1 6055 101 THE CXXC1 SUBUNIT OF THE TRITHORAX COMPLEX DIRECTS EPIGENETIC LICENSING OF CD4+ T CELL DIFFERENTIATION. DIFFERENT DYNAMICS OF GENE EXPRESSION ARE OBSERVED DURING CELL DIFFERENTIATION. IN T CELLS, GENES THAT ARE TURNED ON EARLY OR TURNED OFF AND STAY OFF HAVE BEEN THOROUGHLY STUDIED. HOWEVER, GENES THAT ARE INITIALLY TURNED OFF BUT THEN TURNED ON AGAIN AFTER STIMULATION HAS CEASED HAVE NOT BEEN DEFINED; THEY ARE OBVIOUSLY IMPORTANT, ESPECIALLY IN THE CONTEXT OF ACUTE VERSUS CHRONIC INFLAMMATION. USING THE TH1/TH2 DIFFERENTIATION PARADIGM, WE FOUND THAT THE CXXC1 SUBUNIT OF THE TRITHORAX COMPLEX DIRECTS TRANSCRIPTION OF GENES INITIALLY DOWN-REGULATED BY TCR STIMULATION BUT UP-REGULATED AGAIN IN A LATER PHASE. THE LATE UP-REGULATION OF THESE GENES WAS IMPAIRED EITHER BY PROLONGED TCR STIMULATION OR CXXC1 DEFICIENCY, WHICH LED TO DECREASED EXPRESSION OF TRIB3 AND KLF2 IN TH1 AND TH2 CELLS, RESPECTIVELY. LOSS OF CXXC1 RESULTED IN ENHANCED PATHOGENICITY IN ALLERGIC AIRWAY INFLAMMATION IN VIVO. THUS, CXXC1 PLAYS ESSENTIAL ROLES IN THE ESTABLISHMENT OF A PROPER CD4+ T CELL IMMUNE SYSTEM VIA EPIGENETIC CONTROL OF A SPECIFIC SET OF GENES. 2021 2 1763 31 EARLY TRANSCRIPTIONAL AND EPIGENETIC DIVERGENCE OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTION. DURING A MICROBIAL INFECTION, RESPONDING CD8+ T CELLS GIVE RISE TO EFFECTOR CELLS THAT PROVIDE ACUTE HOST DEFENSE AND MEMORY CELLS THAT PROVIDE SUSTAINED PROTECTION. AN ALTERNATIVE OUTCOME IS EXHAUSTION, A STATE OF T CELL DYSFUNCTION THAT OCCURS IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCER. ALTHOUGH IT IS EVIDENT THAT EXHAUSTED CD8+ T (TEX) CELLS ARE PHENOTYPICALLY AND MOLECULARLY DISTINCT FROM EFFECTOR AND MEMORY CD8+ T CELLS, THE FACTORS REGULATING THE EARLIEST EVENTS IN THE DIFFERENTIATION PROCESS OF TEX CELLS REMAIN INCOMPLETELY UNDERSTOOD. HERE, WE PERFORMED SINGLE-CELL RNA-SEQUENCING AND SINGLE-CELL ATAC-SEQUENCING OF CD8+ T CELLS RESPONDING TO LCMV-ARMSTRONG (LCMV-ARM) OR LCMV-CLONE 13 (LCMV-CL13), WHICH RESULT IN ACUTE OR CHRONIC INFECTIONS, RESPECTIVELY. COMPARED TO CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-ARM (DIV1ARM) CELLS, CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-CL13 (DIV1CL13) EXPRESSED HIGHER LEVELS OF GENES ENCODING TRANSCRIPTION FACTORS PREVIOUSLY ASSOCIATED WITH EXHAUSTION, ALONG WITH HIGHER LEVELS OF EZH2, THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COMPLEX, WHICH MEDIATES EPIGENETIC SILENCING. MODULATION OF EZH2 RESULTED IN ALTERED EXPRESSION OF EXHAUSTION-ASSOCIATED MOLECULES BY CD8+ T CELLS RESPONDING TO LCMV-CL13, THOUGH THE SPECIFIC CELLULAR AND INFECTIOUS CONTEXTS, RATHER THAN SIMPLY THE LEVEL OF EZH2 EXPRESSION, LIKELY DETERMINE THE EVENTUAL OUTCOME. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THE DIFFERENTIATION PATHS OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTIONS MAY DIVERGE EARLIER THAN PREVIOUSLY APPRECIATED. 