1 3386 155 HOMEOSTATIC TISSUE RESPONSES IN SKIN BIOPSIES FROM NOMID PATIENTS WITH CONSTITUTIVE OVERPRODUCTION OF IL-1BETA. THE AUTOINFLAMMATORY DISORDER, NEONATAL-ONSET MULTISYSTEM INFLAMMATORY DISEASE (NOMID) IS THE MOST SEVERE PHENOTYPE OF DISORDERS CAUSED BY MUTATIONS IN CIAS1 THAT RESULT IN INCREASED PRODUCTION AND SECRETION OF ACTIVE IL-1BETA. NOMID PATIENTS PRESENT WITH SYSTEMIC AND ORGAN-SPECIFIC INFLAMMATION OF THE SKIN, CENTRAL NERVOUS SYSTEM AND BONE, AND RESPOND DRAMATICALLY TO TREATMENT WITH IL-1 BLOCKING AGENTS. WE COMPARED THE CELLULAR INFILTRATES AND TRANSCRIPTOME OF SKIN BIOPSIES FROM PATIENTS WITH NOMID (N = 14) BEFORE TREATMENT (LESIONAL (LS) AND NON-LESIONAL (PRE-NL) SKIN) AND AFTER TREATMENT (POST-NL) WITH THE IL-1 BLOCKER ANAKINRA (RECOMBINANT IL-1 RECEPTOR ANTAGONIST, KINERET(R), SWEDISH ORPHAN BIOVITRUM AB, SOBI), TO NORMAL SKIN (N = 5) TO ASSESS TISSUE RESPONSES IN THE CONTEXT OF UNTREATED AND TREATED DISEASE. ABUNDANT NEUTROPHILS DISTINGUISH LS SKIN FROM PRE-NL AND POST-NL SKIN. CD11C(+) DERMAL DENDRITIC CELLS AND CD163(+) MACROPHAGES EXPRESSED ACTIVATED CASPASE-1 AND ARE A LIKELY SOURCE OF CUTANEOUS IL-1 PRODUCTION. TREATMENT WITH ANAKINRA LED TO THE DISAPPEARANCE OF NEUTROPHILS, BUT CD3(+) T CELLS AND HLA-DR(+) CELLS REMAINED ELEVATED. AMONG THE UPREGULATED GENES IL-6, IL-8, TNF, IL-17A, CCL20, AND THE NEUTROPHIL DEFENSINS DEFA1 AND DEFA3 WERE DIFFERENTIALLY REGULATED IN LS TISSUES (COMPARED TO NORMAL SKIN). IMPORTANT SIGNIFICANTLY DOWNREGULATED PATHWAYS IN LS SKIN INCLUDED IL-1R/TLR SIGNALING, TYPE I AND II CYTOKINE RECEPTOR SIGNALING, MITOCHONDRIAL DYSFUNCTION, AND ANTIGEN PRESENTATION. THE DIFFERENTIAL EXPRESSION AND REGULATION OF MICRORNAS AND PATHWAYS INVOLVED IN POST-TRANSCRIPTIONAL MODIFICATION WERE SUGGESTIVE OF EPIGENETIC MODIFICATION IN THE CHRONICALLY INFLAMED TISSUE. OVERALL, THE DYSREGULATED GENES AND PATHWAYS SUGGEST EXTENSIVE "ADAPTIVE" MECHANISMS TO CONTROL INFLAMMATION AND MAINTAIN TISSUE HOMEOSTASIS, LIKELY TRIGGERED BY CHRONIC IL-1 RELEASE IN THE SKIN OF PATIENTS WITH NOMID. 2012 2 1335 31 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 3 5153 28 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 4 3049 30 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 5 272 36 AGE-DEPENDENT DECREASE IN THE INDUCTION OF REGULATORY T CELLS IS ASSOCIATED WITH DECREASED EXPRESSION OF RALDH2 IN MESENTERIC LYMPH NODE DENDRITIC CELLS. A DECLINE IN IMMUNE FUNCTION WITH AGING HAS BEEN REPORTED. REGULATORY T CELL (TREG) INDUCTION IS KNOWN TO DECREASE WITH AGE, AND ELUCIDATING THE UNDERLYING MECHANISM IS IMPORTANT FOR PREVENTING AGE-RELATED DISEASES DUE