1 669 126 BONE MARROW STROMAL CELL ANTIGEN-1 (CD157) REGULATED BY SPHINGOSINE KINASE 2 MEDIATES KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE IS A PROGRESSIVE DISEASE THAT MAY LEAD TO END-STAGE RENAL DISEASE. INTERSTITIAL FIBROSIS DEVELOPS AS THE DISEASE PROGRESSES. THERAPIES THAT FOCUS ON FIBROSIS TO DELAY OR REVERSE PROGRESSIVE RENAL FAILURE ARE LIMITED. WE AND OTHERS SHOWED THAT SPHINGOSINE KINASE 2-DEFICIENT MICE (SPHK2 (-/-)) DEVELOP LESS FIBROSIS IN MOUSE MODELS OF KIDNEY FIBROSIS. SPHINGOSINE KINASE2 (SPHK2), ONE OF TWO SPHINGOSINE KINASES THAT PRODUCE SPHINGOSINE 1-PHOSPHATE (S1P), IS PRIMARILY LOCATED IN THE NUCLEUS. S1P PRODUCED BY SPHK2 INHIBITS HISTONE DEACETYLASE (HDAC) AND CHANGES HISTONE ACETYLATION STATUS, WHICH CAN LEAD TO ALTERED TARGET GENE EXPRESSION. WE HYPOTHESIZED THAT SPHK2 EPIGENETICALLY REGULATES DOWNSTREAM GENES TO INDUCE FIBROSIS, AND WE PERFORMED A COMPREHENSIVE ANALYSIS USING THE COMBINATION OF RNA-SEQ AND CHIP-SEQ. BST1/CD157 WAS IDENTIFIED AS A GENE THAT IS REGULATED BY SPHK2 THROUGH A CHANGE IN HISTONE ACETYLATION LEVEL, AND BST1 (-/-) MICE WERE FOUND TO DEVELOP LESS RENAL FIBROSIS AFTER UNILATERAL ISCHEMIA-REPERFUSION INJURY, A MOUSE MODEL OF KIDNEY FIBROSIS. ALTHOUGH BST1 IS A CELL-SURFACE MOLECULE THAT HAS A WIDE VARIETY OF FUNCTIONS THROUGH ITS VARIED ENZYMATIC ACTIVITIES AND DOWNSTREAM INTRACELLULAR SIGNALING PATHWAYS, NO STUDIES ON THE ROLE OF BST1 IN KIDNEY DISEASES HAVE BEEN REPORTED PREVIOUSLY. IN THE CURRENT STUDY, WE DEMONSTRATED THAT BST1 IS A GENE THAT IS REGULATED BY SPHK2 THROUGH EPIGENETIC CHANGE AND IS CRITICAL IN KIDNEY FIBROSIS. 2022 2 2818 23 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 3 5636 46 SERELAXIN ALLEVIATES CARDIAC FIBROSIS THROUGH INHIBITING ENDOTHELIAL-TO-MESENCHYMAL TRANSITION VIA RXFP1. RATIONALE: CARDIAC FIBROSIS IS AN INTEGRAL CONSTITUENT OF EVERY FORM OF CHRONIC HEART DISEASE, AND PERSISTENCE OF FIBROSIS REDUCES TISSUE COMPLIANCE AND ACCELERATES THE PROGRESSION TO HEART FAILURE. RELAXIN-2 IS A HUMAN HORMONE, WHICH HAS VARIOUS PHYSIOLOGICAL FUNCTIONS SUCH AS MEDIATING RENAL VASODILATION IN PREGNANCY. ITS RECOMBINANT FORM SERELAXIN HAS RECENTLY BEEN TESTED IN CLINICAL TRIALS AS A THERAPY FOR ACUTE HEART FAILURE BUT DID NOT MEET ITS PRIMARY ENDPOINTS. THE AIM OF THIS STUDY IS TO EXAMINE WHETHER SERELAXIN HAS AN ANTI-FIBROTIC EFFECT IN THE HEART AND THEREFORE COULD BE BENEFICIAL IN CHRONIC HEART FAILURE. METHODS: WE UTILIZED TWO DIFFERENT CARDIAC FIBROSIS MOUSE MODELS (ASCENDING AORTIC CONSTRICTION (AAC) AND ANGIOTENSIN II (ATII) ADMINISTRATION VIA OSMOTIC MINIPUMPS) TO ASSESS THE ANTI-FIBROTIC POTENTIAL OF