1 3875 122 KDM2A DEFICIENCY IN MACROPHAGES ENHANCES THERMOGENESIS TO PROTECT MICE AGAINST HFD-INDUCED OBESITY BY ENHANCING H3K36ME2 AT THE PPARG LOCUS. KDM2A CATALYZES H3K36ME2 DEMETHYLATION TO PLAY AN INTRIGUING EPIGENETIC REGULATORY ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HEREIN WE FOUND THAT MYELOID-SPECIFIC KNOCKOUT OF KDM2A (LYSM-CRE-KDM2A(F/F), KDM2A(-/-)) PROMOTED MACROPHAGE M2 PROGRAM BY REPROGRAMING METABOLIC HOMEOSTASIS THROUGH ENHANCING FATTY ACID UPTAKE AND LIPOLYSIS. KDM2A(-/-) INCREASED H3K36ME2 LEVELS AT THE PPARG LOCUS ALONG WITH AUGMENTED CHROMATIN ACCESSIBILITY AND STAT6 RECRUITMENT, WHICH RENDERED MACROPHAGES WITH PREFERENTIAL M2 POLARIZATION. THEREFORE, THE KDM2A(-/-) MICE WERE HIGHLY PROTECTED FROM HIGH-FAT DIET (HFD)-INDUCED OBESITY, INSULIN RESISTANCE, AND HEPATIC STEATOSIS, AND FEATURED BY THE REDUCED ACCUMULATION OF ADIPOSE TISSUE MACROPHAGES AND REPRESSED CHRONIC INFLAMMATION FOLLOWING HFD CHALLENGE. PARTICULARLY, KDM2A(-/-) MACROPHAGES PROVIDED A MICROENVIRONMENT IN FAVOR OF THERMOGENESIS. UPON HFD OR COLD CHALLENGE, THE KDM2A(-/-) MICE MANIFESTED HIGHER CAPACITY FOR INDUCING ADIPOSE BROWNING AND BEIGING TO PROMOTE ENERGY EXPENDITURE. COLLECTIVELY, OUR FINDINGS DEMONSTRATE THE IMPORTANCE OF KDM2A-MEDIATED H3K36 DEMETHYLATION IN ORCHESTRATING MACROPHAGE POLARIZATION, PROVIDING NOVEL INSIGHT THAT TARGETING KDM2A IN MACROPHAGES COULD BE A VIABLE THERAPEUTIC APPROACH AGAINST OBESITY AND INSULIN RESISTANCE. 2021 2 5009 27 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 3 5332 36 PYRUVATE DEHYDROGENASE KINASE 1 AND 2 DEFICIENCY REDUCES HIGH-FAT DIET-INDUCED HYPERTROPHIC OBESITY AND INHIBITS THE DIFFERENTIATION OF PREADIPOCYTES INTO MATURE ADIPOCYTES. OBESITY IS NOW RECOGNIZED AS A DISEASE. THIS STUDY REVEALED A NOVEL ROLE FOR PYRUVATE DEHYDROGENASE KINASE (PDK) IN DIET-INDUCED HYPERTROPHIC OBESITY. MICE WITH GLOBAL OR ADIPOSE TISSUE-SPECIFIC PDK2 DEFICIENCY WERE PROTECTED AGAINST DIET-INDUCED OBESITY. THE WEIGHT OF ADIPOSE TISSUES AND THE SIZE OF ADIPOCYTES WERE REDUCED. ADIPOCYTE-SPECIFIC PDK2 DEFICIENCY SLIGHTLY INCREASED INSULIN SENSITIVITY IN HFD-FED MICE. IN STUDIES WITH 3T3-L1 PREADIPOCYTES, PDK2 AND PDK1 EXPRESSION WAS STRONGLY INCREASED DURING ADIPOGENESIS. EVIDENCE WAS FOUND FOR EPIGENETIC INDUCTION OF BOTH PDK1 AND PDK2. GAIN- AND LOSS-OF-FUNCTION STUDIES WITH 3T3-L1 CELLS REVEALED A CRITICAL ROLE FOR PDK1/2 IN ADIPOCYTE DIFFERENTIATION AND LIPID ACCUMULATION. PDK1/2 INDUCTION DURING DIFFERENTIATION WAS ALSO ACCOMPANIED BY INCREASED EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF1ALPHA) AND ENHANCED LACTATE PRODUCTION, BOTH OF WHICH WERE ABSENT IN THE CONTEXT OF PDK1/2 DEFICIENCY. EXOGENOUS LACTATE SUPPLEMENTATION INCREASED