1 2889 132 GAIN-OF-FUNCTION STAT1 MUTATIONS IMPAIR STAT3 ACTIVITY IN PATIENTS WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) TRIGGERED PRODUCTION OF TH-17 CYTOKINES MEDIATES PROTECTIVE IMMUNITY AGAINST FUNGI. MUTATIONS AFFECTING THE STAT3/INTERLEUKIN 17 (IL-17) PATHWAY CAUSE SELECTIVE SUSCEPTIBILITY TO FUNGAL (CANDIDA) INFECTIONS, A HALLMARK OF CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). IN PATIENTS WITH AUTOSOMAL DOMINANT CMC, WE AND OTHERS PREVIOUSLY REPORTED DEFECTIVE TH17 RESPONSES AND UNDERLYING GAIN-OF-FUNCTION (GOF) STAT1 MUTATIONS, BUT HOW THIS AFFECTS STAT3 FUNCTION LEADING TO DECREASED IL-17 IS UNCLEAR. WE ALSO ASSESSED HOW GOF-STAT1 MUTATIONS AFFECT STAT3 ACTIVATION, DNA BINDING, GENE EXPRESSION, CYTOKINE PRODUCTION, AND EPIGENETIC MODIFICATIONS. WE EXCLUDED IMPAIRED STAT3 PHOSPHORYLATION, NUCLEAR TRANSLOCATION, AND SEQUESTRATION OF STAT3 INTO STAT1/STAT3 HETERODIMERS AND CONFIRM SIGNIFICANTLY REDUCED TRANSCRIPTION OF STAT3-INDUCIBLE GENES (RORC/IL-17/IL-22/IL-10/C-FOS/SOCS3/C-MYC) AS LIKELY UNDERLYING MECHANISM. STAT BINDING TO THE HIGH AFFINITY SIS-INDUCIBLE ELEMENT WAS INTACT BUT BINDING TO AN ENDOGENOUS STAT3 DNA TARGET WAS IMPAIRED. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION WAS REVERSED BY INHIBITING STAT1 ACTIVATION WITH FLUDARABINE OR ENHANCING HISTONE, BUT NOT STAT1 OR STAT3 ACETYLATION WITH HISTONE DEACETYLASE (HDAC) INHIBITORS TRICHOSTATIN A OR ITF2357. SILENCING HDAC1, HDAC2, AND HDAC3 INDICATED A ROLE FOR HDAC1 AND 2. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION UNDERLIES LOW TH-17 RESPONSES IN GOF-STAT1 CMC, WHICH CAN BE REVERSED BY INHIBITING ACETYLATION, OFFERING NOVEL TARGETS FOR FUTURE THERAPIES. 2015 2 1303 40 DEFECTIVE TRAINED IMMUNITY IN PATIENTS WITH STAT-1-DEPENDENT CHRONIC MUCOCUTANEAOUS CANDIDIASIS. PATIENTS WITH SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1)-DEPENDENT CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC) AND PATIENTS WITH STAT3-DEPENDENT HYPER-IMMUNOGLOBULIN (IG)E SYNDROME (HIES) DISPLAY DEFECTS IN T HELPER TYPE 17 (TH17) CYTOKINE PRODUCTION CAPACITY. DESPITE THIS SIMILAR IMMUNE DEFECT IN TH17 FUNCTION, THEY SHOW IMPORTANT DIFFERENCES IN THE TYPE OF INFECTIONS TO WHICH THEY ARE SUSCEPTIBLE. RECENTLY, OUR GROUP REPORTED DIFFERENTIAL REGULATION OF STAT-1 AND STAT-3 TRANSCRIPTION FACTORS DURING EPIGENETIC REPROGRAMMING OF TRAINED IMMUNITY, AN IMPORTANT HOST DEFENCE MECHANISM BASED ON INNATE IMMUNE MEMORY. WE THEREFORE HYPOTHESIZED THAT STAT1 AND STAT3 DEFECTS HAVE DIFFERENT EFFECTS ON TRAINED IMMUNITY, AND THIS MAY PARTLY EXPLAIN THE DIFFERENCES BETWEEN CMC AND HIES REGARDING THE SUSCEPTIBILITY TO INFECTIONS. INDEED, WHILE TRAINED IMMUNITY WAS NORMALLY INDUCED IN CELLS ISOLATED FROM PATIENTS WITH HIES, THE INDUCTION OF INNATE TRAINING WAS DEFECTIVE IN CMC PATIENTS. THIS DEFECT WAS SPECIFIC FOR TRAINING WITH CANDIDA ALBICANS, THE MAIN PATHOGEN ENCOUNTERED IN CMC, AND IT INVOLVED A TYPE II INTERFERON-DEPENDENT MECHANISM. THESE FINDINGS DESCRIBE THE ROLE OF STAT-1 FOR THE INDUCTION OF TRAINED IMMUNITY, AND MAY CONTRIBUTE TO THE UNDERSTANDING OF THE DIFFERENCES IN SUSCEPTIBILITY TO INFECTION BETWEEN CMC AND HIES PATIENTS. THIS STUDY COULD ALSO PROVIDE DIRECTIONS FOR PERSONALIZED IMMUNOTHERAPY IN PATIENTS SUFFERING FROM THESE IMMUNODEFICIENCIES. 