SERELAXIN. HISTOLOGICAL ANALYSIS, IMMUNOFLUORESCENCE STAINING AND MOLECULAR ANALYSIS WERE PERFORMED TO ASSESS THE FIBROSIS LEVEL AND INDICATE ENDOTHELIAL CELLS WHICH ARE UNDERGOING ENDMT. IN VITRO TGFBETA1-INDUCED ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (ENDMT) ASSAYS WERE PERFORMED IN HUMAN CORONARY ARTERY ENDOTHELIAL CELLS AND MOUSE CARDIAC ENDOTHELIAL CELLS (MCECS) AND WERE EXAMINED USING MOLECULAR METHODS. CHROMATIN IMMUNOPRECIPITATION-QPCR ASSAY WAS UTILIZED TO IDENTIFY THE SERELAXIN EFFECT ON CHROMATIN REMODELING IN THE RXFP1 PROMOTER REGION IN MCECS. RESULTS: OUR RESULTS DEMONSTRATE A SIGNIFICANT AND DOSE-DEPENDENT ANTI-FIBROTIC EFFECT OF SERELAXIN IN THE HEART IN BOTH MODELS. WE FURTHER SHOW THAT SERELAXIN MEDIATES THIS EFFECT, AT LEAST IN PART, THROUGH INHIBITION OF ENDMT THROUGH THE ENDOTHELIAL RELAXIN FAMILY PEPTIDE RECEPTOR 1 (RXFP1). WE FURTHER DEMONSTRATE THAT SERELAXIN ADMINISTRATION IS ABLE TO INCREASE ITS OWN RECEPTOR EXPRESSION (RXFP1) THROUGH EPIGENETIC REGULATION IN FORM OF HISTONE MODIFICATIONS BY ATTENUATING TGFBETA-PSMAD2/3 SIGNALING IN ENDOTHELIAL CELLS. CONCLUSIONS: THIS STUDY IS THE FIRST TO IDENTIFY THAT SERELAXIN INCREASES THE EXPRESSION OF ITS OWN RECEPTOR RXFP1 AND THAT THIS MEDIATES THE INHIBITION OF ENDMT AND CARDIAC FIBROSIS, SUGGESTING THAT SERELAXIN MAY HAVE A BENEFICIAL EFFECT AS ANTI-FIBROTIC THERAPY IN CHRONIC HEART FAILURE. 2020 4 3327 33 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS. 2015 5 5153 25 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 6 3049 32 GENOME-WIDE ANALYSIS REVEALS ZINC TRANSPORTER ZIP9 REGULATED BY DNA METHYLATION PROMOTES RADIATION-INDUCED SKIN FIBROSIS VIA THE TGF-BETA SIGNALING PATHWAY. RADIATION-INDUCED SKIN FIBROSIS IS A DETRIMENTAL AND CHRONIC DISORDER THAT OCCURS AFTER RADIATION EXPOSURE. DNA METHYLATION HAS BEEN CHARACTERIZED AS AN IMPORTANT REGULATORY MECHANISM OF MULTIPLE PATHOLOGICAL PROCESSES. IN THIS STUDY, WE COMPARED THE GENOME-WIDE DNA METHYLATION STATUS IN RADIATION-INDUCED FIBROTIC SKIN AND ADJACENT NORMAL TISSUES OF RATS BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. RADIATION-INDUCED FIBROTIC SKIN SHOWED DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH 3,650 PROTEIN-CODING GENES, 72 MICRORNAS, 5,836 LONG NONCODING RNAS AND 3 PIWI-INTERACTING RNAS. BY INTEGRATING THE MRNA AND METHYLATION PROFILES, THE ZINC TRANSPORTER SLC39A9/ZIP9 WAS INVESTIGATED IN GREATER DETAIL. THE PROTEIN LEVEL OF ZIP9 WAS INCREASED IN IRRADIATED SKIN TISSUES OF HUMANS, MONKEYS, AND RATS, ESPECIALLY IN RADIOGENIC FIBROTIC SKIN TISSUES. RADIATION INDUCED THE DEMETHYLATION OF A CPG DINUCLEOTIDE IN EXON 1 OF ZIP9 