1 5009 117 PERK IS A CRITICAL METABOLIC HUB FOR IMMUNOSUPPRESSIVE FUNCTION IN MACROPHAGES. CHRONIC INFLAMMATION TRIGGERS COMPENSATORY IMMUNOSUPPRESSION TO STOP INFLAMMATION AND MINIMIZE TISSUE DAMAGE. STUDIES HAVE DEMONSTRATED THAT ENDOPLASMIC RETICULUM (ER) STRESS AUGMENTS THE SUPPRESSIVE PHENOTYPES OF IMMUNE CELLS; HOWEVER, THE MOLECULAR MECHANISMS UNDERPINNING THIS PROCESS AND HOW IT LINKS TO THE METABOLIC REPROGRAMMING OF IMMUNOSUPPRESSIVE MACROPHAGES REMAIN ELUSIVE. IN THE PRESENT STUDY, WE REPORT THAT THE HELPER T CELL 2 CYTOKINE INTERLEUKIN-4 AND THE TUMOR MICROENVIRONMENT INCREASE THE ACTIVITY OF A PROTEIN KINASE RNA-LIKE ER KINASE (PERK)-SIGNALING CASCADE IN MACROPHAGES AND PROMOTE IMMUNOSUPPRESSIVE M2 ACTIVATION AND PROLIFERATION. LOSS OF PERK SIGNALING IMPEDED MITOCHONDRIAL RESPIRATION AND LIPID OXIDATION CRITICAL FOR M2 MACROPHAGES. PERK ACTIVATION MEDIATED THE UPREGULATION OF PHOSPHOSERINE AMINOTRANSFERASE 1 (PSAT1) AND SERINE BIOSYNTHESIS VIA THE DOWNSTREAM TRANSCRIPTION FACTOR ATF-4. INCREASED SERINE BIOSYNTHESIS RESULTED IN ENHANCED MITOCHONDRIAL FUNCTION AND ALPHA-KETOGLUTARATE PRODUCTION REQUIRED FOR JMJD3-DEPENDENT EPIGENETIC MODIFICATION. INHIBITION OF PERK SUPPRESSED MACROPHAGE IMMUNOSUPPRESSIVE ACTIVITY AND COULD ENHANCE THE EFFICACY OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 INHIBITION IN MELANOMA. OUR FINDINGS DELINEATE A PREVIOUSLY UNDESCRIBED CONNECTION BETWEEN PERK SIGNALING AND PSAT1-MEDIATED SERINE METABOLISM CRITICAL FOR PROMOTING IMMUNOSUPPRESSIVE FUNCTION IN M2 MACROPHAGES. 2022 2 5153 27 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 3 6578 29 TREATMENT WITH TRICHURIS SUIS SOLUBLE PRODUCTS DURING MONOCYTE-TO-MACROPHAGE DIFFERENTIATION REDUCES INFLAMMATORY RESPONSES THROUGH EPIGENETIC REMODELING. HELMINTHS HAVE STRONG IMMUNOREGULATORY PROPERTIES THAT MAY BE EXPLOITED IN TREATMENT OF CHRONIC IMMUNE DISORDERS, SUCH AS MULTIPLE SCLEROSIS AND INFLAMMATORY BOWEL DISEASE. ESSENTIAL PLAYERS IN THE PATHOGENESIS OF THESE DISEASES ARE PROINFLAMMATORY MACROPHAGES. WE PRESENT EVIDENCE THAT HELMINTHS MODULATE THE FUNCTION AND PHENOTYPE OF THESE INNATE IMMUNE CELLS. WE FOUND THAT SOLUBLE PRODUCTS DERIVED FROM THE TRICHURIS SUIS (TSSP) SIGNIFICANTLY AFFECT THE DIFFERENTIATION OF MONOCYTES INTO MACROPHAGES AND THEIR SUBSEQUENT POLARIZATION. TSSPS REDUCE THE EXPRESSION AND PRODUCTION OF INFLAMMATORY CYTOKINES, INCLUDING IL-6 AND TNF, IN HUMAN PROINFLAMMATORY M1 