2015 3 3781 43 INTERFERON SIGNATURE IN PATIENTS WITH STAT1 GAIN-OF-FUNCTION MUTATION IS EPIGENETICALLY DETERMINED. STAT1 GAIN-OF-FUNCTION (GOF) VARIANTS LEAD TO DEFECTIVE TH17 CELL DEVELOPMENT AND CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC), BUT FREQUENTLY ALSO TO AUTOIMMUNITY. STIMULATION OF CELLS WITH STAT1 INDUCING CYTOKINES LIKE INTERFERONS (IFN) RESULT IN HYPERPHOSPHORYLATION AND DELAYED DEPHOSPHORYLATION OF GOF STAT1. HOWEVER, THE MECHANISM HOW THE DELAYED DEPHOSPHORYLATION EXACTLY CAUSES THE INCREASED EXPRESSION OF STAT1-DEPENDENT GENES, AND HOW THE INTRACELLULAR SIGNAL TRANSDUCTION FROM CYTOKINE RECEPTORS IS AFFECTED, REMAINS UNKNOWN. IN THIS STUDY WE SHOW THAT THE CIRCULATING LEVELS OF IFN-ALPHA WERE NOT PERSISTENTLY ELEVATED IN STAT1 GOF PATIENTS. NEVERTHELESS, THE EXPRESSION OF INTERFERON SIGNATURE GENES WAS EVIDENT EVEN IN THE PATIENT WITH LOW OR UNDETECTABLE SERUM IFN-ALPHA LEVELS. CHROMATIN IMMUNOPRECIPITATION (CHIP) EXPERIMENTS REVEALED THAT THE ACTIVE CHROMATIN MARK TRIMETHYLATION OF LYSINE 4 OF HISTONE 3 (H3K4ME3), WAS SIGNIFICANTLY ENRICHED IN AREAS ASSOCIATED WITH INTERFERON-STIMULATED GENES IN STAT1 GOF CELLS IN COMPARISON TO CELLS FROM HEALTHY DONORS. THIS SUGGESTS THAT THE CHROMATIN BINDING OF GOF STAT1 VARIANT PROMOTES EPIGENETIC CHANGES COMPATIBLE WITH HIGHER GENE EXPRESSION AND ELEVATED REACTIVITY TO TYPE I INTERFERONS, AND POSSIBLY PREDISPOSES FOR INTERFERON-RELATED AUTOIMMUNITY. THE RESULTS ALSO SUGGEST THAT EPIGENETIC REWIRING MAY BE RESPONSIBLE FOR TREATMENT FAILURE OF JANUS KINASE 1/2 (JAK1/2) INHIBITORS IN CERTAIN PATIENTS. 2019 4 550 22 AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY IN TWO SIBLINGS: SAME MUTATIONS BUT VERY DIFFERENT PHENOTYPES. AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY (APECED), CAUSED BY MUTATIONS IN THE AIRE GENE, IS MAINLY CHARACTERIZED BY THE TRIAD OF HYPOPARATHYROIDISM, PRIMARY ADRENOCORTICAL INSUFFICIENCY AND CHRONIC MUCOCUTANEOUS CANDIDIASIS, BUT CAN INCLUDE MANY OTHER MANIFESTATIONS, WITH NO CURRENTLY CLEAR GENOTYPE-PHENOTYPE CORRELATION. WE PRESENT THE CLINICAL FEATURES OF TWO SIBLINGS, A MALE AND A FEMALE, WITH THE SAME MUTATIONS IN THE AIRE GENE ASSOCIATED WITH TWO VERY DIFFERENT PHENOTYPES. INTERESTINGLY, THE BROTHER RECENTLY EXPERIENCED COVID-19 INFECTION WITH PNEUMONIA, COMPLICATED BY HYPERTENSION, HYPOKALEMIA AND HYPERCALCEMIA. ALTHOUGH APECED IS A MONOGENIC DISEASE, ITS EXPRESSIVENESS CAN BE EXTREMELY DIFFERENT. IN ADDITION TO THE GENETIC BASIS, EPIGENETIC AND ENVIRONMENTAL FACTORS MIGHT INFLUENCE THE PHENOTYPIC EXPRESSION, ALTHOUGH THEIR EXACT ROLE REMAINS TO BE ELUCIDATED. 2021 5 131 23 A2B ADENOSINE SIGNALING REPRESSES CIITA TRANSCRIPTION VIA AN EPIGENETIC MECHANISM IN VASCULAR SMOOTH MUSCLE CELLS. CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. VASCULAR SMOOTH MUSCLE CELLS (VSMC), BY EXPRESSING AND PRESENTING MAJOR HISTOCOMPATIBILITY COMPLEX II (MHC II) MOLECULES, HELP RECRUIT T LYMPHOCYTE AND INITIATE THE INFLAMMATORY RESPONSE WITHIN THE VASCULATURE. WE HAVE PREVIOUSLY SHOWN THAT VSMCS ISOLATED FROM MICE WITH DEFICIENT ADENOSINE A2B RECEPTOR (A2B-NULL) EXHIBIT HIGHER EXPRESSION OF CLASS II TRANSACTIVATOR (CIITA), THE MASTER REGULATOR OF MHC II TRANSCRIPTION, COMPARED TO WILD TYPE LITTERMATES. HERE WE REPORT THAT ACTIVATION OF A2B ADENOSINE SIGNALING SUPPRESSES CIITA EXPRESSION IN HUMAN AORTIC SMOOTH MUSCLE CELLS. DOWN-REGULATION OF CIITA EXPRESSION WAS LARGELY ATTRIBUTABLE TO TRANSCRIPTIONAL REPRESSION OF TYPE III AND IV PROMOTERS. CHROMATIN IMMUNOPRECIPITATION (CHIP) ANALYSES REVEALED THAT A2B SIGNALING REPRESSED CIITA TRANSCRIPTION BY ATTENUATING SPECIFIC HISTONE MODIFICATIONS ON THE CIITA PROMOTERS IN A STAT1-DEPENDENT MANNER. STAT1 INTERACTED WITH PCAF/GCN5, HISTONE H3K9 ACETYLTRANSFERASES, AND WDR5, A KEY COMPONENT OF THE MAMMALIAN H3K4 METHYLTRANSFERASE COMPLEX, TO ACTIVATE CIITA TRANSCRIPTION. A2B SIGNALING PREVENTED RECRUITMENT OF PCAF/GCN5 AND WDR5 TO THE CIITA PROMOTERS IN A STAT1-DEPENDENT MANNER. IN CONCLUSION, OUR DATA SUGGEST THAT ADENOSINE A2B SIGNALING REPRESSES CIITA TRANSCRIPTION IN VSMCS BY MANIPULATING THE INTERACTION BETWEEN STAT1 AND THE EPIGENETIC MACHINERY. 