THAT RESULTED IN RECRUITMENT OF THE TRANSCRIPTIONAL FACTOR SP1 AND INCREASED ZIP9 EXPRESSION. OVEREXPRESSION OF ZIP9 RESULTED IN ACTIVATION OF THE PROFIBROTIC TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY THROUGH PROTEIN KINASE B IN HUMAN FIBROBLASTS. IN ADDITION, RADIATION-INDUCED SKIN FIBROSIS WAS ASSOCIATED WITH INCREASED ZINC ACCUMULATION. THE ZINC CHELATOR N,N,N',N'-TETRAKIS(2-PYRIDYLMETHYL)-1,2-ETHYLENEDIAMINE ABROGATED ZIP9-INDUCED ACTIVATION OF THE TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY AND ATTENUATED RADIATION-INDUCED SKIN FIBROSIS IN A RAT MODEL. IN SUMMARY, OUR FINDINGS ILLUSTRATE EPIGENETIC REGULATION OF ZIP9 AND ITS CRITICAL ROLE IN PROMOTING RADIATION-INDUCED SKIN FIBROSIS. 2020 7 3390 39 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS. 2021 8 4143 23 MECHANISMS OF SCARRING IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) PRESENTS WITH SCAR IN PARTS OF SOME GLOMERULI AND OFTEN PROGRESSES TO GLOBAL AND DIFFUSE GLOMERULOSCLEROSIS. PODOCYTE INJURY IS THE INITIAL TARGET IN PRIMARY FSGS, INDUCED BY A CIRCULATING FACTOR. SEVERAL GENE VARIANTS, FOR EXAMPLE, APOL1, ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO FSGS. PRIMARY FSGS MAY BE DUE TO GENETIC MUTATION IN KEY PODOCYTE GENES. INCREASED WORK STRESS AFTER LOSS OF NEPHRONS, EPIGENETIC MECHANISMS, AND VARIOUS PROFIBROTIC PATHWAYS CAN CONTRIBUTE TO PROGRESSIVE SCLEROSIS, REGARDLESS OF THE INITIAL INJURY. THE PROGRESSION OF FSGS LESIONS ALSO INVOLVES CROSSTALK BETWEEN PODOCYTES AND OTHER KIDNEY CELLS, SUCH AS PARIETAL EPITHELIAL CELLS, GLOMERULAR ENDOTHELIAL CELLS, AND EVEN TUBULAR EPITHELIAL CELLS. NEW INSIGHTS RELATED TO THESE MECHANISMS COULD POTENTIALLY LEAD TO NEW THERAPEUTIC STRATEGIES TO PREVENT PROGRESSION OF FSGS. 2019 9 3096 35 GENOMIC CHARACTERIZATION REVEALS NOVEL MECHANISMS UNDERLYING THE VALOSIN-CONTAINING PROTEIN-MEDIATED CARDIAC PROTECTION AGAINST HEART FAILURE. CHRONIC HYPERTENSION IS A KEY RISK FACTOR FOR HEART FAILURE. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS ARE NOT FULLY UNDERSTOOD. OUR PREVIOUS STUDIES FOUND THAT THE VALOSIN-CONTAINING PROTEIN (VCP), AN ATPASE-ASSOCIATED PROTEIN, WAS SIGNIFICANTLY DECREASED IN THE HYPERTENSIVE HEART TISSUES. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT RESTORATION OF VCP PROTECTED THE HEART AGAINST PRESSURE OVERLOAD-INDUCED HEART FAILURE. WITH A CARDIAC-SPECIFIC TRANSGENIC (TG) MOUSE MODEL, WE SHOWED THAT A MODERATE INCREASE OF VCP WAS ABLE TO ATTENUATE CHRONIC PRESSURE OVERLOAD-INDUCED MALADAPTIVE CARDIAC HYPERTROPHY AND DYSFUNCTION. RNA SEQUENCING AND A COMPREHENSIVE BIOINFORMATIC ANALYSIS FURTHER DEMONSTRATED THAT