2023 3 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 4 272 34 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 5 984 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 6 102 17 A REGULATORY ROLE FOR CHD2 IN MYELOPOIESIS. THE TRANSCRIPTIONAL PROGRAM THAT DICTATES HAEMATOPOIETIC CELL FATE AND DIFFERENTIATION REQUIRES AN EPIGENETIC REGULATORY AND MEMORY FUNCTION, PROVIDED BY A NETWORK OF EPIGENETIC FACTORS THAT REGULATE DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE. DISTURBED EPIGENETIC REGULATION CAUSES PERTURBATIONS IN THE BLOOD CELL DIFFERENTIATION PROGRAM THAT RESULTS IN VARIOUS TYPES OF HAEMATOPOIETIC DISORDERS. THUS, ACCURATE EPIGENETIC REGULATION IS ESSENTIAL FOR FUNCTIONAL HAEMATOPOIESIS. IN THIS STUDY, WE USED A CRISPR-CAS9 SCREENING APPROACH TO IDENTIFY NEW EPIGENETIC REGULATORS IN MYELOID DIFFERENTIATION. WE DESIGNED A CHROMATIN-UMI CRISPR GUIDE LIBRARY TARGETING 1092 EPIGENETIC REGULATORS. PHORBOL 12-MYRISTATE 13-ACETATE (PMA) TREATMENT OF THE CHRONIC MYELOID LEUKAEMIA CELL LINE K-562 WAS USED AS A MEGAKARYOCYTIC MYELOID DIFFERENTIATION MODEL. BOTH PREVIOUSLY DESCRIBED DEVELOPMENTAL EPIGENETIC REGULATORS AND NOVEL FACTORS WERE IDENTIFIED IN OUR SCREEN. IN THIS STUDY, WE VALIDATED AND CHARACTERIZED A ROLE FOR THE CHROMATIN REMODELLER CHD2 IN MYELOID PROLIFERATION AND MEGAKARYOCYTIC DIFFERENTIATION. 2020 7 4866 26 ORTHOGONAL CRISPR SCREENS TO IDENTIFY TRANSCRIPTIONAL AND EPIGENETIC REGULATORS OF HUMAN CD8 T CELL FUNCTION. THE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPIES IS STRONGLY ASSOCIATED WITH TRANSCRIPTIONAL AND EPIGENETIC STATE. THUS, TECHNOLOGIES TO DISCOVER REGULATORS OF T CELL GENE NETWORKS AND THEIR CORRESPONDING PHENOTYPES HAVE GREAT POTENTIAL TO IMPROVE THE EFFICACY OF T CELL THERAPIES. WE DEVELOPED POOLED CRISPR SCREENING APPROACHES WITH COMPACT EPIGENOME EDITORS TO SYSTEMATICALLY PROFILE THE EFFECTS OF ACTIVATION AND REPRESSION OF 120 TRANSCRIPTION FACTORS AND EPIGENETIC MODIFIERS ON HUMAN CD8+ T CELL STATE. THESE SCREENS NOMINATED KNOWN AND NOVEL REGULATORS OF T CELL PHENOTYPES WITH BATF3 EMERGING AS A HIGH CONFIDENCE GENE IN BOTH SCREENS. WE FOUND THAT BATF3 OVEREXPRESSION PROMOTED SPECIFIC FEATURES OF MEMORY T CELLS SUCH AS INCREASED IL7R EXPRESSION AND GLYCOLYTIC CAPACITY, WHILE ATTENUATING GENE PROGRAMS ASSOCIATED WITH CYTOTOXICITY, REGULATORY T CELL FUNCTION, AND T CELL EXHAUSTION. IN THE CONTEXT OF CHRONIC ANTIGEN STIMULATION, BATF3 OVEREXPRESSION COUNTERED PHENOTYPIC AND EPIGENETIC SIGNATURES OF T CELL EXHAUSTION. CAR T CELLS OVEREXPRESSING BATF3 SIGNIFICANTLY OUTPERFORMED CONTROL CAR T CELLS IN BOTH IN VITRO AND IN VIVO TUMOR MODELS. MOREOVER, WE FOUND THAT BATF3 PROGRAMMED A TRANSCRIPTIONAL PROFILE THAT CORRELATED WITH POSITIVE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPY. FINALLY, WE PERFORMED CRISPR KNOCKOUT SCREENS WITH AND WITHOUT BATF3 OVEREXPRESSION TO DEFINE CO-FACTORS AND DOWNSTREAM FACTORS OF BATF3, AS WELL AS OTHER THERAPEUTIC TARGETS. THESE SCREENS POINTED TO A MODEL WHERE BATF3 INTERACTS WITH JUNB AND IRF4 TO REGULATE GENE EXPRESSION AND ILLUMINATED SEVERAL OTHER NOVEL TARGETS FOR FURTHER INVESTIGATION. 