TO AGE-RELATED CHRONIC INFLAMMATION. IN THE INTESTINE, DENDRITIC CELLS (DCS) PLAY AN IMPORTANT ROLE IN INDUCING TREGS SPECIFIC TO ORAL ANTIGENS, AND THEY EFFICIENTLY INDUCE TREGS VIA PRODUCTION OF RETINOIC ACID (RA), A VITAMIN A METABOLITE, CATALYZED BY THE ENZYME RETINALDEHYDE DEHYDROGENASE 2 (RALDH2). WE HAVE PREVIOUSLY REPORTED THAT IN THE MESENTERIC LYMPH NODE (MLN), A SECONDARY LYMPHOID TISSUE IN WHICH IMMUNE RESPONSES TO ORAL ANTIGENS ARE INDUCED, FOUR DC SUBSETS EXPRESS DIFFERENT LEVELS OF CD11B, CD103, AND PD-L1, AND WE HAVE REPORTED THAT THE CD11B(-)CD103(+)PD-L1(HIGH) SUBSET EXPRESSES THE HIGHEST LEVELS OF THE RALDH2 GENE AND INDUCES TREGS IN VITRO. WE EXAMINED TREG INDUCTION IN YOUNG AND AGED MICE USING A TREG INDUCTION MODEL BY ADMINISTERING A FOOD ANTIGEN, AND WE FOUND THAT ANTIGEN-SPECIFIC TREG INDUCTION WAS DECREASED IN AGED MICE. WE FURTHER INVESTIGATED THE MLN DCS, AND A SIGNIFICANT DECREASE IN RALDH2 GENE EXPRESSION WAS OBSERVED IN MLN DCS FROM AGED MICE. AS FACTORS, WE FOUND THAT THE PROPORTION OF THE CD11B(-)CD103(+)PD-L1(HIGH) SUBSET WAS DECREASED IN AGED MICE COMPARED WITH THAT IN YOUNG MICE AND THAT RALDH ENZYME ACTIVITY WAS DECREASED IN THE CD11B(-)CD103(+)PD-L1(HIGH) AND CD11B(+)CD103(+)PD-L1(HIGH) SUBSETS. FURTHERMORE, ANALYSIS OF THE METHYLATION OF THE RALDH2 GENE PROMOTER REGION REVEALED THAT CPG MOTIFS WERE MORE METHYLATED IN THE MLN DCS OF AGED MICE, SUGGESTING THAT RALDH2 EXPRESSION WAS SUPPRESSED BY EPIGENETIC CHANGES. FINALLY, WE FOUND THAT RA TREATMENT TENDED TO INCREASE TREG INDUCTION. THESE RESULTS SUGGEST THAT THE REGULATION OF RA PRODUCTION MAY BE INVOLVED IN THE AGE-RELATED DECREASE IN ANTIGEN-SPECIFIC TREG INDUCTION. 2020 6 6578 37 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 7 1121 23 COMPARISON OF EPIGENETIC PROFILES OF HUMAN ORAL EPITHELIAL CELLS FROM HIV-POSITIVE (ON HAART) AND HIV-NEGATIVE SUBJECTS. HIV-INFECTED SUBJECTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ARE SUSCEPTIBLE TO COMORBID MICROBIAL INFECTIONS IN THE ORAL CAVITY. WE OBSERVED THAT PRIMARY ORAL EPITHELIAL CELLS (POECS) ISOLATED FROM HIV+ SUBJECTS ON HAART GROW MORE SLOWLY AND ARE LESS INNATE IMMUNE RESPONSIVE TO MICROBIAL CHALLENGE WHEN COMPARED WITH POECS FROM NORMAL SUBJECTS. THESE ABERRANT CELLS ALSO DEMONSTRATE EPIGENETIC DIFFERENCES THAT INCLUDE REDUCTION IN HISTONE DEACETYLASE 1 (HDAC-1) LEVELS AND REDUCED TOTAL DNA METHYLTRANSFERASE (DNMT) ACTIVITY SPECIFIC TO ENZYMES DNMT1 AND DNMT3A. THE DNMT ACTIVITY CORRELATES WELL WITH GLOBAL DNA METHYLATION, INDICATING THAT ABERRANT DNMT ACTIVITY IN HIV+ (ON HAART) POECS LEADS TO AN ABERRANTLY METHYLATED EPITHELIAL CELL PHENOTYPE. OVERALL, OUR RESULTS LEAD US TO HYPOTHESIZE THAT, IN PATIENTS WITH CHRONIC HIV INFECTION ON HAART, EPIGENETIC CHANGES IN KEY GENES RESULT IN INCREASED VULNERABILITY TO MICROBIAL INFECTION IN THE ORAL CAVITY. 