OVEREXPRESSION OF VCP IN THE HEART NORMALIZED THE PRESSURE OVERLOAD-STIMULATED HYPERTROPHIC SIGNALS AND REPRESSED THE STRESS-INDUCED INFLAMMATORY RESPONSE. IN ADDITION, VCP OVEREXPRESSION PROMOTED CELL SURVIVAL BY ENHANCING THE MITOCHONDRIA RESISTANCE TO THE OXIDATIVE STRESS VIA ACTIVATING THE RICTOR-MEDIATED-GENE NETWORKS. VCP WAS ALSO FOUND TO BE INVOLVED IN THE REGULATION OF THE ALTERNATIVE SPLICING AND DIFFERENTIAL ISOFORM EXPRESSION FOR SOME GENES THAT ARE RELATED TO ATP PRODUCTION AND PROTEIN SYNTHESIS BY INTERACTING WITH LONG NO-CODING RNAS AND HISTONE DEACETYLASES, INDICATING A NOVEL EPIGENETIC REGULATION OF VCP IN INTEGRATING CODING AND NONCODING GENOMIC NETWORK IN THE STRESSED HEART. IN SUMMARY, OUR STUDY DEMONSTRATED THAT THE RESCUING OF A DEFICIENT VCP IN THE HEART COULD PREVENT PRESSURE OVERLOAD-INDUCED HEART FAILURE BY RECTIFYING CARDIAC HYPERTROPHIC AND INFLAMMATORY SIGNALING AND ENHANCING THE CARDIAC RESISTANCE TO OXIDATIVE STRESS, WHICH BROUGHT IN NOVEL INSIGHTS INTO THE UNDERSTANDING OF THE MECHANISM OF VCP IN PROTECTING PATIENTS FROM HYPERTENSIVE HEART FAILURE. 2020 10 662 26 BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME ANALYSES REVEAL LOCI ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. LITTLE IS KNOWN REGARDING THE EPIGENETIC BASIS OF ATHEROSCLEROSIS. HERE WE PRESENT THE CD14+ BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME SIGNATURES ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. THE TRANSCRIPTOME SIGNATURE INCLUDES TRANSCRIPTION COACTIVATOR, ARID5B, WHICH IS KNOWN TO FORM A CHROMATIN DEREPRESSOR COMPLEX WITH A HISTONE H3K9ME2-SPECIFIC DEMETHYLASE AND PROMOTE ADIPOGENESIS AND SMOOTH MUSCLE DEVELOPMENT. ARID5B CPG (CG25953130) METHYLATION IS INVERSELY ASSOCIATED WITH BOTH ARID5B EXPRESSION AND ATHEROSCLEROSIS, CONSISTENT WITH THIS CPG RESIDING IN AN ARID5B ENHANCER REGION, BASED ON CHROMATIN CAPTURE AND HISTONE MARKS DATA. MEDIATION ANALYSIS SUPPORTS ASSUMPTIONS THAT ARID5B EXPRESSION MEDIATES EFFECTS OF CG25953130 METHYLATION AND SEVERAL CARDIOVASCULAR DISEASE RISK FACTORS ON ATHEROSCLEROTIC BURDEN. IN LIPOPOLYSACCHARIDE-STIMULATED HUMAN THP1 MONOCYTES, ARID5B KNOCKDOWN REDUCED EXPRESSION OF GENES INVOLVED IN ATHEROSCLEROSIS-RELATED INFLAMMATORY AND LIPID METABOLISM PATHWAYS, AND INHIBITED CELL MIGRATION AND PHAGOCYTOSIS. THESE DATA SUGGEST THAT ARID5B EXPRESSION, POSSIBLY REGULATED BY AN EPIGENETICALLY CONTROLLED ENHANCER, PROMOTES ATHEROSCLEROSIS BY DYSREGULATING IMMUNOMETABOLISM TOWARDS A CHRONIC INFLAMMATORY PHENOTYPE.THE MOLECULAR MECHANISMS MEDIATING THE IMPACT OF ENVIRONMENTAL FACTORS IN ATHEROSCLEROSIS ARE UNCLEAR. HERE, THE AUTHORS EXAMINE CD14+ BLOOD MONOCYTE'S TRANSCRIPTOME AND EPIGENOME SIGNATURES TO FIND DIFFERENTIAL METHYLATION AND EXPRESSION OF ARID5B TO BE ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. 