2015 6 3249 33 HEPATITIS B VIRUS HIJACKS CTHRC1 TO EVADE HOST IMMUNITY AND MAINTAIN REPLICATION. HEPATITIS B VIRUS (HBV) INFECTION CAUSES ACUTE AND CHRONIC LIVER DISEASES, BUT IS NOT DIRECTLY CYTOPATHIC. LIVER INJURY RESULTS FROM REPEATED ATTEMPTS OF THE CELLULAR IMMUNE RESPONSE SYSTEM TO CONTROL THE VIRAL INFECTION. HERE, WE INVESTIGATE THE ROLES OF CELLULAR FACTORS AND SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF HBV REPLICATION TO REVEAL THE MECHANISM UNDERLYING HBV INFECTION AND PATHOGENESIS. WE SHOW THAT COLLAGEN TRIPLE HELIX REPEAT CONTAINING 1 (CTHRC1) EXPRESSION IS ELEVATED IN HBV-INFECTED PATIENTS AND IN HBV-TRANSFECTED CELLS THROUGH EPIGENETIC MODIFICATION AND TRANSCRIPTIONAL REGULATION. CTHRC1 FACILITATES HBV REPLICATION IN CULTURED CELLS AND BALB/C MICE BY ACTIVATING THE PKCALPHA/ERK/JNK/C-JUN CASCADE TO REPRESS THE IFN/JAK/STAT PATHWAY. HBV-ACTIVATED CTHRC1 DOWNREGULATES THE ACTIVITY OF TYPE I INTERFERON (IFN), THE PRODUCTION OF IFN-STIMULATED GENES (ISGS), AND THE PHOSPHORYLATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1/2 (STAT1/2), WHEREAS IT UPREGULATES THE PHOSPHORYLATION AND UBIQUITINATION OF TYPE I IFN RECEPTORS (IFNARALPHA/BETA). THUS, OUR RESULTS SHOW THAT HBV USES A NOVEL MECHANISM TO HIJACK CELLULAR FACTORS AND SIGNAL CASCADES IN ORDER TO EVADE HOST ANTIVIRAL IMMUNITY AND MAINTAIN PERSISTENT INFECTION. WE ALSO DEMONSTRATE THAT CTHRC1 HAS A NOVEL ROLE IN VIRAL INFECTION. 2015 7 6657 31 UPREGULATED KAT7 IN SYNOVIAL FIBROBLASTS PROMOTES TH17 CELL DIFFERENTIATION AND INFILTRATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE INVOLVING MULTIPLE CELLULAR PARTICIPANTS, OF WHICH SYNOVIAL FIBROBLASTS (SFS) ARE TIGHTLY CONNECTED WITH THE DEVELOPMENT AND PROGRESSION OF RA. HERE, WE PROVIDE EVIDENCE CONFIRMING THAT KAT7, AN H4-SPECIFIC HISTONE ACETYLASE, IS UPREGULATED IN SFS OF RA PATIENTS, WHICH IS AT LEAST ATTRIBUTED TO THE STIMULATION BY RA-ASSOCIATED PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, IL-1BETA OR IFN-GAMMA. IN ADDITION, KAT7 OVEREXPRESSION IN CULTURED HUMAN FIBROBLAST-LIKE SYNOVIOCYTES (HFLSS) INDUCES IL-6 AND TGF-BETA EXPRESSION THROUGH AN EPIGENETIC MECHANISM, AND IN VITRO T HELPER 17 (TH17) CELL POLARIZATION CULTURED IN THESE SUPERNATANTS SHOWS PROMOTED CELL DIFFERENTIATION. MOREOVER, KAT7 OVEREXPRESSION IN HFLSS INDUCES CCL20 EXPRESSION VIA P44/42 MAPK PATHWAY, WHEREBY PROMOTING TH17 CELL MIGRATION. THESE TWO ACTIVITIES OF KAT7 IN RA SFS INDICATE ITS POTENTIAL ROLES IN ACCELERATING RA PATHOLOGY. OVERALL, THESE RESULTS DEMONSTRATE SOME CONNECTIONS BETWEEN KAT7 UPREGULATED IN RA SFS AND RA PROGRESSION AND PRESENT THE INHIBITION OF KAT7 ACTIVITY AS A NOVEL THERAPEUTIC TARGET FOR INTERFERING RA DISEASE. 2017 8 1668 32 DOWNREGULATION OF SOCS1 INCREASES INTERFERON-INDUCED ISGYLATION DURING DIFFERENTIATION OF INDUCED-PLURIPOTENT STEM CELLS TO HEPATOCYTES. BACKGROUND & AIMS: INCREASED EXPRESSION OF IFN-STIMULATED GENE 15 (ISG15) AND SUBSEQUENTLY INCREASED ISGYLATION ARE KEY FACTORS IN THE HOST RESPONSE TO VIRAL INFECTION. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE EXPRESSION OF ISG15, ISGYLATION, AND ASSOCIATED ENZYMES AT EACH STAGE OF DIFFERENTIATION FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) TO HEPATOCYTES. METHODS: TO STUDY THE REGULATION OF ISGYLATION, WE UTILIZED PATIENT SAMPLES AND IN VITRO CELL CULTURE MODELS INCLUDING IPSCS, HEPATOCYTES-LIKE CELLS, IMMORTALIZED CELL LINES, AND PRIMARY HUMAN HEPATOCYTES. PROTEIN/MRNA EXPRESSION WERE MEASURED FOLLOWING TREATMENT WITH POLY(I:C), IFNALPHA AND HCV INFECTION. RESULTS: WHEN COMPARED TO HLCS, WE OBSERVED SEVERAL NOVEL ASPECTS OF THE ISGYLATION PATHWAY IN IPSCS. THESE INCLUDE A LOWER BASELINE EXPRESSION OF THE ISGYLATION-ACTIVATING ENZYME, UBE1L, A LACK OF IFN-INDUCED EXPRESSION OF THE ISGYLATION-CONJUGATION ENZYME UBE2L6, AN ATTENUATED ACTIVATION OF THE TRANSCRIPTION FACTOR STAT1 AND CONSTITUTIVE EXPRESSION OF SOCS1. ISGYLATION WAS OBSERVED IN IPSCS FOLLOWING DOWNREGULATION OF SOCS1, WHICH FACILITATED STAT1 ACTIVATION AND SUBSEQUENTLY INCREASED EXPRESSION OF UBE2L6. INTRIGUINGLY, HCV PERMISSIVE TRANSFORMED HEPATOMA CELL LINES DEMONSTRATED HIGHER INTRINSIC EXPRESSION OF SOCS1 AND WEAKER ISGYLATION FOLLOWING IFN TREATMENT. SOCS1 DOWNREGULATION IN HCV-INFECTED HUH 7.5.1 CELLS LED TO INCREASED ISGYLATION. CONCLUSIONS: HEREIN, WE SHOW THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. FURTHERMORE, AS IPSCS DIFFERENTIATE INTO HEPATOCYTES, EPIGENETIC MECHANISMS REGULATE ISGYLATION BY MODIFYING UBE1L AND SOCS1 EXPRESSION LEVELS. OVERALL, THIS STUDY DEMONSTRATES THAT THE DEVELOPMENT OF CELL-INTRINSIC INNATE IMMUNITY DURING THE DIFFERENTIATION OF IPSCS TO HEPATOCYTES PROVIDES INSIGHT INTO CELL TYPE-SPECIFIC REGULATION OF HOST DEFENSE RESPONSES AND RELATED ONCOGENIC PROCESSES. IMPACT AND IMPLICATIONS: TO ELUCIDATE THE MECHANISM UNDERLYING REGULATION OF ISGYLATION, A KEY PROCESS IN THE INNATE IMMUNE RESPONSE, WE STUDIED CHANGES IN ISGYLATION-ASSOCIATED GENES AT THE DIFFERENT STAGES OF DIFFERENTIATION FROM IPSCS TO HEPATOCYTES. WE FOUND THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. IMPORTANTLY, EPIGENETIC REGULATION OF SOCS1 AND SUBSEQUENTLY ISGYLATION MAY BE IMPORTANT FACTORS IN THE DEVELOPMENT OF CELL TYPE-SPECIFIC HOST DEFENSE RESPONSES IN HEPATOCYTES THAT SHOULD BE CONSIDERED WHEN STUDYING CHRONIC INFECTIONS AND ONCOGENIC PROCESSES IN THE LIVER. 2022 9 6509 27 TRANSCRIPTION FACTOR RFX1 IS UBIQUITINATED BY E3 LIGASE STUB1 IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CAUSED BY COMPLEX INTERACTIONS BETWEEN GENES AND THE ENVIRONMENT. THE EXPRESSION LEVEL OF TRANSCRIPTION FACTOR REGULATORY FACTOR X 1 (RFX1) IS REDUCED IN T CELLS FROM SLE PATIENTS. RFX1 CAN REGULATE EPIGENETIC MODIFICATIONS OF CD70 AND CD11A AND PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OF SLE. HOWEVER, THE MECHANISMS THAT MEDIATE REDUCTION OF RFX1 IN SLE ARE UNCLEAR. HERE, WE DEMONSTRATE THAT RFX1 PROTEIN EXPRESSION CAN BE TIGHTLY REGULATED BY POLYUBIQUITINATION-MEDIATED PROTEOSOMAL DEGRADATION VIA STIP1 HOMOLOGY AND U-BOX CONTAINING PROTEIN 1 (STUB1). THE E3 LIGASE STUB1 IS UPREGULATED IN CD4(+)T CELLS OF SLE PATIENTS COMPARED TO HEALTHY SUBJECTS. OVEREXPRESSION OF STUB1 IN CD4(+)T CELLS LEADS TO UPREGULATION OF LEVELS OF CD70 AND CD11A IN T CELLS. THE MODULATION OF STUB1 ACTIVITY MAY PROVIDE A NOVEL THERAPEUTIC APPROACH FOR SLE. 2016 10 6518 38 TRANSCRIPTIONAL AND EPIGENETIC MODULATION OF HUMAN RHINOVIRUS-INDUCED CXCL10 PRODUCTION BY CIGARETTE SMOKE. HUMAN RHINOVIRUS (HRV) TRIGGERS EXACERBATIONS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CIGARETTE SMOKING IS THE PRIMARY RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND 25% OF INDIVIDUALS WITH ASTHMA SMOKE. SMOKERS EXPERIENCE BOTH LONGER AND MORE SEVERE COLDS. WE PREVIOUSLY SHOWED THAT CIGARETTE SMOKE EXTRACT (CSE) INHIBITED HRV-INDUCED EXPRESSION OF A RANGE OF EPITHELIAL ANTIVIRAL