2013 8 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 9 984 44 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 10 662 29 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 5009 30 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 12 460 29 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE. 2021 13 136 26 ABERRANT DNA HYPERMETHYLATION PATTERNS LEAD TO TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS OF MICE. OVEREXPOSURE OF THE HUMAN SKIN TO SOLAR ULTRAVIOLET (UV) RADIATION IS THE MAJOR ETIOLOGIC FACTOR FOR DEVELOPMENT OF SKIN CANCERS. HERE, WE REPORT THE RESULTS OF EPIGENETIC MODIFICATIONS IN UV-EXPOSED SKIN AND SKIN TUMORS IN A SYSTEMATIC MANNER. THE SKIN AND TUMOR SAMPLES WERE COLLECTED AFTER CHRONIC EXPOSURE OF THE SKIN OF SKH-1 HAIRLESS MICE TO UVB RADIATION USING A WELL-ESTABLISHED PHOTOCARCINOGENESIS PROTOCOL. WE FOUND A DISTINCT DNA HYPERMETHYLATION PATTERN IN THE UVB-EXPOSED EPIDERMAL SKIN AND UVB-INDUCED SKIN TUMORS THAT WAS ASSOCIATED WITH THE ELEVATED EXPRESSION AND ACTIVITY OF THE DNA METHYLTRANSFERASES (DNMT) 1, DNMT3A AND DNMT3B. TO EXPLORE THE ROLE OF HYPERMETHYLATION IN SKIN PHOTOCARCINOGENESIS, WE FOCUSED ON THE P16(INK4A) AND RASSF1A TUMOR SUPPRESSOR GENES, WHICH ARE TRANSCRIPTIONALLY SILENCED ON METHYLATION. WE ESTABLISHED THAT THE SILENCING OF THESE GENES IN UVB-EXPOSED EPIDERMIS AND UVB-INDUCED SKIN TUMORS IS ASSOCIATED WITH A NETWORK OF EPIGENETIC MODIFICATIONS, INCLUDING HYPOACETYLATION OF HISTONE H3 AND H4 AND INCREASED HISTONE DEACETYLATION, AS WELL AS RECRUITMENT OF METHYL-BINDING PROTEINS, INCLUDING MECP2 AND MBD1, TO THE METHYLATED CPGS. HIGHER LEVELS OF DNA METHYLATION AND DNMT ACTIVITY IN HUMAN SQUAMOUS CELL CARCINOMA SPECIMENS THAN IN NORMAL HUMAN SKIN SUGGEST THAT THE DATA ARE RELEVANT CLINICALLY. OUR DATA INDICATE FOR THE FIRST TIME THAT UVB-INDUCED DNA HYPERMETHYLATION, ENHANCED DNMT ACTIVITY AND HISTONE MODIFICATIONS OCCUR IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS AND SUGGEST THAT THESE EVENTS ARE INVOLVED IN THE SILENCING OF TUMOR SUPPRESSOR GENES AND IN SKIN TUMOR DEVELOPMENT. 