2017 11 3074 30 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 12 984 35 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION. 2022 13 1461 38 DISRUPTION OF RCAN1.4 EXPRESSION MEDIATED BY YY1/HDAC2 MODULATES CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS. CHRONIC ALLOGRAFT DYSFUNCTION (CAD) IS A MAJOR FACTOR THAT HINDERS KIDNEY TRANSPLANT SURVIVAL IN THE LONG RUN. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) HAS BEEN CONFIRMED TO SIGNIFICANTLY CONTRIBUTE TO INTERSTITIAL FIBROSIS/TUBULAR ATROPHY (IF/TA), WHICH IS THE MAIN HISTOPATHOLOGICAL FEATURE OF CAD. ABERRANT EXPRESSION OF THE REGULATOR OF CALCINEURIN 1 (RCAN1), RECOGNIZED AS AN ENDOGENOUS INHIBITOR OF THE CALCINEURIN PHOSPHATASE, HAS BEEN SHOWN TO BE EXTENSIVELY INVOLVED IN VARIOUS KIDNEY DISEASES. HOWEVER, IT REMAINS UNCLEAR HOW RCAN1.4 REGULATES IF/TA FORMATION IN CAD PATIENTS. HEREIN, AN IN VIVO MOUSE RENAL TRANSPLANTATION MODEL AND AN IN VITRO MODEL OF HUMAN RENAL TUBULAR EPITHELIAL CELLS (HK-2) TREATED WITH TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE EMPLOYED. OUR RESULTS PROVED THAT RCAN1.4 EXPRESSION WAS DECREASED IN VIVO AND IN VITRO, IN ADDITION TO THE UP-REGULATION OF YIN YANG 1 (YY1), A TRANSCRIPTION FACTOR THAT HAS BEEN REPORTED TO CONVEY MULTIPLE FUNCTIONS IN CHRONIC KIDNEY DISEASE (CKD). KNOCKING IN OF RCAN1.4 EFFICIENTLY ATTENUATED CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS IN VIVO AND INHIBITED TNF-ALPHA-INDUCED EMT IN VITRO THROUGH REGULATING ANTI-OXIDATIVE STRESS AND THE CALCINEURIN/NUCLEAR FACTOR OF ACTIVATED T CELLS CYTOPLASMIC 1 (NFATC1) SIGNALING PATHWAY. IN ADDITION, SUPPRESSION OF YY1 MEDIATED BY SHRNA OR SIRNA ALLEVIATED TNF-ALPHA-INDUCED EMT THROUGH ABOLISHING REACTIVE SPECIES PARTLY IN AN RCAN1.4-DEPENDENT MANNER. NOTABLY, WE CONFIRMED THAT YY1 NEGATIVELY REGULATED RCAN1.4 TRANSCRIPTION BY DIRECTLY INTERACTING WITH THE RCAN1.4 PROMOTER. IN ADDITION, HISTONE DEACETYLASE 2 (HDAC2) INTERACTED WITH YY1 TO FORM A MULTI-MOLECULAR COMPLEX, WHICH WAS INVOLVED IN TNF-ALPHA-INDUCED RCAN1.4 TRANSCRIPTIONAL REPRESSION. THEREFORE, RCAN1.4 IS SUGGESTED TO BE MODULATED BY THE YY1/HDAC2 TRANSCRIPTION REPRESSOR COMPLEX IN AN EPIGENETIC MANNER, WHICH IS A MEDIATED NEPHROPROTECTIVE EFFECT PARTLY THROUGH MODULATING O2?- GENERATION AND THE CALCINEURIN/NFATC1 SIGNALING PATHWAY. THUS, THE YY1-RCAN1.4 AXIS CONSTITUTES AN INNOVATIVE TARGET FOR IF/TA TREATMENT IN CAD PATIENTS. 