MOLECULES. HERE, WE USE CXCL10 AS A MODEL ANTIVIRAL GENE TO EXAMINE THE MECHANISMS BY WHICH CSE INHIBITS EPITHELIAL ANTIVIRAL IMMUNITY. HRV-INDUCED CXCL10 TRANSCRIPTION DEPENDS ON ACTIVATION OF NF-KB AND IFN-REGULATORY FACTOR-1 (IRF-1), AND WE NOW ALSO IMPLICATE TWO SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) CONSENSUS SEQUENCES IN THE CXCL10 PROMOTER IN HRV-INDUCED CXCL10 EXPRESSION. CSE INHIBITED HRV-INDUCED ACTIVATION AND NUCLEAR TRANSLOCATION/BINDING OF BOTH NF-KB, AND IRF-1 TO THEIR RESPECTIVE RECOGNITION SEQUENCES IN THE CXCL10 PROMOTER. HRV ALSO INDUCED FORMATION OF COMPLEXES AT THE STAT REGION IN THE CXCL10 PROMOTER, AND HRV-INDUCED ACTIVATION OF STAT-1 WAS INHIBITED BY CSE. IN ADDITION, CSE INHIBITED HRV-INDUCED CHROMATIN ACCESSIBILITY AROUND THE TRANSCRIPTIONAL START SITE OF THE CXCL10 PROMOTER. ALTHOUGH CSE INHIBITED HRV-INDUCED EXPRESSION OF BOTH THE VIRAL DOUBLE-STRANDED RNA SENSORS, RETINOIC ACID-INDUCIBLE GENE-I AND MELANOMA DIFFERENTIATION-ASSOCIATED GENE (MDA) 5, ONLY SPECIFIC SHORT INTERFERING RNA (SIRNA) TO MDA5, BUT NOT NONTARGETING SIRNA, OR SIRNA TO RETINOIC ACID-INDUCIBLE GENE-I, INHIBITED HRV-INDUCED CXCL10 INDUCTION. WE CONCLUDE THAT CSE REDUCES CHROMATIN ACCESSIBILITY AND INHIBITS VIRAL SIGNALING VIA NF-KB, IRF-1, STAT-1, AND MDA5. THUS, WE SHOW THAT CSE CAN SIMULTANEOUSLY MODULATE MULTIPLE PATHWAYS LINKED TO INNATE IMMUNE RESPONSES TO HRV INFECTION. 2014 11 3945 36 LNCRNA IL21-AS1 INTERACTS WITH HNRNPU PROTEIN TO PROMOTE IL21 OVEREXPRESSION AND ABERRANT DIFFERENTIATION OF TFH CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS. BACKGROUND: THE ABERRANT DIFFERENTIATION OF T FOLLICULAR HELPER (TFH) CELLS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). HOWEVER, THE MECHANISM OF REGULATING TFH CELLS DIFFERENTIATION REMAINS UNCLEAR. LONG NONCODING RNAS (LNCRNAS) ACT AS IMPORTANT REGULATORS IN THE PROCESSES OF INNATE AND ADAPTIVE IMMUNE RESPONSE. WHETHER LNCRNAS ARE INVOLVED IN REGULATING TFH CELL DIFFERENTIATION AND AUTOIMMUNE RESPONSES NEED TO BE FURTHER IDENTIFIED. METHODS: THE CHARACTERS AND FUNCTIONS OF HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE INVESTIGATED BY A SERIES OF BIOCHEMICAL ASSAYS AND CELL TRANSFECTION ASSAY. MIL21-AS1 REGULATING HUMORAL IMMUNE RESPONSE IN VIVO WAS EXPLORED BY KEYHOLE LIMPET HAEMOCYANIN (KLH) AND CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) MODEL. RESULTS: HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE IDENTIFIED AND CLONED. WE UNCOVERED THAT IL21-AS1 WAS HIGHLY EXPRESSED IN CD4(+) T CELLS OF SLE PATIENTS AND TFH CELLS, WHICH PROMOTED DIFFERENTIATION OF TFH CELLS. MECHANISTICALLY, IL21-AS1 BOUND HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN U AND RECRUITED ACETYLTRANSFERASES CREB-BINDING PROTEIN TO THE PROMOTER OF IL21, LEADING TO THE TRANSCRIPTIONAL ACTIVATION OF IL21 AND TFH CELLS DIFFERENTIATION THROUGH INCREASING HISTONE H3 ACETYLATION LEVEL ON IL21 PROMOTER. MOREOVER, TFH PROPORTION AND ANTIBODIES PRODUCTION WERE SIGNIFICANTLY INCREASED IN MIL21-AS KNOCK-IN MICE IMMUNIZED WITH KLH. MIL21-AS1 OVEREXPRESSION ALSO EXACERBATED THE LUPUS-LIKE PHENOTYPE IN CGVHD MICE MODEL. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT IL21-AS1 ACTIVATES IL21 TRANSCRIPTION VIA EPIGENETIC MECHANISM TO PROMOTE GERMINAL CENTRE RESPONSE, ADDING INSIGHT INTO THE MOLECULAR REGULATION OF AUTOIMMUNE PATHOGENESIS AND PROVIDING A NOVEL TARGET FOR SLE TREATMENT. 