2023 8 5433 20 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 6294 23 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 10 3390 23 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 11 5918 23 TARGETING BMI-1 IN B CELLS RESTORES EFFECTIVE HUMORAL IMMUNE RESPONSES AND CONTROLS CHRONIC VIRAL INFECTION. INEFFECTIVE ANTIBODY-MEDIATED RESPONSES ARE A KEY CHARACTERISTIC OF CHRONIC VIRAL INFECTION. HOWEVER, OUR UNDERSTANDING OF THE INTRINSIC MECHANISMS THAT DRIVE THIS DYSREGULATION ARE UNCLEAR. HERE, WE IDENTIFY THAT TARGETING THE EPIGENETIC MODIFIER BMI-1 IN MICE IMPROVES HUMORAL RESPONSES TO CHRONIC LYMPHOCYTIC CHORIOMENINGITIS VIRUS. BMI-1 WAS UPREGULATED BY GERMINAL CENTER B CELLS IN CHRONIC VIRAL INFECTION, CORRELATING WITH CHANGES TO THE ACCESSIBLE CHROMATIN LANDSCAPE, COMPARED TO ACUTE INFECTION. B CELL-INTRINSIC DELETION OF BMI1 ACCELERATED VIRAL CLEARANCE, REDUCED SPLENOMEGALY AND RESTORED SPLENIC ARCHITECTURE. DELETION OF BMI1 RESTORED C-MYC EXPRESSION IN B CELLS, CONCOMITANT WITH IMPROVED QUALITY OF ANTIBODY AND COUPLED WITH REDUCED ANTIBODY-SECRETING CELL NUMBERS. SPECIFICALLY, BMI-1-DEFICIENCY INDUCED ANTIBODY WITH INCREASED NEUTRALIZING CAPACITY AND ENHANCED ANTIBODY-DEPENDENT EFFECTOR FUNCTION. USING A SMALL MOLECULE INHIBITOR TO MURINE BMI-1, WE COULD DEPLETE ANTIBODY-SECRETING CELLS AND PROHIBIT DETRIMENTAL IMMUNE COMPLEX FORMATION IN VIVO. THIS STUDY DEFINES BMI-1 AS A CRUCIAL IMMUNE MODIFIER THAT CONTROLS ANTIBODY-MEDIATED RESPONSES IN CHRONIC INFECTION. 2022 12 2395 30 EPIGENETIC REPROGRAMMING IN MIST1(-/-) MICE PREDICTS THE MOLECULAR RESPONSE TO CERULEIN-INDUCED PANCREATITIS. GENE EXPRESSION IS AFFECTED BY MODIFICATIONS TO HISTONE CORE PROTEINS WITHIN CHROMATIN. CHANGES IN THESE MODIFICATIONS, OR EPIGENETIC REPROGRAMMING, CAN DICTATE CELL FATE AND PROMOTE SUSCEPTIBILITY TO DISEASE. THE GOAL OF THIS STUDY WAS TO DETERMINE THE EXTENT OF EPIGENETIC REPROGRAMMING IN RESPONSE TO CHRONIC STRESS THAT OCCURS FOLLOWING ABLATION OF MIST1 (MIST1(-/-) ), WHICH IS REPRESSED IN PANCREATIC DISEASE. CHROMATIN IMMUNOPRECIPITATION FOR TRIMETHYLATION OF LYSINE RESIDUE 4 ON HISTONE 3 (H3K4ME3) IN PURIFIED ACINAR CELLS FROM WILD TYPE AND MIST1(-/-) MICE WAS FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) OR CHIP-QPCR. H3K4ME3-ENRICHED GENES WERE ASSESSED FOR EXPRESSION BY QRT-PCR IN PANCREATIC TISSUE BEFORE AND AFTER INDUCTION OF CERULEIN-INDUCED PANCREATITIS. WHILE MOST OF H3K4ME3-ENRICHMENT IS RESTRICTED TO TRANSCRIPTIONAL START SITES, >25% OF ENRICHMENT SITES ARE FOUND WITHIN, DOWNSTREAM