MACROPHAGES. TSSPS INDUCE A CONCOMITANT ANTI-INFLAMMATORY M2 SIGNATURE, WITH INCREASED IL-10 PRODUCTION. FURTHERMORE, THEY SUPPRESS CHIT ACTIVITY AND ENHANCE SECRETION OF MATRIX METALLOPROTEINASE 9. SHORT-TERM TRIGGERING OF MONOCYTES WITH TSSPS EARLY DURING MONOCYTE-TO-MACROPHAGE DIFFERENTIATION IMPRINTED THESE PHENOTYPIC ALTERATIONS, SUGGESTING LONG-LASTING EPIGENETIC CHANGES. THE TSSP-INDUCED EFFECTS IN M1 MACROPHAGES WERE COMPLETELY REVERSED BY INHIBITING HISTONE DEACETYLASES, WHICH CORRESPONDED WITH DECREASED HISTONE ACETYLATION AT THE TNF AND IL6 PROMOTERS. THESE RESULTS DEMONSTRATE THAT TSSPS HAVE A POTENT AND SUSTAINED IMMUNOMODULATORY EFFECT ON HUMAN MACROPHAGE DIFFERENTIATION AND POLARIZATION THROUGH EPIGENETIC REMODELING AND PROVIDE NEW INSIGHTS INTO THE MECHANISMS BY WHICH HELMINTHS MODULATE HUMAN IMMUNE RESPONSES.-HOEKSEMA, M. A., LAAN, L. C., POSTMA, J. J., CUMMINGS, R. D., DE WINTHER, M. P. J., DIJKSTRA, C. D., VAN DIE, I., KOOIJ, G. TREATMENT WITH TRICHURIS SUIS SOLUBLE PRODUCTS DURING MONOCYTE-TO-MACROPHAGE DIFFERENTIATION REDUCES INFLAMMATORY RESPONSES THROUGH EPIGENETIC REMODELING. 2016 4 3327 24 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 5 984 34 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 6 3778 33 INTERFERING WITH ALTERNATIVELY ACTIVATED MACROPHAGES BY CSF-1R INHIBITION EXERTS THERAPEUTIC CAPACITY ON ALLERGIC AIRWAY INFLAMMATION. PURPOSE: ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY DISORDER WITH AIRWAY HYPERRESPONSIVENESS AND TISSUE REMODELING AS THE MAIN PATHOLOGICAL CHARACTERISTICS. THE ETIOLOGY OF ASTHMA IS RELATIVELY COMPLICATED, INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC REGULATION, ENVIRONMENTAL FACTORS, AND IMMUNE IMBALANCE. COLONY STIMULATING FACTOR 1 RECEPTOR (CSF-1R), HIGHLY EXPRESSED IN MYELOID MONOCYTES, PLAYS AN IMPORTANT ROLE IN REGULATING INFLAMMATION. HOWEVER, THE PATHOLOGICAL ROLE OF CSF-1R AND THE THERAPEUTIC EFFECTS OF CSF-1R INHIBITOR IN ALLERGIC AIRWAY INFLAMMATION REMAIN INDISTINCT. METHODS: THE HOUSE DUST MITE (HDM)-TRIGGERED ALLERGIC AIRWAY INFLAMMATION MODEL WAS CONDUCTED TO FULLY UNCOVER THE EFFICACIES OF CSF-1R INHIBITION, AS ILLUSTRATED BY HISTOPATHOLOGICAL EXAMINATIONS, BIOCHEMICAL ANALYSIS, ELISA, RT-PCR, WESTERN BLOTTING ASSAY, IMMUNOFLUORESCENCE, AND FLOW CYTOMETRY. FURTHERMORE, BONE MARROW-DERIVED MACROPHAGES (BMDMS) WERE DIFFERENTIATED AND POLARIZED UPON IL-4/IL-13 INDUCTION TO CLARIFY THE UNDERLYING