1 4574 128 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 2 4171 45 MEGAKARYOCYTIC LEUKEMIA 1 DIRECTS A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO REGULATE HYPOXIC PULMONARY HYPERTENSION. ENHANCED INTERACTION BETWEEN VASCULAR ENDOTHELIAL CELLS AND CIRCULATING LEUKOCYTES, AS A RESULT OF TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAM), HELPS ESTABLISH A PROINFLAMMATORY MILIEU CONTRIBUTING TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION. THE MOLECULAR SWITCH THAT DICTATES CAM TRANSACTIVATION IS NOT CLEARLY DEFINED. OUR GOAL WAS TO DETERMINE THE INVOLVEMENT OF THE TRANSCRIPTIONAL MODULATOR MEGAKARYOCYTIC LEUKEMIA 1 (MKL1), ALSO KNOWN AS MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A), IN CAM TRANSACTIVATION AND THE UNDERLYING MECHANISM. WE REPORT HERE THAT COMPARED WITH WILD-TYPE LITTERMATES, MKL1/MRTF-A KNOCKOUT MICE WERE MORE RESISTANT TO THE DEVELOPMENT OF HYPOXIA-INDUCED PULMONARY HYPERTENSION WHEN EXPOSED TO LOW OXYGEN PRESSURE. NOTABLY, CAM INDUCTION IN KNOCKOUT MICE WAS SIGNIFICANTLY ATTENUATED WITH A CONCOMITANT REDUCTION OF LEUKOCYTE ADHESION. IN CULTURED VASCULAR ENDOTHELIAL CELLS, OVEREXPRESSION OF MKL1/MRTF-A ENHANCED, WHEREAS DEPLETION OF MKL1/MRTF-A DAMPENED, HYPOXIA-INDUCED CAM TRANSACTIVATION. IN RESPONSE TO HYPOXIA, MKL1/MRTF-A FORMED A COMPLEX WITH NF-KAPPAB ON THE CAM PROMOTERS. OF INTEREST, MKL1/MRTF-A WAS RESPONSIBLE FOR RECRUITING A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO THE CAM PROMOTERS. FINALLY, ENDOTHELIAL-SPECIFIC SILENCING OF ASH2 AND WDR5, 2 KEY COMPONENTS OF THE HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX, AMELIORATED HYPOXIA-INDUCED PULMONARY HYPERTENSION IN MICE. IN CONCLUSION, OUR DATA SUGGEST THAT MKL1/MRTF-A, BY COORDINATING KEY EPIGENETIC ALTERATIONS ON CAM PROMOTERS, PROVIDES A CRITICAL LINK TO HYPOXIA-INDUCED ENDOTHELIAL MALFUNCTION AND CONTRIBUTES TO THE PATHOGENESIS OF HYPOXIA-INDUCED PULMONARY HYPERTENSION. 2015 3 3367 25 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 4 5571 37 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY. 2013 5 6321 21 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 6 199 31 ACTIVATED HISTONE ACETYLTRANSFERASE P300/CBP-RELATED SIGNALLING PATHWAYS MEDIATE UP-REGULATION OF NADPH OXIDASE, INFLAMMATION, AND FIBROSIS IN DIABETIC KIDNEY. ACCUMULATING EVIDENCE IMPLICATES THE HISTONE ACETYLATION-BASED EPIGENETIC MECHANISMS IN THE PATHOETIOLOGY OF DIABETES-ASSOCIATED MICRO-/MACROVASCULAR COMPLICATIONS. DIABETIC KIDNEY DISEASE (DKD) IS A PROGRESSIVE CHRONIC INFLAMMATORY MICROVASCULAR DISORDER ULTIMATELY LEADING TO GLOMERULOSCLEROSIS AND KIDNEY FAILURE. WE HYPOTHESIZED THAT HISTONE ACETYLTRANSFERASE P300/CBP MAY BE INVOLVED IN MEDIATING DIABETES-ACCELERATED RENAL DAMAGE. IN THIS STUDY, WE AIMED AT INVESTIGATING THE POTENTIAL ROLE OF P300/CBP IN THE UP-REGULATION OF RENAL NADPH OXIDASE (NOX), REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, INFLAMMATION, AND FIBROSIS IN DIABETIC