OR BETWEEN ANNOTATED GENES. LESS THAN 10% OF THESE SITES WERE ALTERED IN MIST1(-/-) ACINI, WITH MOST CHANGES IN H3K4ME3 ENRICHMENT NOT REFLECTING ALTERED GENE EXPRESSION. INGENUITY PATHWAY ANALYSIS OF GENES DIFFERENTIALLY-ENRICHED FOR H3K4ME3 REVEALED AN ASSOCIATION WITH PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA IN MIST1(-/-) TISSUE. MOST OF THESE GENES WERE NOT DIFFERENTIALLY EXPRESSED BUT SEVERAL WERE READILY INDUCED BY ACUTE EXPERIMENTAL PANCREATITIS, WITH SIGNIFICANTLY INCREASED EXPRESSION IN MIST1(-/-) TISSUE RELATIVE TO WILD TYPE MICE. WE SUGGEST THAT THE CHRONIC CELL STRESS OBSERVED IN THE ABSENCE OF MIST1 RESULTS IN EPIGENETIC REPROGRAMMING OF GENES INVOLVED IN PROMOTING PANCREATITIS TO A POISED STATE, THEREBY INCREASING THE SENSITIVITY TO EVENTS THAT PROMOTE DISEASE. 2014 13 3465 30 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019 14 3468 29 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA. 2012 15 3948 19 LNCRNA-CD160 DECREASES THE IMMUNITY OF CD8(+) T CELLS THROUGH EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS INFECTION. THE TRANSFER AND DEVELOPMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ASSOCIATED WITH THE T CELL IMMUNE RESPONSE, THEREFORE INVESTIGATING THE KEY REGULATORS OF CELL IMMUNE RESPONSE IS NEEDED TO IMPROVE CHRONIC HBV TREATMENT. BLOOD SAMPLES FROM PATIENTS WITH CHRONIC HBV INFECTION WERE USED TO CONFIRM THE CORRELATION BETWEEN HBV INFECTION STAGE AND CD160 RECEPTOR EXPRESSION LEVELS IN CD8(+) T CELLS, THE CD8(+) T CELLS ARE USED TO RESEARCH THE MECHANISM OF T CELL IMMUNE RESPONSE MODULATION, MOREOVER, C3H/HEN MICE WITH REDUCED CD160 EXPRESSION LEVELS WERE USED TO INVESTIGATE THE ASSOCIATION BETWEEN LONG NON-CODING (LNC)RNA-CD160 AND HBV INFECTION. LONG NON-CODING (LNC)RNA-CD160 AND HISTONE-MODIFICATION ENZYME GENE HISTONE DEACETYLASE 11 (HDAC11) EXPRESSION LEVELS WERE NEGATIVELY ASSOCIATED WITH CD160 EXPRESSION. LNCRNA-CD160 CAN INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA THROUGH HDAC11 RECRUITMENT AND BIND TO HDAC11 TO FORM A COMPLEX ON THE PROMOTERS OF IFN-GAMMA AND TNF-ALPHA. THE HDAC11, IFN-GAMMA AND TNF-ALPHA FORM A COMPLEX AND ENHANCE THE METHYLATION OF H3K9ME1, CHROMATIN CHANGES INTO THE HETEROCHROMATIN AND THE TRANSCRIPTION OF IFN-GAMMA AND TNF-ALPHA IS BLOCKED; MOREOVER, THE HDAC11/IFN-GAMMA/TNF-ALPHA COMPLEX CAN ALSO INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA IN CD160(-) CD8(+) T CELLS AND SUPPRESSES THE FUNCTION OF CD8(+) T CELLS. FURTHERMORE, SMALL INTERFERING RNA TARGETING LNCRNA-CD160 CAN BLOCK HBV INFECTION PROGRESSION. LNCRNA-CD160 ACTS AS AN IMMUNE SUPPRESSIVE FACTOR AND IS EXPRESSED AT A HIGH LEVEL IN PERIPHERAL BLOOD CD8(+) T CELLS OF HBV INFECTED PATIENTS. FURTHERMORE, HIGH EXPRESSION LEVELS OF LNCRNA-CD160 CAN CONTRIBUTE TO THE INHIBITION OF IFN-GAMMA AND TNF-ALPHA SECRETION IN CD8(+) T CELLS AND DECREASE THE IMMUNE RESPONSE OF CD8(+) T CELLS. THEREFORE, LNCRNA-CD160 MAY BECOME A NEW TARGET FOR IMMUNOTHERAPY OF CHRONIC HBV INFECTION IN THE FUTURE AND MAY PROVIDE A NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF HBV INFECTION. 