1 1862 137 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011 2 4113 45 MECHANISMS CONTRIBUTING TO THE DYSREGULATION OF MIRNA-124 IN PULMONARY HYPERTENSION. CHRONIC PULMONARY HYPERTENSION (PH) IS A FATAL DISEASE CHARACTERIZED BY THE PERSISTENT ACTIVATION OF PULMONARY VASCULAR CELLS THAT EXHIBIT ABERRANT EXPRESSION OF GENES INCLUDING MIRNAS. WE AND OTHERS REPORTED THAT DECREASED LEVELS OF MATURE MICRORNA-124 (MIR-124) PLAYS AN IMPORTANT ROLE IN MODULATING THE ACTIVATED PHENOTYPE OF PULMONARY VASCULAR CELLS AND HDAC INHIBITORS (HDACI) CAN RESTORE THE LEVELS OF MATURE MIR-124 AND REVERSE THE PERSISTENTLY ACTIVATED PHENOTYPE OF PH VASCULAR CELLS. IN THIS STUDY, WE SOUGHT TO DETERMINE THE MECHANISMS CONTRIBUTING TO REDUCED LEVELS OF MIRNAS, AS WELL AS HOW HDACI RESTORES THE LEVELS OF REDUCED MIRNA IN PH VASCULAR CELLS. WE FOUND THAT PULMONARY ARTERY FIBROBLASTS ISOLATED FROM IPAH PATIENTS (PH-FIBS) EXHIBIT REDUCED LEVELS OF MATURE MIR-124 AND SEVERAL OTHER MIRNAS INCLUDING LET-7I, MIR-224, AND MIR-210, AND THAT THESE REDUCED LEVELS CAN BE RESTORED BY HDACI. USING MIR-124 EXPRESSION IN HUMAN PH-FIBS AS A MODEL, WE DETERMINED THAT REDUCED MIR-124 GENE TRANSCRIPTION, NOT DECREASED EXPRESSION OF MIRNA PROCESSING GENES, IS RESPONSIBLE FOR REDUCED LEVELS OF MATURE MIR-124 IN HUMAN PH-FIBS. USING BOTH DNASE I SENSITIVITY AND CHROMATIN IMMUNOPRECIPITATION ASSAYS, WE FOUND THAT THE MIR-124-1 GENE EXHIBITS A MORE CONDENSED CHROMATIN STRUCTURE IN HUMAN PH-FIBS, COMPARED TO CORRESPONDING CONTROLS. HDACI RELAXED MIR-124-1 CHROMATIN STRUCTURE, EVIDENCED BY INCREASED LEVELS OF THE OPEN CHROMATIN MARK H3K27AC, BUT DECREASED LEVELS OF CLOSED CHROMATIN MARK H3K27ME(3). MOST IMPORTANTLY, THE DELIVERY OF HISTONE ACETYLTRANSFERASE (HAT) VIA CRISPR-DCAS9-HAT AND GUIDING RNAS TO THE PROMOTER OF THE MIR-124-1 GENE INCREASED MIR-124-1 GENE TRANSCRIPTION. THUS, OUR DATA INDICATE EPIGENETIC EVENTS PLAY IMPORTANT ROLE IN CONTROLLING MIR-124 AND LIKELY OTHER MIRNA LEVELS AND EPIGENETIC REGULATORS SUCH AS HDACS APPEAR TO BE PROMISING THERAPEUTIC TARGETS FOR CHRONIC PH. 2021 3 2067 36 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015 4 172 35 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 5 2493 44 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 6 5937 39 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 7 2228 29 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 8 4111 42 MECHANISMS CONTRIBUTING TO PERSISTENTLY ACTIVATED CELL PHENOTYPES IN PULMONARY HYPERTENSION. CHRONIC PULMONARY HYPERTENSION (PH) IS CHARACTERIZED BY THE ACCUMULATION OF PERSISTENTLY ACTIVATED CELL TYPES IN THE PULMONARY VESSEL EXHIBITING ABERRANT EXPRESSION OF GENES INVOLVED IN APOPTOSIS RESISTANCE, PROLIFERATION, INFLAMMATION AND