYTE ULTRA STRUCTURAL DEFECTS SIMILAR TO CHRONIC GLOMERULAR DISEASE. LOSS OF PTIP RESULTED IN SUBTLE CHANGES IN GENE EXPRESSION PATTERNS PRIOR TO THE ONSET OF A RENAL DISEASE PHENOTYPE. CHROMATIN IMMUNOPRECIPITATION SHOWED A LOSS OF PTIP BINDING AND LOWER H3K4 METHYLATION AT THE NTRK3 (NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 3) LOCUS, WHOSE EXPRESSION WAS SIGNIFICANTLY REDUCED AND WHOSE FUNCTION MAY BE ESSENTIAL FOR PODOCYTE FOOT PROCESS PATTERNING. THESE DATA DEMONSTRATE THAT ALTERATIONS OR MUTATIONS IN AN EPIGENETIC REGULATORY PATHWAY CAN ALTER THE PHENOTYPES OF DIFFERENTIATED CELLS AND LEAD TO A CHRONIC DISEASE STATE. 2010