2023 14 3198 31 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES. 2018 15 1335 29 DERMAL FIBROBLASTS CULTURED FROM DONORS WITH TYPE 2 DIABETES MELLITUS RETAIN AN EPIGENETIC MEMORY ASSOCIATED WITH POOR WOUND HEALING RESPONSES. THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) IS ESCALATING GLOBALLY. PATIENTS SUFFER FROM MULTIPLE COMPLICATIONS INCLUDING THE DEVELOPMENT OF CHRONIC WOUNDS THAT CAN LEAD TO AMPUTATION. THESE WOUNDS ARE CHARACTERISED BY AN INFLAMMATORY ENVIRONMENT INCLUDING ELEVATED TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA). DERMAL FIBROBLASTS (DF) ARE CRITICAL FOR EFFECTIVE WOUND HEALING, SO WE SOUGHT TO ESTABLISH WHETHER THERE WERE ANY DIFFERENCES IN DF CULTURED FROM T2DM DONORS OR THOSE WITHOUT DIABETES (ND-DF). ND- AND T2DM-DF WHEN CULTURED SIMILARLY IN VITRO SECRETED COMPARABLE CONCENTRATIONS OF TNF-ALPHA. FUNCTIONALLY, PRE-TREATMENT WITH TNF-ALPHA REDUCED THE PROLIFERATION OF ND-DF AND TRANSIENTLY ALTERED ND-DF MORPHOLOGY; HOWEVER, T2DM-DF WERE RESISTANT TO THESE TNF-ALPHA INDUCED CHANGES. IN CONTRAST, TNF-ALPHA INHIBITED ND- AND T2DM-DF MIGRATION AND MATRIX METALLOPROTEASE EXPRESSION TO THE SAME DEGREE, ALTHOUGH T2DM-DF EXPRESSED SIGNIFICANTLY HIGHER LEVELS OF TISSUE INHIBITOR OF METALLOPROTEASES (TIMP)-2. FINALLY, TNF-ALPHA SIGNIFICANTLY INCREASED THE SECRETION OF PRO-INFLAMMATORY CYTOKINES (INCLUDING CCL2, CXCL1 AND SERPINE1) IN ND-DF, WHILST THIS EFFECT IN T2DM-DF WAS BLUNTED, PRESUMABLY DUE TO THE TENDENCY TO HIGHER BASELINE PRO-INFLAMMATORY CYTOKINE EXPRESSION OBSERVED IN THIS CELL TYPE. COLLECTIVELY, THESE DATA DEMONSTRATE THAT T2DM-DF EXHIBIT A SELECTIVE LOSS OF RESPONSIVENESS TO TNF-ALPHA, PARTICULARLY REGARDING PROLIFERATIVE AND SECRETORY FUNCTIONS. THIS HIGHLIGHTS IMPORTANT PHENOTYPIC CHANGES IN T2DM-DF THAT MAY EXPLAIN THE SUSCEPTIBILITY TO CHRONIC WOUNDS IN THESE PATIENTS. 2021 16 1728 39 DYSREGULATION OF MICRORNAS IN HYPERTROPHY AND OSSIFICATION OF LIGAMENTUM FLAVUM: NEW ADVANCES, CHALLENGES, AND POTENTIAL DIRECTIONS. PATHOLOGICAL CHANGES IN THE LIGAMENTUM FLAVUM (LF) CAN BE DEFINED AS A PROCESS OF CHRONIC PROGRESSIVE ABERRATIONS IN THE NATURE AND STRUCTURE OF LIGAMENTOUS TISSUES CHARACTERIZED BY INCREASED THICKNESS, REDUCED ELASTICITY, LOCAL CALCIFICATION, OR AGGRAVATED OSSIFICATION, WHICH MAY CAUSE SEVERE MYELOPATHY, RADICULOPATHY, OR BOTH. HYPERTROPHY OF LIGAMENTUM FLAVUM (HLF) AND OSSIFICATION OF LIGAMENTUM FLAVUM (OLF) ARE CLINICALLY COMMON ENTITIES. THOUGH ACCUMULATED EVIDENCE HAS INDICATED BOTH GENETIC AND ENVIRONMENTAL FACTORS COULD CONTRIBUTE TO THE INITIATION AND PROGRESSION OF HLF/OLF, THE DEFINITE PATHOGENESIS REMAINS FULLY UNCLEAR. MICRORNAS (MIRNAS), ONE