2020 16 5688 26 SILENCING EFFECTS OF MUTANT RAS SIGNALLING ON TRANSCRIPTOMES. MUTATED GENES OF THE RAS FAMILY ENCODING SMALL GTP-BINDING PROTEINS DRIVE NUMEROUS CANCERS, INCLUDING PANCREATIC, COLON AND LUNG TUMORS. BESIDES THE NUMEROUS EFFECTS OF MUTANT RAS GENE EXPRESSION ON ABERRANT PROLIFERATION, TRANSFORMED PHENOTYPES, METABOLISM, AND THERAPY RESISTANCE, THE MOST STRIKING CONSEQUENCES OF CHRONIC RAS ACTIVATION ARE CHANGES OF THE GENETIC PROGRAM. BY PERFORMING SYSTEMATIC GENE EXPRESSION STUDIES IN CELLULAR MODELS THAT ALLOW COMPARISONS OF PRE-NEOPLASTIC WITH RAS-TRANSFORMED CELLS, WE AND OTHERS HAVE ESTIMATED THAT 7 PERCENT OR MORE OF ALL TRANSCRIPTS ARE ALTERED IN CONJUNCTION WITH THE EXPRESSION OF THE ONCOGENE. IN THIS CONTEXT, THE NUMBER OF UP-REGULATED TRANSCRIPTS APPROXIMATES THAT OF DOWN-REGULATED TRANSCRIPTS. WHILE UP-REGULATED TRANSCRIPTION FACTORS SUCH AS MYC, FOSL1, AND HMGA2 HAVE BEEN IDENTIFIED AND CHARACTERIZED AS RAS-RESPONSIVE DRIVERS OF THE ALTERED TRANSCRIPTOME, THE SUPPRESSED FACTORS HAVE BEEN LESS WELL STUDIED AS POTENTIAL REGULATORS OF THE GENETIC PROGRAM AND TRANSFORMED PHENOTYPE IN THE BREADTH OF THEIR OCCURRENCE. WE THEREFORE HAVE COLLECTED INFORMATION ON DOWNREGULATED RAS-RESPONSIVE FACTORS AND DISCUSS THEIR POTENTIAL ROLE AS TUMOR SUPPRESSORS THAT ARE LIKELY TO ANTAGONIZE ACTIVE CANCER DRIVERS. TO BETTER UNDERSTAND THE ACTIVE MECHANISMS THAT ENTAIL ANTI-RAS FUNCTION AND THOSE THAT LEAD TO LOSS OF TUMOR SUPPRESSOR ACTIVITY, WE FOCUS ON THE TUMOR SUPPRESSOR HREV107 (ALIAS PLAAT3 [PHOSPHOLIPASE A AND ACYLTRANSFERASE 3], PLA2G16 [PHOSPHOLIPASE A2, GROUP XVI] AND HRASLS3 [HRAS-LIKE SUPPRESSOR 3]). INACTIVATING HREV107 MUTATIONS IN TUMORS ARE EXTREMELY RARE, HENCE EPIGENETIC CAUSES MODULATED BY THE RAS PATHWAY ARE LIKELY TO LEAD TO DOWN-REGULATION AND LOSS OF FUNCTION. 2023 17 217 28 ACUTE EXERCISE INCREASES THE EXPRESSION OF KIR2DS4 BY PROMOTER DEMETHYLATION IN NK CELLS. POSITIVE EFFECTS OF EXERCISE ON CANCER PREVENTION AND PROGRESSION HAVE BEEN PROPOSED TO BE MEDIATED BY STIMULATING NATURAL KILLER (NK) CELLS. BECAUSE NK CELL RECEPTORS ARE REGULATED BY EPIGENETIC MODIFICATIONS, WE INVESTIGATED WHETHER ACUTE AEROBIC EXERCISE AND TRAINING CHANGE PROMOTER DNA METHYLATION AND GENE EXPRESSION OF THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1 GENE. SIXTEEN HEALTHY WOMEN (50-60 YEARS) PERFORMED A GRADED EXERCISE TEST (GXT) AND WERE RANDOMIZED INTO EITHER A PASSIVE CONTROL GROUP OR AN INTERVENTION GROUP PERFORMING A FOUR-WEEK ENDURANCE EXERCISE INTERVENTION. BLOOD SAMPLES (PRE-, POST-GXT AND POST-TRAINING) WERE USED FOR ISOLATION OF DNA/RNA OF NK CELLS TO ASSESS DNA