THE STABILITY OF HIF1ALPHA AND PROMOTED ADIPOGENESIS. PDK1/2 OVEREXPRESSION-MEDIATED ADIPOGENESIS WAS ABOLISHED BY HIF1ALPHA INHIBITION, SUGGESTING A ROLE FOR THE PDK-LACTATE-HIF1ALPHA AXIS DURING ADIPOGENESIS. IN HUMAN ADIPOSE TISSUE, THE EXPRESSION OF PDK1/2 WAS POSITIVELY CORRELATED WITH THAT OF THE ADIPOGENIC MARKER PPARGAMMA AND INVERSELY CORRELATED WITH OBESITY. SIMILARLY, PDK1/2 EXPRESSION IN MOUSE ADIPOSE TISSUE WAS DECREASED BY CHRONIC HIGH-FAT DIET FEEDING. WE CONCLUDE THAT PDK1 AND 2 ARE NOVEL REGULATORS OF ADIPOGENESIS THAT PLAY CRITICAL ROLES IN OBESITY. 2021 4 6578 25 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 5 3237 40 HEPATIC COX-2 EXPRESSION PROTECTS MICE FROM AN ALCOHOL-HIGH FAT DIET-INDUCED METABOLIC DISORDER BY INVOLVING PROTEIN ACETYLATION RELATED ENERGY METABOLISM. PURPOSE: A DIET HIGH IN FAT AND ETHANOL OFTEN RESULTS IN CHRONIC METABOLIC DISORDER, HEPATIC STEATOSIS, AND LIVER INFLAMMATION. CONSTITUTIVE HEPATIC CYCLOOXYGENASE-2 (COX-2) EXPRESSION COULD PROTECT FROM HIGH FAT-INDUCED METABOLISM DISTURBANCE IN A MURINE MODEL. IN THIS STUDY, WE EXPLORED THE INFLUENCE OF HCOX-2 TRANSGENIC [TG] TO HIGH FAT WITH ETHANOL-INDUCED METABOLIC DISORDER AND LIVER INJURY USING A MOUSE ANIMAL MODEL. METHODS: 12-WEEK-OLD MALE HEPATIC HCOX-2 TRANSGENIC (TG) OR WILD TYPE MICE (WT) WERE FED EITHER A HIGH FAT AND ETHANOL LIQUID DIET (HF+ETH) OR A REGULAR CONTROL DIET (RCD) FOR 5 WEEKS (FOUR GROUPS: RCD/WT, RCD/TG; HF+ETH/TG, HF+ETH/WT). WE ASSESSED METABOLIC BIOMARKERS, CYTOKINE PROFILES, HISTOMORPHOLOGY, AND GENE EXPRESSION TO STUDY THE IMPACT OF PERSISTENT HEPATIC COX-2 EXPRESSION ON DIET-INDUCED LIVER INJURY. RESULTS: IN THE HF+ETH DIET, CONSTITUTIVELY HEPATIC HUMAN COX-2 EXPRESSION PROTECTS MICE FROM BODY WEIGHT GAIN AND WHITE ADIPOSE TISSUE ACCUMULATION, ACCOMPANIED BY IMPROVED IPGTT RESPONSE, SERUM TRIGLYCERIDE/CHOLESTEROL LEVELS, AND LOWER LEVELS OF SERUM AND LIVER INFLAMMATORY CYTOKINES. HISTOLOGICALLY, HCOX-2 MICE SHOWED DECREASED HEPATIC LIPID DROPLETS ACCUMULATION, DECREASED HEPATOCYTE BALLOONING, AND IMPROVED STEATOSIS SCORES. HEPATIC HCOX-2 OVEREXPRESSION ENHANCED AKT INSULIN SIGNALING AND INCREASED FATTY ACID SYNTHESIS IN BOTH RCD AND HF+ETH DIET GROUPS. THE ANTI-LIPOGENIC EFFECT OF HCOX-2 TG IN THE HF+ETH DIET ANIMALS WAS MEDIATED BY INCREASING LIPID DISPOSAL THROUGH ENHANCED BETA-OXIDATION VIA ELEVATIONS IN THE EXPRESSION OF PPARALPHA AND PPARGAMMA, AND INCREASED HEPATIC AUTOPHAGY AS ASSESSED BY THE RATIO OF AUTOPHAGY MARKERS LC3 II/I IN HEPATIC TISSUE. VARIOUS PROTEIN ACETYLATION PATHWAY COMPONENTS, INCLUDING HAT, HDAC1, SIRT1, AND SNAIL1, WERE MODULATED IN HCOX-2 TG MICE IN EITHER RCD OR HF+ETH DIET. CONCLUSIONS: HEPATIC HUMAN COX-2 EXPRESSION PROTECTED MICE FROM THE METABOLIC DISORDER AND LIVER INJURY INDUCED BY A HIGH FAT AND ETHANOL DIET BY ENHANCING HEPATIC LIPID EXPENDITURE. EPIGENETIC REPROGRAMMING OF DIVERSE METABOLIC GENES MIGHT BE INVOLVED IN THE ANTI-LIPOGENIC EFFECT OF COX-2. 