EXTRACELLULAR MATRIX (ECM) REMODELLING. CURRENT THERAPIES FOR PH, FOCUSING ON VASODILATATION, DO NOT NORMALIZE THESE ACTIVATED PHENOTYPES. FURTHERMORE, CURRENT APPROACHES TO DEFINE ADDITIONAL THERAPEUTIC TARGETS HAVE FOCUSED ON DETERMINING THE INITIATING SIGNALS AND THEIR DOWNSTREAM EFFECTORS THAT ARE IMPORTANT IN PH ONSET AND DEVELOPMENT. ALTHOUGH THESE APPROACHES HAVE PRODUCED A LARGE NUMBER OF COMPELLING PH TREATMENT TARGETS, MANY PROMISING HUMAN DRUGS HAVE FAILED IN PH CLINICAL TRIALS. HEREIN, WE PROPOSE THAT ONE CONTRIBUTING FACTOR TO THESE FAILURES IS THAT PROCESSES IMPORTANT IN PH DEVELOPMENT MAY NOT BE GOOD TREATMENT TARGETS IN THE ESTABLISHED PHASE OF CHRONIC PH. WE HYPOTHESIZE THAT THIS IS DUE TO ALTERATIONS OF CHROMATIN STRUCTURE IN PH CELLS, RESULTING IN FUNCTIONAL DIFFERENCES BETWEEN THE SAME FACTOR OR PATHWAY IN NORMAL OR EARLY PH CELLS VERSUS CELLS IN CHRONIC PH. WE PROPOSE THAT THE HIGH EXPRESSION OF GENES INVOLVED IN THE PERSISTENTLY ACTIVATED PHENOTYPE OF PH VASCULAR CELLS IS PERPETUATED BY AN OPEN CHROMATIN STRUCTURE AND MULTIPLE TRANSCRIPTION FACTORS (TFS) VIA THE RECRUITMENT OF HIGH LEVELS OF EPIGENETIC REGULATORS INCLUDING THE HISTONE ACETYLASES P300/CBP, HISTONE ACETYLATION READERS INCLUDING BRDS, THE MEDIATOR COMPLEX AND THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (ABSTRACT FIGURE). THUS, DETERMINING HOW GENE EXPRESSION IS CONTROLLED BY EXAMINING CHROMATIN STRUCTURE, TFS AND EPIGENETIC REGULATORS ASSOCIATED WITH ABERRANTLY EXPRESSED GENES IN PULMONARY VASCULAR CELLS IN CHRONIC PH, MAY UNCOVER NEW PH THERAPEUTIC TARGETS. 2019 9 911 31 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 10 3436 31 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 11 4772 31 NUCLEAR SIRTUINS AND INFLAMMATORY SIGNALING PATHWAYS. THE REGULATION OF CHRONIC INFLAMMATION HAS RECEIVED CONSIDERABLE RESEARCH ATTENTION IN RECENT YEARS BECAUSE OF ITS CONTRIBUTION TO THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS ARTHRITIS, DIABETES, METABOLIC SYNDROME AND OBESITY. THUS, STRATEGIES THAT INHIBIT THE INFLAMMATORY STATE MAY BE BENEFICIAL IN IMPROVING THE PATHOPHYSIOLOGY OF SEVERAL INFLAMMATION-RELATED DISORDERS. SIRTUINS ARE A FAMILY OF HISTONE DEACETYLASES THAT CONTAIN SEVEN ENZYMATIC ACTIVITIES IN MAMMALS (SIRT1-SIRT7) AND FUNCTION TO SUPPRESS GENE TRANSCRIPTION BY EPIGENETIC MECHANISMS. NUCLEAR SIRTUINS (SIRT 1, 2, 6 AND 7) IN PARTICULAR MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF INFLAMMATORY RESPONSES. IN THE PRESENT REVIEW, WE ASSESSED THE ROLES OF NUCLEAR SIRTUINS IN INFLAMMATORY REACTIONS: SIRT1 HAS BEEN SHOWN TO SUPPRESS NF-KAPPAB ACTIVITY, THE MASTER REGULATOR OF CELLULAR INFLAMMATORY RESPONSE, DECREASE COX-2 AND INOS PRODUCTION, AND INCREASE ANTIOXIDANT GENE EXPRESSION