MICE. DIABETIC C57BL/6J MICE WERE RANDOMIZED TO RECEIVE 10 MG/KG C646, A SELECTIVE P300/CBP INHIBITOR, OR ITS VEHICLE FOR 4 WEEKS. WE FOUND THAT IN THE KIDNEY OF C646-TREATED DIABETIC MICE, THE LEVEL OF H3K27AC, AN EPIGENETIC MARK OF ACTIVE GENE EXPRESSION, WAS SIGNIFICANTLY REDUCED. PHARMACOLOGICAL INHIBITION OF P300/CBP SIGNIFICANTLY DOWN-REGULATED THE DIABETES-INDUCED ENHANCED EXPRESSION OF NOX SUBTYPES, PRO-INFLAMMATORY, AND PRO-FIBROTIC MOLECULES IN THE KIDNEY OF MICE, AND THE GLOMERULAR ROS OVERPRODUCTION. OUR STUDY PROVIDES EVIDENCE THAT THE ACTIVATION OF P300/CBP ENHANCES ROS PRODUCTION, POTENTIALLY GENERATED BY UP-REGULATED NOX, INFLAMMATION, AND THE PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN THE DIABETIC KIDNEY. THE DATA SUGGEST THAT P300/CBP-PHARMACOLOGICAL INHIBITORS MAY BE ATTRACTIVE TOOLS TO MODULATE DIABETES-ASSOCIATED PATHOLOGICAL PROCESSES TO EFFICIENTLY REDUCE THE BURDEN OF DKD. 2021 7 2791 33 FAT-FREE P300 IS GOOD FOR SCAR-FREE TISSUE REPAIR. FIBROSIS, THE DEADLY PATHOLOGICAL MANIFESTATION OF AN ABNORMAL TISSUE REMODELING IN ANY ORGAN DUE TO EXCESSIVE COLLAGEN DEPOSITION, IS ASSOCIATED WITH A WIDE VARIETY OF ORGAN FAILURE-RELATED HUMAN DISEASES. CHRONIC STRESS OR REPEATED INJURY IN A PARTICULAR ORGAN INDUCES ABNORMAL MOLECULAR SIGNALS THAT LEAD TO SUPER-ACTIVATION OF MATRIX PROTEIN PRODUCING FIBROBLASTS, EXCESSIVE MATRIX PROTEINS ACCUMULATION, LOSS OF PHYSIOLOGICAL TISSUE ARCHITECTURE OR ELASTICITY, AND ULTIMATELY LEADING TO ORGAN FAILURE. THERE IS NO EFFECTIVE THERAPY FOR FIBROSIS. FACTOR ACETYLTRANSFERASE P300 (FATP300), A MAJOR EPIGENETIC REGULATOR THAT ACETYLATES SPECIFIC LYSINES IN HISTONES AND TRANSCRIPTION FACTORS, IS ESSENTIAL FOR ELEVATED COLLAGEN SYNTHESIS AND THE LEVELS OF FATP300 ARE SIGNIFICANTLY ELEVATED IN DIFFERENT FIBROTIC TISSUES. PHARMACOLOGICAL INHIBITION OF FAT ACTIVITY OF P300 IS ASSOCIATED WITH DECREASED COLLAGEN SYNTHESIS BY FIBROBLASTS IN TISSUES AND AMELIORATION OF ORGAN FIBROSIS. THEREFORE, FAT-FREE P300 IS SUPERIOR FOR PHYSIOLOGICAL TISSUE REPAIR AND MUST BE EXPLOITED AS A VIABLE THERAPEUTIC TARGET AGAINST MULTI-ORGAN FIBROSIS. 2014 8 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 9 172 28 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 10 5995 28 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 11 5972 31 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 12 273 35 AGE-INDUCED SUPPRESSION OF EZH2 MEDIATES INJURY OF PODOCYTES BY REDUCING H3K27ME3. BACKGROUND: CHRONIC HYPERGLYCEMIA, A PIVOTAL FEATURE OF DIABETES MELLITUS (DM), INITIATES THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) AND THE DYSREGULATION OF EPIGENETIC MECHANISMS, WHICH MAY CAUSE INJURY TO RENAL PODOCYTES, A CENTRAL FEATURE OF DIABETIC KIDNEY DISEASE (DKD). PREVIOUS DATA OF OUR GROUP SHOWED THAT AGES SIGNIFICANTLY REDUCE THE EXPRESSION OF NIPP1 (NUCLEAR INHIBITOR OF PROTEIN PHOSPHATASE 1) IN PODOCYTES IN VITRO AS WELL AS IN HUMAN AND MURINE DKD. NIPP1 WAS SHOWN BY OTHERS TO INTERACT