2022 12 5017 25 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION. 1995 13 35 24 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES. 2014 14 3281 25 HETEROGENEOUS TFH CELL POPULATIONS THAT DEVELOP DURING ENTERIC HELMINTH INFECTION PREDICT THE QUALITY OF TYPE 2 PROTECTIVE RESPONSE. T FOLLICULAR HELPER (TFH) CELLS ARE AN IMPORTANT COMPONENT OF GERMINAL CENTER (GC)-MEDIATED HUMORAL IMMUNITY. YET, HOW A CHRONIC TYPE 1 VERSUS PROTECTIVE TYPE 2 HELMINTH INFECTION MODULATES TFH-GC RESPONSES REMAINS POORLY UNDERSTOOD. HERE, WE EMPLOY THE HELMINTH TRICHURIS MURIS MODEL AND DEMONSTRATE THAT TFH CELL PHENOTYPES AND GC ARE DIFFERENTIALLY REGULATED IN ACUTE VERSUS CHRONIC INFECTION. THE LATTER FAILED TO INDUCE TFH-GC B CELL RESPONSES, WITH TFH CELLS EXPRESSING TAU-BET AND INTERFERON-GAMMA. IN CONTRAST, INTERLEUKIN-4-PRODUCING TFH CELLS DOMINATE RESPONSES TO AN ACUTE, RESOLVING INFECTION. HEIGHTENED EXPRESSION AND INCREASED CHROMATIN ACCESSIBILITY OF T HELPER (TH)1- AND TH2 CELL-ASSOCIATED GENES ARE OBSERVED IN CHRONIC AND ACUTE INDUCED TFH CELLS, RESPECTIVELY. BLOCKADE OF THE TH1 CELL RESPONSE BY T-CELL-INTRINSIC T-BET DELETION PROMOTED TFH CELL EXPANSION DURING CHRONIC INFECTION, POINTING TO A CORRELATION BETWEEN A ROBUST TFH CELL RESPONSE AND PROTECTIVE IMMUNITY TO PARASITES. FINALLY, BLOCKADE OF TFH-GC INTERACTIONS IMPAIRED TYPE 2 IMMUNITY, REVEALING THE CRITICAL PROTECTIVE ROLE OF GC-DEPENDENT TH2-LIKE TFH CELL RESPONSES DURING ACUTE INFECTION. COLLECTIVELY, THESE RESULTS PROVIDE NEW INSIGHTS INTO THE PROTECTIVE ROLES OF TFH-GC RESPONSES AND IDENTIFY DISTINCT TRANSCRIPTIONAL AND EPIGENETIC FEATURES OF TFH CELLS THAT EMERGE DURING RESOLVING OR CHRONIC T. MURIS INFECTION. 2023 15 3526 37 IL-6 AND SIL-6R INDUCES STAT3-DEPENDENT DIFFERENTIATION OF HUMAN VSMCS INTO OSTEOBLAST-LIKE CELLS THROUGH JMJD2B-MEDIATED HISTONE DEMETHYLATION OF RUNX2. INFLAMMATION AND VASCULAR CALCIFICATION ARE INDEPENDENT RISK FACTORS OF CARDIOVASCULAR EVENTS. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) EXHIBIT OSTEOBLAST-LIKE CHARACTERISTICS IN RESPONSE TO VARIOUS STIMULI SUCH AS OXIDIZED CHOLESTEROL AND INFLAMMATION. HOWEVER THE PRECISE MECHANISM OF TRANSCRIPTIONAL REGULATION OF VSMCS BY INFLAMMATORY STIMULI REMAINS UNCLEAR. WE INVESTIGATED THE PROCESS AND MECHANISMS OF INFLAMMATORY CYTOKINE-INDUCED TRANSFORMATION OF HUMAN VSMCS (HVSMCS) INTO OSTEOBLAST-LIKE CELLS, WITH A SPECIAL FOCUS ON EPIGENETIC CHANGES. OUR RESULTS DEMONSTRATED: (1) INTERLEUKIN-6 (IL-6)/SOLUBLE INTERLEUKIN-6 RECEPTOR (SIL-6R) INDUCED TRANSFORMATION OF HVSMCS INTO AN OSTEOBLAST PHENOTYPE, WITH SUBSEQUENT VASCULAR CALCIFICATION, BASED ON THE RESULTS OF ALIZARIN RED S STAINING AND O-CRESOLPHTHALEIN COMPLEXONE METHOD; (2) IL-6/SIL-6R ACCELERATED THE EXPRESSION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2) BASED ON THE RESULTS OF QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION; (3) KNOCKDOWN OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3 REDUCED IL-6/SIL-6R-INDUCED RUNX2 MRNA EXPRESSION AND OSTEOBLAST TRANSDIFFERENTIATION OF HVSMCS; (4) CHROMATIN IMMUNOPRECIPITATION (CHIP) COUPLED WITH PCR (CHIP-PCR) IDENTIFIED A STAT-BINDING SITE IN RUNX2 PROMOTER REGION CONTAINING TRIMETHYLATED HISTONE 3 LYSINE 9 (H3K9ME3), A TRANSCRIPTIONAL REPRESSOR, AND H3K4ME3, A TRANSCRIPTIONAL ENHANCER. STIMULATION WITH IL-6/SIL-6R SUPPRESSED H3K9ME3 BUT NOT H3K4ME3 THROUGH THE RECRUITMENT OF JUMONJI DOMAIN-CONTAINING PROTEIN (JMJD) 2B, A HISTONE LYSINE DEMETHYLASE, AT THE STAT-BINDING SITE IN RUNX2 PROMOTER REGION; (5) IL-6/SIL-6R-INDUCED RUNX2 GENE EXPRESSION WAS INHIBITED IN HVSMCS PRETREATED WITH JIB04, JMJD2 INHIBITOR, AND THE INHIBITORY EFFECT WAS JIB04 DOSE-DEPENDENT. OUR RESULTS INDICATE THAT THE IL-6/STAT3/JMJD2B PATHWAY REGULATES HVSMCS DIFFERENTIATION INTO OSTEOBLAST-LIKE CELLS, WHICH SUGGEST ITS PATHOGENIC ROLE IN VASCULAR CALCIFICATION ASSOCIATED WITH CHRONIC INFLAMMATION. 