PROMOTER METHYLATION BY TARGETED DEEP-AMPLICON SEQUENCING AND GENE EXPRESSION BY QRT-PCR. POTENTIAL CHANGES IN NK CELL SUBSETS WERE DETERMINED BY FLOW CYTOMETRY. ACUTE AND CHRONIC EXERCISE DID NOT PROVOKE SIGNIFICANT ALTERATIONS OF NK CELL PROPORTIONS. PROMOTER METHYLATION DECREASED AND GENE EXPRESSION INCREASED FOR KIR2DS4 AFTER ACUTE EXERCISE. A HIGH GENE EXPRESSION CORRELATED WITH A LOW METHYLATION OF CPGS THAT WERE ALTERED BY ACUTE EXERCISE. CHRONIC EXERCISE RESULTED IN A MINOR DECREASE OF DNA METHYLATION AND DID NOT ALTER GENE EXPRESSION. ACUTE EXERCISE PROVOKES EPIGENETIC MODIFICATIONS, AFFECTING THE BALANCE BETWEEN THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1, WITH POTENTIAL BENEFITS ON NK CELL FUNCTION. 2019 18 2340 32 EPIGENETIC REGULATION OF LEUKOCYTE INFLAMMATORY MEDIATOR PRODUCTION DICTATES STAPHYLOCOCCUS AUREUS CRANIOTOMY INFECTION OUTCOME. STAPHYLOCOCCUS AUREUS IS A COMMON CAUSE OF SURGICAL-SITE INFECTIONS, INCLUDING THOSE ARISING AFTER CRANIOTOMY, WHICH IS PERFORMED TO ACCESS THE BRAIN FOR THE TREATMENT OF TUMORS, EPILEPSY, OR HEMORRHAGE. CRANIOTOMY INFECTION IS CHARACTERIZED BY COMPLEX SPATIAL AND TEMPORAL DYNAMICS OF LEUKOCYTE RECRUITMENT AND MICROGLIAL ACTIVATION. WE RECENTLY IDENTIFIED UNIQUE TRANSCRIPTIONAL PROFILES OF THESE IMMUNE POPULATIONS DURING S. AUREUS CRANIOTOMY INFECTION. EPIGENETIC PROCESSES ALLOW RAPID AND REVERSIBLE CONTROL OVER GENE TRANSCRIPTION; HOWEVER, LITTLE IS KNOWN ABOUT HOW EPIGENETIC PATHWAYS INFLUENCE IMMUNITY TO LIVE S. AUREUS. AN EPIGENETIC COMPOUND LIBRARY SCREEN IDENTIFIED BROMODOMAIN AND EXTRATERMINAL DOMAIN-CONTAINING (BET) PROTEINS AND HISTONE DEACETYLASES (HDACS) AS CRITICAL FOR REGULATING TNF, IL-6, IL-10, AND CCL2 PRODUCTION BY PRIMARY MOUSE MICROGLIA, MACROPHAGES, NEUTROPHILS, AND GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN RESPONSE TO LIVE S. AUREUS. CLASS I HDACS (C1HDACS) WERE INCREASED IN THESE CELL TYPES IN VITRO AND IN VIVO DURING ACUTE DISEASE IN A MOUSE MODEL OF S. AUREUS CRANIOTOMY INFECTION. HOWEVER, SUBSTANTIAL REDUCTIONS IN C1HDACS WERE OBSERVED DURING CHRONIC INFECTION, HIGHLIGHTING TEMPORAL REGULATION AND THE IMPORTANCE OF THE TISSUE MICROENVIRONMENT FOR DICTATING C1HDAC EXPRESSION. MICROPARTICLE DELIVERY OF HDAC AND BET INHIBITORS IN VIVO CAUSED WIDESPREAD DECREASES IN INFLAMMATORY MEDIATOR PRODUCTION, WHICH SIGNIFICANTLY INCREASED BACTERIAL BURDEN IN THE BRAIN, GALEA, AND BONE FLAP. THESE FINDINGS IDENTIFY HISTONE ACETYLATION AS AN IMPORTANT MECHANISM FOR REGULATING CYTOKINE AND CHEMOKINE PRODUCTION ACROSS DIVERSE IMMUNE CELL LINEAGES THAT IS CRITICAL FOR BACTERIAL CONTAINMENT. ACCORDINGLY, ABERRANT EPIGENETIC REGULATION MAY BE IMPORTANT FOR PROMOTING S. AUREUS PERSISTENCE DURING CRANIOTOMY INFECTION. 2023 19 3762 23 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 20 662 23 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