MECHANISMS OF CSF-1R INHIBITION. RESULTS: HEREIN, WE PRESENTED THAT THE EXPRESSION OF CSF-1R WAS INCREASED IN HDM-INDUCED EXPERIMENTAL ASTHMA AND INHIBITION OF CSF-1R DISPLAYED DRAMATIC EFFECTS ON THE DISEASE SEVERITY OF ASTHMA, REFERRING TO SUPPRESSING THE SECRETION OF ALLERGIC MEDIATORS, DYSFUNCTION OF AIRWAY EPITHELIUM, AND INFILTRATION OF INFLAMMATORY CELLS. FURTHERMORE, CSF-1R INHIBITOR COULD MARKEDLY RESTRAIN THE POLARIZATION AND EXPRESSION OF TRANSCRIPTIONAL FACTORS OF ALTERNATIVELY ACTIVATED MACROPHAGES (AAMS) IN THE PRESENCE OF IL-4/IL-13 AND REDUCE THE RECRUITMENT OF CSF-1R-DOMINANT MACROPHAGES, BOTH IN ACUTE AND CHRONIC ALLERGIC AIRWAY INFLAMMATION MODEL. CONCLUSION: COLLECTIVELY, OUR FINDINGS DEMONSTRATED THE MOLECULAR PATHOLOGICAL MECHANISM OF CSF-1R IN ALLERGIC AIRWAY DISEASES AND SUGGESTED THAT TARGETING CSF-1R MIGHT BE AN ALTERNATIVE INTERVENTION STRATEGY ON THE HOMEOSTASIS OF AIRWAY IMMUNE MICROENVIRONMENT IN ASTHMA. 2022 7 3762 34 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022 8 5433 19 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 9 222 27 ACUTE LIVER STEATOSIS TRANSLATIONALLY CONTROLS THE EPIGENETIC REGULATOR MIER1 TO PROMOTE LIVER REGENERATION IN A STUDY WITH MALE MICE. THE EARLY PHASE LIPID ACCUMULATION IS ESSENTIAL FOR LIVER REGENERATION. HOWEVER, WHETHER THIS ACUTE LIPID ACCUMULATION CAN SERVE AS SIGNALS TO DIRECT LIVER REGENERATION RATHER THAN SIMPLY PROVIDING BUILDING BLOCKS FOR CELL PROLIFERATION REMAINS UNCLEAR. THROUGH IN VIVO CRISPR SCREENING, WE IDENTIFY MIER1 (MESODERM INDUCTION EARLY RESPONSE 1) AS A KEY EPIGENETIC REGULATOR THAT BRIDGES THE ACUTE LIPID ACCUMULATION AND CELL CYCLE GENE EXPRESSION DURING LIVER REGENERATION IN MALE ANIMALS. PHYSIOLOGICALLY, LIVER ACUTE LIPID ACCUMULATION INDUCES THE PHOSPHORYLATION OF EIF2S1(EUKARYOTIC TRANSLATION INITIATION FACTOR 2), WHICH CONSEQUENTLY ATTENUATED MIER1 TRANSLATION. MIER1 DOWNREGULATION IN TURN PROMOTES CELL CYCLE GENE EXPRESSION AND REGENERATION THROUGH CHROMATIN REMODELING. IMPORTANTLY, THE LIPIDS-EIF2S1-MIER1 PATHWAY IS IMPAIRED IN ANIMALS WITH CHRONIC LIVER STEATOSIS; WHEREAS MIER1 DEPLETION SIGNIFICANTLY IMPROVES REGENERATION IN THESE ANIMALS. TAKEN TOGETHER, OUR STUDIES IDENTIFY AN EPIGENETIC MECHANISM BY WHICH THE EARLY PHASE LIPID REDISTRIBUTION FROM ADIPOSE TISSUE TO LIVER DURING REGENERATION IMPACTS HEPATOCYTE PROLIFERATION, AND SUGGEST A POTENTIAL STRATEGY TO BOOST LIVER REGENERATION. 