2019 16 5510 30 RIBAVIRIN RESTORES IFNALPHA RESPONSIVENESS IN HCV-INFECTED LIVERS BY EPIGENETIC REMODELLING AT INTERFERON STIMULATED GENES. OBJECTIVES: CAVEATS IN THE UNDERSTANDING OF RIBAVIRIN (RBV) MECHANISMS OF ACTION HAS SOMEHOW PREVENTED THE DEVELOPMENT OF BETTER ANALOGUES ABLE TO FURTHER IMPROVE ITS THERAPEUTIC CONTRIBUTION IN INTERFERON (IFN)-BASED AND DIRECT ANTIVIRAL AGENT-BASED REGIMENS FOR CHRONIC HCV OR OTHER INDICATIONS. HERE, WE DESCRIBE A NEW MECHANISM BY WHICH RBV MODULATES IFN-STIMULATED GENES (ISGS) AND CONTRIBUTES TO RESTORE HEPATIC IMMUNE RESPONSIVENESS. DESIGN: RBV EFFECT ON ISG EXPRESSION WAS MONITORED IN VITRO AND IN VIVO, THAT IS, IN NON-TRANSFORMED HEPATOCYTES AND IN THE LIVER OF RBV MONO-TREATED PATIENTS, RESPECTIVELY. MODULATION OF HISTONE MODIFICATIONS AND RECRUITMENT OF HISTONE-MODIFYING ENZYMES AT TARGET PROMOTERS WAS ANALYSED BY CHROMATIN IMMUNOPRECIPITATION IN RBV-TREATED PRIMARY HUMAN HEPATOCYTES AND IN PATIENTS' LIVER BIOPSIES. RESULTS: RBV DECREASES THE MRNA LEVELS OF SEVERAL ABNORMALLY PREACTIVATED ISGS IN PATIENTS WITH HCV, WHO ARE NON-RESPONDERS TO IFN THERAPY. RBV INCREASES G9A HISTONE METHYLTRANSFERASE RECRUITMENT AND HISTONE-H3 LYSINE-9 DIMETHYLATION/TRIMETHYLATION AT SELECTED ISG PROMOTERS IN VITRO AND IN VIVO. G9A PHARMACOLOGICAL BLOCKADE ABOLISHES RBV-INDUCED ISG DOWNREGULATION AND SEVERELY IMPAIRS RBV ABILITY TO POTENTIATE IFN ANTIVIRAL ACTION AND INDUCTION OF ISGS FOLLOWING HCV INFECTION OF PRIMARY HUMAN HEPATOCYTES. CONCLUSIONS: RBV-INDUCED EPIGENETIC CHANGES, LEADING TO DECREASED ISG EXPRESSION, RESTORE AN IFN-RESPONSIVE HEPATIC ENVIRONMENT IN PATIENTS WITH HCV, WHICH MAY ALSO PROVE USEFUL IN IFN-FREE REGIMENS. 2016 17 4919 27 PANNEXIN-1 UP-REGULATION IN THE DORSAL ROOT GANGLION CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT. PANNEXIN-1 (PANX1) IS A LARGE-PORE MEMBRANE CHANNEL INVOLVED IN THE RELEASE OF ATP AND OTHER SIGNALING MEDIATORS. LITTLE IS KNOWN ABOUT THE EXPRESSION AND FUNCTIONAL ROLE OF PANX1 IN THE DORSAL ROOT GANGLION (DRG) IN THE DEVELOPMENT OF CHRONIC NEUROPATHIC PAIN. IN THIS STUDY, WE DETERMINED THE EPIGENETIC MECHANISM INVOLVED IN INCREASED PANX1 EXPRESSION IN THE DRG AFTER NERVE INJURY. SPINAL NERVE LIGATION IN RATS SIGNIFICANTLY INCREASED THE MRNA AND PROTEIN LEVELS OF PANX1 IN THE DRG BUT NOT IN THE SPINAL CORD. IMMUNOCYTOCHEMICAL LABELING SHOWED THAT PANX1 WAS PRIMARILY EXPRESSED IN A SUBSET OF MEDIUM AND LARGE DRG NEURONS IN CONTROL RATS AND THAT NERVE INJURY MARKEDLY INCREASED THE NUMBER OF PANX1-IMMUNOREACTIVE DRG NEURONS. NERVE INJURY SIGNIFICANTLY INCREASED THE ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME2 AND H3K9AC) AND DECREASED THE OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AROUND THE PROMOTER REGION OF PANX1 IN THE DRG. HOWEVER, NERVE INJURY HAD NO EFFECT ON THE DNA METHYLATION LEVEL AROUND THE PANX1 PROMOTER IN THE DRG. FURTHERMORE, INTRATHECAL INJECTION OF THE PANX1 BLOCKERS OR PANX1-SPECIFIC SIRNA SIGNIFICANTLY REDUCED PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN ADDITION, SIRNA KNOCKDOWN OF PANX1 EXPRESSION IN A DRG CELL LINE SIGNIFICANTLY REDUCED CASPASE-1 RELEASE INDUCED BY NEURONAL DEPOLARIZATION. OUR FINDINGS SUGGEST THAT NERVE INJURY INCREASES PANX1 EXPRESSION LEVELS IN THE DRG THROUGH ALTERED HISTONE MODIFICATIONS. PANX1 UP-REGULATION CONTRIBUTES TO THE DEVELOPMENT OF NEUROPATHIC PAIN AND STIMULATION OF INFLAMMASOME SIGNALING. 