THAT SUPPRESSED INFLAMMATION. SIRT2 ACTIVITY INCLUDED THE DEACETYLATION OF P65 SUBUNIT OF NF-KAPPABETA AND RIP-1, WHILE SIRT6 HAS BEEN SHOWN TO INTERACT WITH P65/RELA BOUND TO THE NF-KAPPABETA PROMOTER REGION AND REPRESS TRANSCRIPTIONAL ACTIVITY. FURTHERMORE, RECENT STUDIES HAVE SHOWN THAT THE ABSENCE OF SIRT7 PRODUCED AN INCREASE IN INFLAMMATION, ILLUSTRATING THAT SIRT7 ALSO FUNCTIONED TO DECREASE INFLAMMATION. GIVEN THEIR SIGNIFICANT ROLES IN THE REGULATION OF CHRONIC INFLAMMATION, NUCLEAR SIRTUINS REPRESENT POTENTIAL THERAPEUTIC TARGETS IN THE CONTROL OF CHRONIC INFLAMMATORY DISEASES. 2017 12 5561 38 ROLE OF HISTONE DEACETYLASES IN MONOCYTE FUNCTION IN HEALTH AND CHRONIC INFLAMMATORY DISEASES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF 18 MEMBERS THAT PARTICIPATE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN ADDITION TO HISTONES, SOME HDACS ALSO DEACETYLATE TRANSCRIPTION FACTORS AND SPECIFIC CYTOPLASMIC PROTEINS.MONOCYTES, AS PART OF THE INNATE IMMUNE SYSTEM, MAINTAIN TISSUE HOMEOSTASIS AND HELP FIGHT INFECTIONS AND CANCER. IN THESE CELLS, HDACS ARE INVOLVED IN MULTIPLE PROCESSES INCLUDING PROLIFERATION, MIGRATION, DIFFERENTIATION, INFLAMMATORY RESPONSE, INFECTIONS, AND TUMORIGENESIS. HERE, A SYSTEMATIC DESCRIPTION OF THE ROLE THAT MOST HDACS PLAY IN THESE FUNCTIONS IS REVIEWED. SPECIFICALLY, SOME HDACS INDUCE A PRO-INFLAMMATORY RESPONSE AND PLAY MAJOR ROLES IN HOST DEFENSE. CONVERSELY, OTHER HDACS REPROGRAM MONOCYTES AND MACROPHAGES TOWARDS AN IMMUNOSUPPRESSIVE PHENOTYPE. THE RIGHT BALANCE BETWEEN BOTH TYPES HELPS MONOCYTES TO RESPOND CORRECTLY TO THE DIFFERENT PHYSIOLOGICAL/PATHOLOGICAL STIMULI. HOWEVER, ABERRANT EXPRESSIONS OR ACTIVITIES OF SPECIFIC HDACS ARE ASSOCIATED WITH AUTOIMMUNE DISEASES ALONG WITH OTHER CHRONIC INFLAMMATORY DISEASES, INFECTIONS, OR CANCER.THIS PAPER CRITICALLY REVIEWS THE INTERESTING AND EXTENSIVE KNOWLEDGE REGARDING THE ROLE OF SOME HDACS IN THESE PATHOLOGIES. IT ALSO SHOWS THAT AS YET, VERY LITTLE PROGRESS HAS BEEN MADE TOWARD THE GOAL OF FINDING EFFECTIVE HDAC-TARGETED THERAPIES. HOWEVER, GIVEN THEIR OBVIOUS POTENTIAL, WE CONCLUDE THAT IT IS WORTH THE EFFORT TO DEVELOP MONOCYTE-SPECIFIC DRUGS THAT SELECTIVELY TARGET HDAC SUBTYPES WITH THE AIM OF FINDING EFFECTIVE TREATMENTS FOR DISEASES IN WHICH OUR INNATE IMMUNE SYSTEM IS INVOLVED. 2021 13 3207 35 HDACI: CELLULAR EFFECTS, OPPORTUNITIES FOR RESTORATIVE DENTISTRY. ACETYLATION OF HISTONE AND NON-HISTONE PROTEINS ALTERS GENE EXPRESSION AND INDUCES A HOST OF CELLULAR EFFECTS. THE ACETYLATION PROCESS IS HOMEOSTATICALLY BALANCED BY TWO GROUPS OF CELLULAR ENZYMES, HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). HAT ACTIVITY RELAXES THE STRUCTURE OF THE HUMAN CHROMATIN, RENDERING IT TRANSCRIPTIONALLY