OF THE IMPORTANT EPIGENETIC MODIFICATIONS, ARE SHORT SINGLE-STRANDED RNA MOLECULES THAT REGULATE PROTEIN-CODING GENE EXPRESSION AT POSTTRANSCRIPTIONAL LEVEL, WHICH CAN DISCLOSE THE MECHANISM UNDERLYING DISEASES, IDENTIFY VALUABLE BIOMARKERS, AND EXPLORE POTENTIAL THERAPEUTIC TARGETS. CONSIDERING THAT MIRNAS PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION, WE SUMMARIZED CURRENT STUDIES FROM THE POINT OF VIEW OF MIRNA-RELATED MOLECULAR REGULATION NETWORKS IN HLF/OLF. EXPLORATORY STUDIES REVEALED A VARIETY OF MIRNA EXPRESSION PROFILES AND IDENTIFIED A BATTERY OF UPREGULATED AND DOWNREGULATED MIRNAS IN OLF/HLF PATIENTS THROUGH MICROARRAY DATASETS OR TRANSCRIPTOME SEQUENCING. EXPERIMENTAL STUDIES VALIDATED THE ROLES OF SPECIFIC MIRNAS (E.G., MIR-132-3P, MIR-199B-5P IN OLF, MIR-155, AND MIR-21 IN HLF) IN REGULATING FIBROSIS OR OSTEOGENESIS DIFFERENTIATION OF LF CELLS AND RELATED TARGET GENES OR MOLECULAR SIGNALING PATHWAYS. FINALLY, WE DISCUSSED THE PERSPECTIVES AND CHALLENGES OF MIRNA-BASED MOLECULAR MECHANISM, DIAGNOSTIC BIOMARKERS, AND THERAPEUTIC TARGETS OF HLF/OLF. 2021 17 3465 37 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019 18 5433 21 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION. 2002 19 3128 42 GIPC-REGULATED IGFBP-3 PROMOTES HSC MIGRATION IN VITRO AND PORTAL HYPERTENSION IN VIVO THROUGH A BETA1-INTEGRIN PATHWAY. BACKGROUND & AIMS: TRANSFORMING GROWTH FACTOR (TGF-BETA)-INDUCED ACTIVATION OF QUIESCENT HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION TO MYOFIBROBLASTS IS A KEY EVENT IN LIVER FIBROSIS AND PORTAL HYPERTENSION. GIPC (ALSO REFERRED TO AS SYNECTIN) IS A DOWNSTREAM SIGNAL ACTIVATION MOLECULE OF TGF-BETA AND OTHER RECEPTORS. IN THIS STUDY, WE SOUGHT TO IDENTIFY NOVEL GENES TARGETED BY TGF-BETA AND GIPC AND ELUCIDATE IF AND HOW THEY MAY CONTRIBUTE TO LIVER FIBROSIS. METHODS: WE PERFORMED SEQUENTIAL MESSENGER RNA SEQUENCING ANALYSIS ON TGF-BETA-STIMULATED HSCS AND THEN ON TGF-BETA-STIMULATED HSCS IN THE PRESENCE AND ABSENCE OF GIPC ALSO REFERRED TO AS SYNECTIN (GIPC) KNOCKDOWN. INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 (IGFBP-3) TRANSPORT PROTEIN EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC. QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, TARGETED CHROMATIN IMMUNOPRECIPITATION, AND WESTERN BLOT ANALYSIS WERE DONE FOR FURTHER CONFIRMATION. RESULTS: IGFBP-3, AN INSULIN GROWTH FACTOR TRANSPORT PROTEIN, EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC, WHICH WAS CONFIRMED BY QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, AND WESTERN BLOT ANALYSIS. TARGETED CHROMATIN IMMUNOPRECIPITATION SHOWED THAT GIPC