WITH ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE REPRESSIVE METHYLATION OF H3K27ME3 ON HISTONE 3. THEREFORE, WE HYPOTHESIZED THAT AGES CAN DIRECTLY INDUCE EPIGENETIC CHANGES IN PODOCYTES. METHODS: WE ANALYZED THE RELEVANCE OF AGES ON EZH2 EXPRESSION AND ACTIVITY IN A MURINE PODOCYTE CELL LINE. CELLS WERE TREATED WITH 5 MG/ML GLYCATED BSA FOR 24 H. TO DETERMINE THE MEANING OF EZH2 SUPPRESSION, EZH2 ACTIVITY WAS INHIBITED BY INCUBATING THE CELLS WITH THE PHARMACOLOGICAL METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A; EZH2 EXPRESSION WAS REPRESSED WITH SIRNA. MRNA EXPRESSION WAS ANALYZED WITH REAL-TIME PCR, AND PROTEIN EXPRESSION WITH WESTERN BLOT. EZH2 EXPRESSION AND LEVEL OF H3K27 TRIMETHYLATION IN PODOCYTES OF DIABETIC DB/DB MICE, A MOUSE MODEL FOR TYPE 2 DM, WERE ANALYZED USING IMMUNOFLUORESCENCE. RESULTS: OUR DATA DEMONSTRATED THAT AGES DECREASE EZH2 EXPRESSION IN PODOCYTES AND CONSEQUENTLY REDUCE H3K27ME3. THIS SUPPRESSION OF EZH2 MIMICKED THE AGE EFFECTS AND CAUSED AN UPREGULATED EXPRESSION OF PATHOLOGICAL FACTORS THAT CONTRIBUTE TO PODOCYTE INJURY IN DKD. IN ADDITION, ANALYSES OF DB/DB MICE SHOWED SIGNIFICANTLY REDUCED H3K27ME3 AND EZH2 EXPRESSION IN PODOCYTES. MOREOVER, THE SUPPRESSION OF NIPP1 AND EZH2 SHOWED SIMILAR EFFECTS REGARDING PODOCYTE INJURY. CONCLUSIONS: OUR STUDIES PROVIDE A NOVEL PATHWAY HOW AGES CONTRIBUTE TO PODOCYTE INJURY AND THE FORMATION OF THE SO-CALLED METABOLIC MEMORY IN DKD. 2020 13 2002 24 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 14 356 33 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 15 141 29 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 16 2055 28 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 17 6431 25 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 18 2589 26 EPIGENETICS OF PROGRESSION OF CHRONIC KIDNEY DISEASE: FACT OR FANTASY? EPIGENETIC MODIFICATIONS ARE IMPORTANT IN THE NORMAL FUNCTIONING OF THE CELL, FROM REGULATING DYNAMIC EXPRESSION OF ESSENTIAL GENES AND ASSOCIATED PROTEINS TO REPRESSING THOSE THAT ARE UNNEEDED. EPIGENETIC CHANGES ARE ESSENTIAL FOR DEVELOPMENT AND FUNCTIONING OF THE KIDNEY, AND ABERRANT METHYLATION, HISTONE MODIFICATIONS, AND EXPRESSION OF MICRORNA COULD LEAD TO CHRONIC KIDNEY DISEASE (CKD). HERE, EPIGENETIC MODIFICATIONS MODULATE TRANSFORMING GROWTH FACTOR BETA SIGNALING, INFLAMMATION, PROFIBROTIC GENES, AND THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, PROMOTING RENAL FIBROSIS AND PROGRESSION OF CKD. IDENTIFICATION OF THESE EPIGENETIC CHANGES IS IMPORTANT BECAUSE THEY ARE POTENTIALLY REVERSIBLE AND MAY SERVE AS THERAPEUTIC TARGETS IN THE FUTURE TO PREVENT SUBSEQUENT RENAL FIBROSIS AND CKD. IN THIS REVIEW WE DISCUSS THE DIFFERENT TYPES OF EPIGENETIC CONTROL, METHODS TO STUDY EPIGENETIC MODIFICATIONS, AND HOW EPIGENETICS PROMOTES PROGRESSION OF CKD. 2013 19 164 32 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET. 2012 20 6510 26 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS. 2015