2021 6 3327 28 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 7 662 25 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 8 3941 30 LNCRNA DRAIR IS DOWNREGULATED IN DIABETIC MONOCYTES AND MODULATES THE INFLAMMATORY PHENOTYPE VIA EPIGENETIC MECHANISMS. LONG NONCODING RNAS (LNCRNAS) ARE INCREASINGLY IMPLICATED IN THE PATHOLOGY OF DIABETIC COMPLICATIONS. HERE, WE EXAMINED THE ROLE OF LNCRNAS IN MONOCYTE DYSFUNCTION AND INFLAMMATION ASSOCIATED WITH HUMAN TYPE 2 DIABETES MELLITUS (T2D). RNA SEQUENCING ANALYSIS OF CD14+ MONOCYTES FROM PATIENTS WITH T2D VERSUS HEALTHY CONTROLS REVEALED DOWNREGULATION OF ANTIINFLAMMATORY AND ANTIPROLIFERATIVE GENES, ALONG WITH SEVERAL LNCRNAS, INCLUDING A POTENTIALLY NOVEL DIVERGENT LNCRNA DIABETES REGULATED ANTIINFLAMMATORY RNA (DRAIR) AND ITS NEARBY GENE CPEB2. HIGH GLUCOSE AND PALMITIC ACID DOWNREGULATED DRAIR IN CULTURED CD14+ MONOCYTES, WHEREAS ANTIINFLAMMATORY CYTOKINES AND MONOCYTE-TO-MACROPHAGE DIFFERENTIATION UPREGULATED DRAIR VIA KLF4 TRANSCRIPTION FACTOR. DRAIR OVEREXPRESSION INCREASED ANTIINFLAMMATORY AND MACROPHAGE DIFFERENTIATION GENES BUT INHIBITED PROINFLAMMATORY GENES. CONVERSELY, DRAIR KNOCKDOWN ATTENUATED ANTIINFLAMMATORY GENES, PROMOTED INFLAMMATORY RESPONSES, AND INHIBITED PHAGOCYTOSIS. DRAIR REGULATED TARGET GENE EXPRESSION THROUGH INTERACTION WITH CHROMATIN, AS WELL AS INHIBITION OF THE REPRESSIVE EPIGENETIC MARK H3K9ME2 AND ITS CORRESPONDING METHYLTRANSFERASE G9A. MOUSE ORTHOLOGOUS DRAIR AND CPEB2 WERE ALSO DOWNREGULATED IN PERITONEAL MACROPHAGES FROM T2D DB/DB MICE, AND DRAIR KNOCKDOWN IN NONDIABETIC MICE ENHANCED PROINFLAMMATORY GENES IN MACROPHAGES. THUS, DRAIR MODULATES THE INFLAMMATORY PHENOTYPE OF MONOCYTES/MACROPHAGES VIA EPIGENETIC MECHANISMS, AND ITS DOWNREGULATION IN T2D MAY PROMOTE CHRONIC INFLAMMATION. AUGMENTATION OF ENDOGENOUS LNCRNAS LIKE DRAIR COULD SERVE AS NOVEL ANTIINFLAMMATORY THERAPIES FOR DIABETIC COMPLICATIONS. 2021 9 5153 23 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 10 3778 38 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 11 6385 34 THE ROLE OF PROMYELOCYTIC LEUKEMIA PROTEIN IN STEATOSIS-ASSOCIATED HEPATIC TUMORS RELATED TO CHRONIC HEPATITIS B VIRUS INFECTION. THE PERSISTENCE OF HEPATITIS B SURFACE ANTIGEN (HBSAG) IS A RISK FACTOR FOR THE DEVELOPMENT OF STEATOSIS-ASSOCIATED TUMORS IN CHRONIC HEPATITIS B VIRUS (HBV) INFECTION, YET LITTLE IS KNOWN ABOUT THE METABOLIC LINK WITH THIS FACTOR. WE CORRELATED HBV-RELATED PATHOGENESIS IN GENETICALLY ENGINEERED