2023 10 4039 31 MACROPHAGE NOX2 NADPH OXIDASE MAINTAINS ALVEOLAR HOMEOSTASIS IN MICE. THE LEUKOCYTE NADPH OXIDASE 2 (NOX2) PLAYS A KEY ROLE IN PATHOGEN KILLING AND IMMUNOREGULATION. GENETIC DEFECTS IN NOX2 RESULT IN CHRONIC GRANULOMATOUS DISEASE (CGD), ASSOCIATED WITH MICROBIAL INFECTIONS AND INFLAMMATORY DISORDERS, OFTEN INVOLVING THE LUNG. ALVEOLAR MACROPHAGES (AMS) ARE THE PREDOMINANT IMMUNE CELL IN THE AIRWAYS AT STEADY STATE, AND LIMITING THEIR ACTIVATION IS IMPORTANT, GIVEN THE CONSTANT EXPOSURE TO INHALED MATERIALS, YET THE IMPORTANCE OF NOX2 IN THIS PROCESS IS NOT WELL UNDERSTOOD. IN THIS STUDY, WE SHOWED A PREVIOUSLY UNDESCRIBED ROLE FOR NOX2 IN MAINTAINING LUNG HOMEOSTASIS BY SUPPRESSING AM ACTIVATION, IN CGD MICE OR MICE WITH SELECTIVE LOSS OF NOX2 PREFERENTIALLY IN MACROPHAGES. AMS LACKING NOX2 HAD INCREASED CYTOKINE RESPONSES TO TOLL-LIKE RECEPTOR-2 (TLR2) AND TLR4 STIMULATION EX VIVO. MOREOVER, BETWEEN 4 AND 12 WEEK OF AGE, MICE WITH GLOBAL NOX2 DELETION DEVELOPED AN ACTIVATED CD11BHIGH SUBSET OF AMS WITH EPIGENETIC AND TRANSCRIPTIONAL PROFILES REFLECTING IMMUNE ACTIVATION COMPARED WITH WT AMS. THE PRESENCE OF CD11BHIGH AMS IN CGD MICE CORRELATED WITH AN INCREASED NUMBER OF ALVEOLAR NEUTROPHILS AND PROINFLAMMATORY CYTOKINES AT STEADY STATE AND INCREASED LUNG INFLAMMATION AFTER INSULTS. MOREOVER, DELETION OF NOX2 PREFERENTIALLY IN MACROPHAGES WAS SUFFICIENT FOR MICE TO DEVELOP AN ACTIVATED CD11BHIGH AM SUBSET AND ACCOMPANYING PROINFLAMMATORY SEQUELAE. IN ADDITION, WE SHOWED THAT THE ALTERED RESIDENT MACROPHAGE TRANSCRIPTIONAL PROFILE IN THE ABSENCE OF NOX2 IS TISSUE SPECIFIC, AS THOSE CHANGES WERE NOT SEEN IN RESIDENT PERITONEAL MACROPHAGES. THUS, THESE DATA DEMONSTRATE THAT THE ABSENCE OF NOX2 IN ALVEOLAR MACROPHAGES LEADS TO THEIR PROINFLAMMATORY REMODELING AND DYSREGULATES ALVEOLAR HOMEOSTASIS. 2022 11 4002 27 LOSS OF P120 CATENIN AND LINKS TO MITOTIC ALTERATIONS, INFLAMMATION, AND SKIN CANCER. TUMOR FORMATION INVOLVES EPIGENETIC MODIFICATIONS AND MICROENVIRONMENTAL CHANGES AS WELL AS CUMULATIVE GENETIC ALTERATIONS ENCOMPASSING SOMATIC MUTATIONS, LOSS OF HETEROZYGOSITY, AND ANEUPLOIDY. HERE, WE SHOW THAT CONDITIONAL TARGETING OF P120 CATENIN IN MICE LEADS TO PROGRESSIVE DEVELOPMENT OF SKIN NEOPLASIAS ASSOCIATED WITH INTRINSIC NF-KAPPAB ACTIVATION. WE FIND THAT, SIMILARLY, SQUAMOUS CELL CARCINOMAS IN HUMANS DISPLAY ALTERED P120 AND ACTIVATED NF-KAPPAB. WE SHOW THAT EPIDERMAL HYPERPROLIFERATION