2015 18 6077 35 THE EFFECT OF CD4 RECEPTOR DOWNREGULATION AND ITS DOWNSTREAM SIGNALING MOLECULES ON HIV-1 LATENCY. HIV-1 CAN ESTABLISH A LATENT INFECTION IN MEMORY CD4+T CELLS TO EVADE THE HOST IMMUNE RESPONSE. CD4 MOLECULES CAN ACT NOT ONLY AS THE HIV-1 RECEPTOR FOR ENTRY BUT ALSO AS THE TRIGGER IN AN INTRACELLULAR SIGNALING CASCADE FOR T-CELL ACTIVATION AND PROLIFERATION VIA PROTEIN TYROSINE KINASES. NOVEL CHRONIC HIV-1-INFECTED A3.01-DERIVED (NCHA) CELLS WERE USED TO EXAMINE THE INVOLVEMENT OF CD4 DOWNSTREAM SIGNALING IN HIV-1 LATENCY. CD4 RECEPTORS IN NCHA CELLS WERE DRAMATICALLY DOWNREGULATED ON ITS SURFACE BUT WERE SLIGHTLY DECREASED IN WHOLE-CELL LYSATES. THE EXPRESSION LEVELS OF CD4 DOWNSTREAM SIGNALING MOLECULES, INCLUDING P56(LCK), ZAP-70, LAT, AND C-JUN, WERE SHARPLY DECREASED IN NCHA CELLS. THE LOWERED HISTONE MODIFICATIONS OF H3K4ME3 AND H3K9AC CORRELATED WITH THE DOWNREGULATION OF P56(LCK), ZAP-70, AND LAT IN NCHA CELLS. AP-1 BINDING ACTIVITY WAS ALSO REDUCED IN NCHA CELLS. LAT AND C-JUN SUPPRESSED IN NCHA CELLS WERE HIGHLY INDUCED AFTER PMA TREATMENT. IN EPIGENETIC ANALYSIS, OTHER SIGNAL TRANSDUCTION MOLECULES WHICH ARE ASSOCIATED WITH ACTIVE AND/OR LATENT HIV-1 INFECTION SHOWED NORMAL STATES IN HIV-1 LATENTLY INFECTED CELLS COMPARED TO A3.01 CELLS. IN CONCLUSION, WE DEMONSTRATED THAT THE HIV-1 LATENT STATE IS SUSTAINED BY THE REDUCTION OF DOWNSTREAM SIGNALING MOLECULES VIA THE DOWNREGULATION OF CD4 AND THE ATTENUATED ACTIVITY OF TRANSCRIPTION FACTOR AS AP-1. THE HIV-1 LATENCY MODEL VIA T-CELL DEACTIVATION MAY PROVIDE SOME CLUES FOR THE DEVELOPMENT OF THE NEW ANTIRESERVOIR THERAPY. 2011 19 5863 27 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 20 216 33 ACUTE BETA-ADRENERGIC ACTIVATION TRIGGERS NUCLEAR IMPORT OF HISTONE DEACETYLASE 5 AND DELAYS G(Q)-INDUCED TRANSCRIPTIONAL ACTIVATION. DURING HEMODYNAMIC STRESS, CATECHOLAMINES AND NEUROHUMORAL STIMULI MAY INDUCE CO-ACTIVATION OF G(Q)-COUPLED RECEPTORS AND BETA-ADRENERGIC RECEPTORS (BETA-AR), LEADING TO CARDIAC REMODELING. DYNAMIC REGULATION OF HISTONE DEACETYLASE 5 (HDAC5), A TRANSCRIPTIONAL REPRESSOR, IS CRUCIAL DURING STRESS SIGNALING DUE TO ITS ROLE IN EPIGENETIC CONTROL OF FETAL GENE MARKERS. LITTLE IS KNOWN ABOUT ITS REGULATION DURING ACUTE AND CHRONIC BETA-AR STIMULATION AND ITS CROSS-INTERACTION WITH G(Q) SIGNALING IN ADULT CARDIAC MYOCYTES. HERE, WE EVALUATE THE POTENTIAL CROSS-TALK BETWEEN G(Q)-DRIVEN AND BETA-AR MEDIATED SIGNALING AT THE LEVEL OF NUCLEOCYTOPLASMIC SHUTTLING OF HDAC5. WE SHOW THE TRANSLOCATION OF GFP-TAGGED WILD TYPE HDAC5 OR MUTANTS (S279A AND S279D) IN RESPONSE TO BETA-AR OR G(Q) AGONISTS. ISOPROTERENOL (ISO) OR PKA ACTIVATION RESULTS IN STRONG NUCLEAR ACCUMULATION OF HDAC5 IN CONTRAST TO NUCLEAR EXPORT DRIVEN BY CA(2+)-CALMODULIN PROTEIN KINASE II AND PROTEIN KINASE D. MOREOVER, NUCLEAR ACCUMULATION OF HDAC5 UNDER ACUTE ISO/PKA SIGNALING IS DEPENDENT ON PHOSPHORYLATION OF SER-279 AND CAN BLOCK SUBSEQUENT G(Q)-MEDIATED NUCLEAR HDAC5 EXPORT. INTRIGUINGLY, THE ATTENUATION OF G(Q)-INDUCED EXPORT IS ABOLISHED AFTER CHRONIC PKA ACTIVATION, YET NUCLEAR HDAC5 REMAINS ELEVATED. LAST, THE EFFECT OF CHRONIC BETA-AR SIGNALING ON HDAC5 TRANSLOCATION WAS EXAMINED IN ADULT MYOCYTES FROM A RABBIT MODEL OF HEART FAILURE, WHERE ISO-INDUCED NUCLEAR IMPORT IS ABLATED, BUT G(Q)-AGONIST MEDIATED EXPORT IS PRESERVED. ACUTE BETA-AR/PKA ACTIVATION PROTECTS AGAINST HYPERTROPHIC SIGNALING BY DELAYING G(Q)-MEDIATED TRANSCRIPTIONAL ACTIVATION. THIS SERVES AS A KEY PHYSIOLOGICAL CONTROL SWITCH BEFORE ALLOWING GENETIC REPROGRAMMING VIA HDAC5 NUCLEAR EXPORT DURING MORE SEVERE STRESS, SUCH AS HEART FAILURE. 2013