MICE AND HUMAN CARRIERS WITH METABOLIC PROTEOMICS AND LIPOGENIC GENE EXPRESSION PROFILES. THE IMMUNOHISTOCHEMISTRY SHOWED THAT THE PROMYELOCYTIC LEUKEMIA PROTEIN (PML, A TUMOR SUPPRESSOR INVOLVED IN GENOME MAINTENANCE AND FATTY ACID OXIDATION), BEING INVERSELY INFLUENCED BY THE DYNAMIC HBSAG LEVELS FROM ACUTE PHASE TO SEROCLEARANCE, APPEARED AS A LIPO-METABOLIC SWITCH LINKING HBSAG-INDUCED STEATOSIS (LIPOGENESIS) TO HBSAG-LOST FAT-BURNING HEPATOCARCINOGENESIS (LIPOLYSIS). KNOCKDOWN OF PML IN HBSAG-TRANSGENIC MICE PREDISPOSED TO OBESITY AND DROVE EARLY STEATOSIS-SPECIFIC LIVER TUMORIGENESIS. PROTEOME ANALYSIS REVEALED THAT THE SIGNALING PATHWAYS CORRESPONDING TO ENERGY METABOLISM AND ITS REGULATORS WERE FREQUENTLY ALTERED BY SUPPRESSION OR DEPLETION OF PML IN THE HBSAG-TRANSGENIC MICE, MAINLY INCLUDING OXIDATIVE PHOSPHORYLATION AND FATTY ACID METABOLISM. EXPRESSION PROFILING FURTHER IDENTIFIED UPREGULATION OF STEAROYL-COA DESATURASE 1 (SCD1) AND EPIGENETIC METHYLATION OF NDUFA13 IN THE MITOCHONDRIAL RESPIRATORY CHAIN AND THE CELL CYCLE INHIBITOR CDKN1C IN CONCORDANCE TO THE INCREASED SEVERITY OF LIPODYSTROPHY AND NEOPLASIA IN THE LIVERS OF HBSAG-TRANSGENIC MICE WITH PML INSUFFICIENCY. THE DEFECT IN LIPOLYSIS IN PML-DEFICIENT HBSAG-TRANSGENIC MICE MADE THE HBSAG-INDUCED ADIPOSE-LIKE LIVER TUMORS VULNERABLE TO SYNTHETIC LETHALITY FROM TOXIC SATURATED FAT ACCUMULATION WITH A SCD1 INHIBITOR. OUR FINDINGS PROVIDE MECHANISTIC INSIGHTS INTO THE EVOLUTION OF STEATOSIS-ASSOCIATED HEPATIC TUMORS DRIVEN BY RECIPROCAL INTERACTIONS OF HBSAG AND PML, AND A POTENTIAL UTILITY OF LIPID METABOLIC REPROGRAMMING AS A TREATMENT TARGET. 2018 12 5601 26 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD). 2019 13 1335 30 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 14 222 30 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 15 3096 33 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 16 669 22 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 17 3353 32 HISTONE DEMETHYLASES REGULATE ADIPOCYTE THERMOGENESIS. ADIPOCYTES PLAY A PIVOTAL ROLE IN THE REGULATION OF ENERGY METABOLISM. WHILE WHITE ADIPOCYTE STORES ENERGY, BROWN ADIPOCYTE DISSIPATES ENERGY BY PRODUCING HEAT. IN ADDITION, ANOTHER TYPE OF HEAT-PRODUCING ADIPOCYTE, BEIGE ADIPOCYTE, EMERGES IN WHITE ADIPOSE TISSUE IN RESPONSE TO CHRONIC COLDNESS. THIS PHENOTYPIC ADAPTATION TO THE COLD ENVIRONMENT IS CONSIDERED TO BE ATTRIBUTED TO THE EPIGENETIC MODIFICATIONS. HISTONE METHYLATION IS A CHEMICALLY STABLE EPIGENETIC MODIFICATION AND THUS A PROPER MECHANISM FOR LONG-LASTING CELLULAR MEMORY. SEVERAL HISTONE METHYL-MODIFYING ENZYMES SUCH AS EHMT1, JMJD1A, JMJD3, AND LSD1 ARE REPORTED TO BE INVOLVED IN THE BEIGE ADIPOSE CELL FATE