ARISING FROM P120 LOSS CAN BE ABROGATED BY IKAPPAB KINASE 2 INHIBITORS. ALTHOUGH THIS UNDERSCORES THE IMPORTANCE OF THIS PATHWAY, THE ROLE OF NF-KAPPAB IN HYPERPROLIFERATION APPEARS ROOTED IN ITS IMPACT ON EPIDERMAL MICROENVIRONMENT BECAUSE AS P120-NULL KERATINOCYTES DISPLAY A GROWTH-ARRESTED PHENOTYPE IN CULTURE. WE TRACE THIS TO A MITOTIC DEFECT, RESULTING IN UNSTABLE, BINUCLEATED CELLS IN VITRO AND IN VIVO. WE SHOW THAT THE ABNORMAL MITOSES CAN BE AMELIORATED BY INHIBITING RHOA, THE ACTIVITY OF WHICH IS ABNORMALLY HIGH. CONVERSELY, WE CAN ELICIT SUCH MITOTIC DEFECTS IN CONTROL KERATINOCYTES BY ELEVATING RHOA ACTIVITY. THE ABILITY OF P120 DEFICIENCY TO ELICIT MITOTIC ALTERATIONS AND CHRONIC INFLAMMATORY RESPONSES, THAT TOGETHER MAY FACILITATE THE DEVELOPMENT OF GENETIC INSTABILITY IN VIVO, PROVIDES INSIGHTS INTO WHY IT FIGURES SO PROMINENTLY IN SKIN CANCER PROGRESSION. 2008 12 662 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 13 1335 28 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 14 1461 31 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 15 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 16 5681 29 SHORT-CHAIN FATTY ACID-MEDIATED EPIGENETIC MODULATION OF INFLAMMATORY T CELLS IN VITRO. SHORT-CHAIN FATTY ACIDS (SCFAS) ARE MAJOR METABOLIC PRODUCTS OF INDIGESTIBLE POLYSACCHARIDES IN THE GUT AND MEDIATE THE FUNCTION OF IMMUNE CELLS TO FACILITATE HOMEOSTASIS. THE IMMUNOMODULATORY EFFECT OF SCFAS HAS BEEN ATTRIBUTED, AT LEAST IN PART, TO THE EPIGENETIC MODULATION OF IMMUNE CELLS THROUGH THE INHIBITION THE NUCLEUS-RESIDENT ENZYME HISTONE DEACETYLASE (HDAC). AMONG THE DOWNSTREAM EFFECTS, SCFAS ENHANCE REGULATORY T CELLS (T(REG)) OVER INFLAMMATORY T HELPER (TH) CELLS, INCLUDING TH17 CELLS, WHICH CAN BE PATHOGENIC. HERE, WE CHARACTERIZE THE POTENTIAL OF TWO COMMON SCFAS-BUTYRATE AND PENTANOATE-IN MODULATING DIFFERENTIATION OF T CELLS IN VITRO. WE SHOW THAT BUTYRATE BUT NOT PENTANOATE EXERTS A CONCENTRATION-DEPENDENT EFFECT ON T(REG) AND TH17 DIFFERENTIATION. INCREASING THE CONCENTRATION OF BUTYRATE SUPPRESSES THE TH17-ASSOCIATED RORGAMMATT AND IL-17 AND INCREASES THE EXPRESSION OF T(REG)-ASSOCIATED FOXP3. TO EFFECTIVELY DELIVER BUTYRATE, ENCAPSULATION OF BUTYRATE IN A LIPOSOMAL CARRIER, TERMED BLIPS, REDUCED CYTOTOXICITY WHILE MAINTAINING THE IMMUNOMODULATORY EFFECT ON T CELLS. CONSISTENT WITH THESE RESULTS, BUTYRATE AND BLIPS INHIBIT HDAC AND PROMOTE A UNIQUE CHROMATIN