2011 14 3198 24 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 3718 28 INHIBITION OF BCL6B PROMOTES GASTRIC CANCER BY AMPLIFYING INFLAMMATION IN MICE. BACKGROUND: CHRONIC GASTRITIS HAS BEEN DEMONSTRATED TO BE A KEY CAUSE OF GASTRIC CANCER (GC), AND CONTROL OF GASTRIC INFLAMMATION IS REGARDED AS AN EFFECTIVE TREATMENT FOR THE CLINICAL PREVENTION OF GASTRIC CARCINOGENESIS. HOWEVER, THERE REMAINS AN UNMET NEED TO IDENTIFY THE DOMINANT REGULATORS OF GASTRIC ONCOGENESIS-ASSOCIATED INFLAMMATION IN VIVO. METHODS: THE MOUSE MODEL FOR THE STUDY OF INFLAMMATION-ASSOCIATED GC WAS INDUCED BY BENZO[A]PYRENE (BAP) INTRAGASTRIC ADMINISTRATION IN BCL6B(-/-) AND WILDTYPE MICE ON A C57BL/6 BACKGROUND. 5-AZA-2'-DEOXYCYTIDINE (5-AZA), THE DEMETHYLATION DRUG, WAS INTRAPERITONEALLY INJECTED TO RESTORE BCL6B EXPRESSION. HUMAN GC TISSUE ARRAY WAS USED TO ANALYSE PATIENT SURVIVAL BASED ON BCL6B AND CD3 PROTEIN EXPRESSION. RESULTS: BCL6B WAS GRADUALLY DOWNREGULATED BY ITS OWN PROMOTER HYPERMETHYLATION IN PARALLEL TO AN INCREASING INFLAMMATORY RESPONSE DURING THE PROGRESSION OF BAP-INDUCED GASTRIC CARCINOGENESIS IN MICE. MOREOVER, KNOCKOUT OF BCL6B DRAMATICALLY WORSENED THE SEVERITY OF GASTRIC CANCER AND AGGRAVATED THE INFLAMMATORY RESPONSE IN THE BAP-INDUCED MICE GC MODEL. RE-ACTIVATION OF BCL6B BY 5-AZA IMPEDED INFLAMMATORY AMPLIFICATION AND BAP-INDUCED GC DEVELOPMENT, PROLONGING SURVIVAL TIME IN WILDTYPE MICE, WHEREAS NO NOTABLE CURATIVE EFFECT OCCURRED IN BCL6B(-/-) MICE WITH 5-AZA TREATMENT. FINALLY, SIGNIFICANT NEGATIVE CORRELATIONS WERE DETECTED BETWEEN THE MRNA LEVELS OF BCL6B AND INFLAMMATORY CYTOKINES IN HUMAN GC TISSUES; PATIENTS HARBOURING BCL6B-NEGETIVE AND SEVERE-INFLAMMATION GC TUMOURS WERE FOUND TO EXHIBIT THE SHORTEST SURVIVAL TIME. CONCLUSIONS: EPIGENETIC INACTIVATION OF BCL6B PROMOTES GASTRIC CANCER THROUGH AMPLIFICATION OF THE GASTRIC INFLAMMATORY RESPONSE IN VIVO AND OFFERS A NEW APPROACH FOR GC TREATMENT AND REGENERATIVE MEDICINE. 2019 16 3390 37 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 17 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 18 1334 27 DEREGULATION OF AIOLOS EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE NEOPLASTIC B CELLS THAT ARE RESISTANT TO APOPTOSIS. AIOLOS, A MEMBER OF THE IKAROS FAMILY OF ZINC-FINGER TRANSCRIPTION FACTORS, PLAYS AN IMPORTANT ROLE IN THE CONTROL OF MATURE B LYMPHOCYTE DIFFERENTIATION AND MATURATION. IN THIS STUDY, WE SHOWED THAT AIOLOS EXPRESSION IS UP-REGULATED IN B-CLL CELLS. THIS OVEREXPRESSION DOES NOT IMPLICATE ISOFORM IMBALANCE OR DISTURB AIOLOS SUBCELLULAR LOCALIZATION. THE CHROMATIN STATUS AT THE AIOLOS PROMOTER IN CLL IS DEFINED BY THE DEMETHYLATION OF DNA AND AN ENRICHMENT OF EUCHROMATIN ASSOCIATED HISTONE MARKERS, SUCH AS THE DIMETHYLATION OF THE LYSINE 4 ON HISTONE H3. THESE EPIGENETIC MODIFICATIONS SHOULD ALLOW ITS UPSTREAM EFFECTORS, SUCH AS NUCLEAR FACTOR-KAPPAB, CONSTITUTIVELY ACTIVATED IN CLL, TO GAIN ACCESS TO