DETERMINATION. AMONG THESE, A HISTONE DEMETHYLASE JMJD1A SENSES COLD ENVIRONMENT BY BEING PHOSPHORYLATED AT S265 IN RESPONSE TO BETA-ADRENERGIC RECEPTOR STIMULATION. PHOSPHORYLATED JMJD1A REGULATES BOTH ACUTE AND COLD THERMOGENESIS. UNDER ACUTE COLDNESS, PHOSPHORYLATED JMJD1A FORMS A COMPLEX WITH CHROMATIN REMODELER SWI/SNF AND DNA-BOUND PPARGAMMA, WHICH RECRUITS JMJD1A TO THE TARGET GENOMIC REGIONS IN BROWN ADIPOCYTE. THIS COMPLEX FORMATION, IN TURN, INDUCES THE EXPRESSION OF TARGET GENES BY BRINGING THE ENHANCER AND THE PROMOTER INTO CLOSE PROXIMITY. DURING CHRONIC COLDNESS, PHOSPHORYLATED JMJD1A REGULATES BEIGE ADIPOGENESIS THROUGH A TWO-STEP MECHANISM. IN THE FIRST STEP, PHOSPHORYLATED JMJD1A IS RECRUITED TO THE REGULATORY REGIONS OF TARGET GENES BY FORMING A COMPLEX WITH PRDM16, PGC1ALPHA, AND DNA-BOUND PPARGAMMA. IN THE SECOND STEP, JMJD1A DEMETHYLATES HISTONE H3K9ME2 AND INDUCES STABLE EXPRESSION OF BEIGE-SELECTIVE GENES. THE PHENOTYPIC ANALYSES OF JMJD1A-NULL MICE AND NON-PHOSPHORYLATED MUTANT S265A JMJD1A KNOCK-IN MICE INDICATE THAT JMJD1A IS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF OBESITY-RELATED DISEASES INCLUDING METABOLIC SYNDROME AND TYPE 2 DIABETES. 2018 18 984 29 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 19 26 25 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 20 5863 24 SUPPRESSION OF ALLERGIC ASTHMA BY LOSS OF FUNCTION OF MIZ1-MEDIATED TH1 SKEWING. ASTHMA IS THE MOST PREVALENT CHRONIC RESPIRATORY DISEASE WORLDWIDE. THERE IS CURRENTLY NO CURE, AND IT REMAINS AN IMPORTANT CAUSE OF MORBIDITY AND MORTALITY. HERE WE REPORT THAT LUNG-SPECIFIC LOSS OF FUNCTION OF THE TRANSCRIPTION FACTOR MIZ1 (C-MYC-INTERACTING ZINC FINGER PROTEIN-1) UPREGULATES THE PRO-T-HELPER CELL TYPE 1 CYTOKINE IL-12. UPREGULATION OF IL-12 IN TURN STIMULATES A TH1 RESPONSE, THEREBY COUNTERACTING T-HELPER CELL TYPE 2 RESPONSE AND PREVENTING THE ALLERGIC RESPONSE IN MOUSE MODELS OF HOUSE DUST MITE- AND OVA (OVALBUMIN)-INDUCED ASTHMA. USING TRANSGENIC MICE EXPRESSING CRE UNDER A CELL-SPECIFIC PROMOTER, WE DEMONSTRATE THAT MIZ1 ACTS IN LUNG EPITHELIAL CELLS AND DENDRITIC CELLS IN ASTHMA. CHROMATIN IMMUNOPRECIPITATION COUPLED WITH HIGH-THROUGHPUT DNA SEQUENCING OR QUANTITATIVE PCR REVEALS THE BINDING OF MIZ1 ON THE IL12 PROMOTER INDICATING DIRECT REPRESSION OF IL-12 BY MIZ1. IN ADDITION, HDAC1 (HISTONE DEACETYLASE 1) IS RECRUITED TO THE IL12 PROMOTER IN A MIZ1-DEPDENENT MANNER, SUGGESTING EPIGENETIC REPRESSION OF IL12 BY MIZ1. FURTHERMORE, MIZ1 IS UPREGULATED IN THE LUNGS OF ASTHMATIC MICE. OUR DATA TOGETHER SUGGEST THAT MIZ1 IS UPREGULATED DURING ASTHMA, WHICH IN TURN PROMOTES ASTHMA PATHOGENESIS BY PREVENTING TH1 SKEWING THROUGH THE TRANSCRIPTIONAL REPRESSION OF IL-12. 2022