LANDSCAPE IN T CELLS UNDER CONDITIONS THAT OTHERWISE PROMOTE CONVERSION INTO A PRO-INFLAMMATORY PHENOTYPE. MOTIF ENRICHMENT ANALYSIS REVEALED THAT BUTYRATE AND BLIP-MEDIATED SUPPRESSION OF TH17-ASSOCIATED CHROMATIN ACCESSIBILITY CORRESPONDED WITH A MARKED DECREASE IN BZIP FAMILY TRANSCRIPTION FACTOR BINDING SITES. THESE RESULTS SUPPORT THE UTILITY AND FURTHER EVALUATION OF BLIPS AS AN IMMUNOMODULATORY AGENT FOR AUTOIMMUNE DISORDERS THAT ARE CHARACTERIZED BY CHRONIC INFLAMMATION AND PATHOGENIC INFLAMMATORY T CELLS. 2023 17 1293 24 DECREASED ERK AND JNK SIGNALING CONTRIBUTE TO GENE OVEREXPRESSION IN "SENESCENT" CD4+CD28- T CELLS THROUGH EPIGENETIC MECHANISMS. AN INFLAMMATORY AND CYTOTOXIC CD4+CD28- T CELL SUBSET INFILTRATES ATHEROSCLEROTIC PLAQUES AND IS IMPLICATED IN PLAQUE RUPTURE AND MYOCARDIAL INFARCTIONS. THIS PATHOLOGIC SUBSET DEVELOPS WITH REPLICATIVE STRESS AND IS FOUND IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES SUCH AS RA AS WELL AS WITH AGING. CD4+CD28- CELLS OVEREXPRESS GENES NORMALLY SUPPRESSED BY DNA METHYLATION IN CD4+CD28+ T CELLS, SUCH AS KIR, PERFORIN, AND CD70. HOW THIS SUBSET OVER EXPRESSES METHYLATION-SENSITIVE GENES IS UNKNOWN. DNA METHYLATION PATTERNS ARE MAINTAINED IN PROLIFERATING CELLS BY DNMTS, WHICH ARE UP-REGULATED DURING MITOSIS BY THE ERK AND JNK SIGNALING PATHWAYS. WE HYPOTHESIZED THAT DEFECTS IN THESE SIGNALING PATHWAYS CONTRIBUTE TO ALTERED GENE EXPRESSION IN HUMAN CD4+CD28- CELLS THROUGH EFFECTS ON DNA METHYLATION. WE REPORT THAT SIGNALING THROUGH THE ERK AND JNK PATHWAYS IS DECREASED IN CD4+CD28- RELATIVE TO CD4+CD28+ CELLS FROM THE SAME INDIVIDUALS AND THAT ERK AND JNK PATHWAY INHIBITION DECREASES DNMT1 AND -3A LEVELS, WHICH IN TURN, CAUSES DEMETHYLATION AND OVEREXPRESSION OF THE TNFSF7 (CD70) GENE. WE ALSO REPORT THAT CD4+CD28- T CELLS OVEREXPRESS PP5, A STRESS-INDUCED INHIBITOR OF THE ERK AND JNK SIGNALING PATHWAYS THAT MAY CONTRIBUTE TO THE SIGNALING DEFECTS. WE CONCLUDE THAT DECREASED ERK AND JNK SIGNALING IN THE CD4+CD28- SUBSET, ARISING WITH REPLICATIVE STRESS, CAN LEAD TO THE OVEREXPRESSION OF NORMALLY SUPPRESSED GENES THROUGH EFFECTS ON DNMTS AND CONSEQUENTLY, CHROMATIN STRUCTURE. 