PROMOTER, RESULTING UP-REGULATION OF AIOLOS. TO DETERMINE THE CONSEQUENCES OF AIOLOS DEREGULATION IN CLL, WE ANALYZED THE EFFECTS OF AIOLOS OVEREXPRESSION OR DOWN-REGULATION ON APOPTOSIS. AIOLOS IS INVOLVED IN CELL SURVIVAL BY REGULATING THE EXPRESSION OF SOME BCL-2 FAMILY MEMBERS. OUR RESULTS STRONGLY SUGGEST THAT AIOLOS DEREGULATION BY EPIGENETIC MODIFICATIONS MAY BE A HALLMARK OF CLL. 2011 19 3074 27 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 20 197 32 ACINAR ATP8B1/LPC PATHWAY PROMOTES MACROPHAGE EFFEROCYTOSIS AND CLEARANCE OF INFLAMMATION DURING CHRONIC PANCREATITIS DEVELOPMENT. NONINFLAMMATORY CLEARANCE OF DYING CELLS BY PROFESSIONAL PHAGOCYTES, TERMED EFFEROCYTOSIS, IS FUNDAMENTAL IN BOTH HOMEOSTASIS AND INFLAMMATORY FIBROSIS DISEASE BUT HAS NOT BEEN CONFIRMED TO OCCUR IN CHRONIC PANCREATITIS (CP). HERE, WE INVESTIGATED WHETHER EFFEROCYTOSIS CONSTITUTES A NOVEL REGULATORY TARGET IN CP AND ITS MECHANISMS. PRSS1 TRANSGENIC (PRSS1(TG)) MICE WERE TREATED WITH CAERULEIN TO MIMIC CP DEVELOPMENT. PHOSPHOLIPID METABOLITE PROFILING AND EPIGENETIC ASSAYS WERE PERFORMED WITH PRSS1(TG) CP MODELS. THE POTENTIAL FUNCTIONS OF ATP8B1 IN CP MODEL WERE CLARIFIED USING ATP8B1-OVEREXPRESSING ADENO-ASSOCIATED VIRUS, IMMUNOFLUORESCENCE, ENZYME-LINKED IMMUNOSORBENT ASSAY(ELISA), AND LIPID METABOLOMIC APPROACHES. ATAC-SEQ COMBINED WITH RNA-SEQ WAS THEN USED TO IDENTIFY TRANSCRIPTION FACTORS BINDING TO THE ATP8B1 PROMOTER, AND CHIP-QPCR AND LUCIFERASE ASSAYS WERE USED TO CONFIRM THAT THE IDENTIFIED TRANSCRIPTION FACTOR BOUND TO THE ATP8B1 PROMOTER, AND TO IDENTIFY THE SPECIFIC BINDING SITE. FLOW CYTOMETRY WAS PERFORMED TO ANALYZE THE PROPORTION OF PANCREATIC MACROPHAGES. DECREASED EFFEROCYTOSIS WITH AGGRAVATED INFLAMMATION WAS IDENTIFIED IN CP. THE LYSOPHOSPHATIDYLCHOLINE (LPC) PATHWAY WAS THE MOST OBVIOUSLY DYSREGULATED PHOSPHOLIPID PATHWAY, AND LPC AND ATP8B1 EXPRESSION GRADUALLY DECREASED DURING CP DEVELOPMENT. H3K27ME3 CHIP-SEQ SHOWED THAT INCREASED ATP8B1 PROMOTER METHYLATION LED TO TRANSCRIPTIONAL INHIBITION. ATP8B1 COMPLEMENTATION SUBSTANTIALLY INCREASED THE LPC CONCENTRATION AND IMPROVED CP OUTCOMES. BHLHA15 WAS IDENTIFIED AS A TRANSCRIPTION FACTOR THAT BINDS TO THE ATP8B1 PROMOTER AND REGULATES PHOSPHOLIPID METABOLISM. OUR STUDY INDICATES THAT THE ACINAR ATP8B1/LPC PATHWAY ACTS AS AN IMPORTANT "FIND-ME" SIGNAL FOR MACROPHAGES AND PLAYS A PROTECTIVE ROLE IN CP, WITH ATP8B1 TRANSCRIPTION PROMOTED BY THE ACINAR CELL-SPECIFIC TRANSCRIPTION FACTOR BHLHA15. BHLHA15, ATP8B1, AND LPC COULD BE CLINICALLY TRANSLATED INTO VALUABLE THERAPEUTIC TARGETS TO OVERCOME THE LIMITATIONS OF CURRENT CP THERAPIES. 2022