INCREASES THE HISTONE 3 LYSINE 27 (H3K27) ACETYLATION ACTIVATING MARK AND CONCURRENTLY DECREASES THE H3K27 INHIBITORY TRIMETHYLATION (H3K27M3) MARK, PROVIDING AN EPIGENETIC CORRELATE TO THE GENE REGULATION CHANGES. IN VIVO, GLOBAL KNOCKOUT OF IGFBP-3 MICE RESULTED IN ATTENUATION OF HSC ACTIVATION MARKERS AND ATTENUATION OF PORTAL PRESSURE IN RESPONSE TO CHRONIC LIVER INJURY MODELS. ANALYSIS OF SERUM LEVELS FROM CIRRHOTIC PATIENTS ALSO SHOWED AN IGFBP-3 INCREASE OF MORE THAN 2-FOLD COMPARED WITH HEALTHY CONTROLS. FINALLY, IN VITRO MECHANISM STUDIES SHOWED THAT IGFBP-3 PROMOTES HSC MIGRATION THROUGH INTEGRIN-DEPENDENT PHOSPHORYLATION OF PROTEIN KINASE B. CONCLUSIONS: TGF-BETA UP-REGULATES IGFBP-3 THROUGH GIPC, LEADING TO INCREASED HSC MIGRATION IN VITRO AND PROMOTES PORTAL HYPERTENSION IN VIVO. THESE STUDIES SUPPORT THE ROLE OF IGFBP-3 AS A POTENTIAL PATHOPHYSIOLOGIC TARGET OR BIOMARKER IN CHRONIC LIVER DISEASE. 2020 20 26 37 A 6-ALKYLSALICYLATE HISTONE ACETYLTRANSFERASE INHIBITOR INHIBITS HISTONE ACETYLATION AND PRO-INFLAMMATORY GENE EXPRESSION IN MURINE PRECISION-CUT LUNG SLICES. LYSINE ACETYLATIONS ARE POST-TRANSLATIONAL MODIFICATIONS OF CELLULAR PROTEINS, THAT ARE CRUCIAL IN THE REGULATION OF MANY CELLULAR PROCESSES. LYSINE ACETYLATIONS ON HISTONE PROTEINS ARE PART OF THE EPIGENETIC CODE REGULATING GENE EXPRESSION AND ARE INSTALLED BY HISTONE ACETYLTRANSFERASES. OBSERVATIONS THAT INFLAMMATORY LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ARE CHARACTERIZED BY INCREASED HISTONE ACETYLTRANSFERASE ACTIVITY INDICATE THAT DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR THESE ENZYMES MIGHT BE A VALUABLE APPROACH TOWARDS NEW THERAPIES FOR THESE DISEASES. THE 6-ALKYLSALICYLATE MG149 IS A CANDIDATE TO EXPLORE THIS HYPOTHESIS BECAUSE IT HAS BEEN DEMONSTRATED TO INHIBIT THE MYST TYPE HISTONE ACETYLTRANSFERASES. IN THIS STUDY, WE DETERMINED THE K(I) VALUE FOR INHIBITION OF THE MYST TYPE HISTONE ACETYLTRANSFERASE KAT8 BY MG149 TO BE 39 +/- 7.7 MUM. UPON INVESTIGATING WHETHER THE INHIBITION OF HISTONE ACETYLTRANSFERASES BY MG149 CORRELATES WITH INHIBITION OF HISTONE ACETYLATION IN MURINE PRECISION-CUT LUNG SLICES, INHIBITION OF ACETYLATION WAS OBSERVED USING AN LC-MS/MS BASED ASSAY ON HISTONE H4 RES 4-17, WHICH CONTAINS THE TARGET LYSINE OF KAT8. FOLLOWING UP ON THIS, UPON TREATMENT WITH MG149, REDUCED PRO-INFLAMMATORY GENE EXPRESSION WAS OBSERVED IN LIPOPOLYSACCHARIDE AND INTERFERON GAMMA STIMULATED MURINE PRECISION-CUT LUNG SLICES. BASED ON THIS, WE PROPOSE THAT 6-ALKYLSALICYLATES SUCH AS MG149 HAVE POTENTIAL FOR DEVELOPMENT TOWARDS APPLICATIONS IN THE TREATMENT OF INFLAMMATORY LUNG DISEASES. 2017