2010 18 3049 27 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 19 6294 22 THE PROINFLAMMATORY CYTOKINE TNFALPHA INDUCES DNA DEMETHYLATION-DEPENDENT AND -INDEPENDENT ACTIVATION OF INTERLEUKIN-32 EXPRESSION. IL-32 IS A CYTOKINE INVOLVED IN PROINFLAMMATORY IMMUNE RESPONSES TO BACTERIAL AND VIRAL INFECTIONS. HOWEVER, THE ROLE OF EPIGENETIC EVENTS IN THE REGULATION OF IL-32 GENE EXPRESSION IS UNDERSTUDIED. HERE WE SHOW THAT IL-32 IS REPRESSED BY DNA METHYLATION IN HEK293 CELLS. USING CHIP SEQUENCING, LOCUS-SPECIFIC METHYLATION ANALYSIS, CRISPR/CAS9-MEDIATED GENOME EDITING, AND RT-QPCR (QUANTITATIVE RT-PCR) AND IMMUNOBLOT ASSAYS, WE FOUND THAT SHORT-TERM TREATMENT (A FEW HOURS) WITH THE PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) ACTIVATES IL-32 IN A DNA DEMETHYLATION-INDEPENDENT MANNER. IN CONTRAST, PROLONGED TNFALPHA TREATMENT (SEVERAL DAYS) INDUCED DNA DEMETHYLATION AT THE PROMOTER AND A CPG ISLAND IN THE IL-32 GENE IN A TET (TEN-ELEVEN TRANSLOCATION) FAMILY ENZYME- AND NF-KAPPAB-DEPENDENT MANNER. NOTABLY, THE HYPOMETHYLATION STATUS OF TRANSCRIPTIONAL REGULATORY ELEMENTS IN IL-32 WAS MAINTAINED FOR A LONG TIME (SEVERAL WEEKS), CAUSING ELEVATED IL-32 EXPRESSION EVEN IN THE ABSENCE OF TNFALPHA. CONSIDERING THAT IL-32 CAN, IN TURN, INDUCE TNFALPHA EXPRESSION, WE SPECULATE THAT SUCH FEEDFORWARD EVENTS MAY CONTRIBUTE TO THE TRANSITION FROM AN ACUTE INFLAMMATORY RESPONSE TO CHRONIC INFLAMMATION. 2019 20 6012 25 THE APKC-CBP PATHWAY REGULATES POST-STROKE NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY. EPIGENETIC MODIFICATIONS HAVE EMERGED AS ATTRACTIVE MOLECULAR SUBSTRATES THAT INTEGRATE EXTRINSIC CHANGES INTO THE DETERMINATION OF CELL IDENTITY. SINCE STROKE-RELATED BRAIN DAMAGE RELEASES MICRO-ENVIRONMENTAL CUES, WE EXAMINED THE ROLE OF A SIGNALING-INDUCED EPIGENETIC PATHWAY, AN ATYPICAL PROTEIN KINASE C (APKC)-MEDIATED PHOSPHORYLATION OF CREB-BINDING PROTEIN (CBP), IN POST-STROKE NEUROVASCULAR REMODELING. USING A KNOCKIN MOUSE STRAIN (CBPS436A) WHERE THE APKC-CBP PATHWAY WAS DEFECTIVE, WE SHOW THAT DISRUPTION OF THE APKC-CBP PATHWAY IN A MURINE FOCAL ISCHEMIC STROKE MODEL INCREASES THE REPROGRAMMING EFFICIENCY OF ISCHEMIA-ACTIVATED PERICYTES (I-PERICYTES) TO NEURAL PRECURSORS. AS A CONSEQUENCE OF ENHANCED CELLULAR REPROGRAMMING, CBPS436A MICE SHOW AN INCREASED TRANSIENT POPULATION OF LOCALLY DERIVED NEURAL PRECURSORS AFTER STROKE, WHILE DISPLAYING A REDUCED NUMBER OF I-PERICYTES, IMPAIRED VASCULAR REMODELING, AND PERTURBED MOTOR RECOVERY DURING THE CHRONIC PHASE OF STROKE. TOGETHER, THIS STUDY ELUCIDATES THE ROLE OF THE APKC-CBP PATHWAY IN MODULATING NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY FOLLOWING FOCAL ISCHEMIC STROKE. 2017