ACTIVE, THEREBY INCREASING GENE EXPRESSION. IN CONTRAST, HDAC ACTIVITY LEADS TO GENE SILENCING. THE ENZYMATIC BALANCE CAN BE 'TIPPED' BY HISTONE DEACETYLASE INHIBITORS (HDACI), LEADING TO AN ACCUMULATION OF ACETYLATED PROTEINS, WHICH SUBSEQUENTLY MODIFY CELLULAR PROCESSES INCLUDING STEM CELL DIFFERENTIATION, CELL CYCLE, APOPTOSIS, GENE EXPRESSION, AND ANGIOGENESIS. THERE IS A VARIETY OF NATURAL AND SYNTHETIC HDACI AVAILABLE, AND THEIR PLEIOTROPIC EFFECTS HAVE CONTRIBUTED TO DIVERSE CLINICAL APPLICATIONS, NOT ONLY IN CANCER BUT ALSO IN NON-CANCER AREAS, SUCH AS CHRONIC INFLAMMATORY DISEASE, BONE ENGINEERING, AND NEURODEGENERATIVE DISEASE. INDEED, IT APPEARS THAT HDACI-MODULATED EFFECTS MAY DIFFER BETWEEN 'NORMAL' AND TRANSFORMED CELLS, PARTICULARLY WITH REGARD TO REACTIVE OXYGEN SPECIES ACCUMULATION, APOPTOSIS, PROLIFERATION, AND CELL CYCLE ARREST. THE POTENTIAL BENEFICIAL EFFECTS OF HDACI FOR HEALTH, RESULTING FROM THEIR ABILITY TO REGULATE GLOBAL GENE EXPRESSION BY EPIGENETIC MODIFICATION OF DNA-ASSOCIATED PROTEINS, ALSO OFFER POTENTIAL FOR APPLICATION WITHIN RESTORATIVE DENTISTRY, WHERE THEY MAY PROMOTE DENTAL TISSUE REGENERATION FOLLOWING PULPAL DAMAGE. 2011 14 4391 36 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 15 5560 33 ROLE OF HISTONE DEACETYLASE 2 IN EPIGENETICS AND CELLULAR SENESCENCE: IMPLICATIONS IN LUNG INFLAMMAGING AND COPD. HISTONE DEACETYLASE 2 (HDAC2) IS A CLASS I HISTONE DEACETYLASE THAT REGULATES VARIOUS CELLULAR PROCESSES, SUCH AS CELL CYCLE, SENESCENCE, PROLIFERATION, DIFFERENTIATION, DEVELOPMENT, APOPTOSIS, AND GLUCOCORTICOID FUNCTION IN INHIBITING INFLAMMATORY RESPONSE. HDAC2 HAS BEEN SHOWN TO PROTECT AGAINST DNA DAMAGE RESPONSE AND CELLULAR SENESCENCE/PREMATURE AGING VIA AN EPIGENETIC MECHANISM IN RESPONSE TO OXIDATIVE STRESS. THESE PHENOMENA ARE OBSERVED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HDAC2 IS POSTTRANSLATIONALLY MODIFIED BY OXIDATIVE/CARBONYL STRESS IMPOSED BY CIGARETTE SMOKE AND OXIDANTS, LEADING TO ITS REDUCTION VIA AN UBIQUITINATION-PROTEASOME DEPENDENT DEGRADATION IN LUNGS OF PATIENTS WITH COPD. IN THIS PERSPECTIVE, WE HAVE DISCUSSED THE ROLE OF HDAC2 POSTTRANSLATIONAL MODIFICATIONS AND ITS ROLE IN REGULATION OF INFLAMMATION, HISTONE/DNA EPIGENETIC MODIFICATIONS, DNA DAMAGE RESPONSE, AND CELLULAR SENESCENCE, PARTICULARLY IN INFLAMMAGING, AND DURING THE DEVELOPMENT OF COPD. WE HAVE ALSO DISCUSSED THE POTENTIAL DIRECTIONS FOR FUTURE TRANSLATIONAL RESEARCH AVENUES IN MODULATING LUNG INFLAMMAGING AND CELLULAR SENESCENCE BASED ON EPIGENETIC CHROMATIN MODIFICATIONS IN DISEASES ASSOCIATED WITH INCREASED OXIDATIVE STRESS. 2012 16 1035 36 CLASS I HISTONE DEACETYLASE INHIBITION IMPROVES PANCREATITIS OUTCOME BY LIMITING LEUKOCYTE RECRUITMENT AND ACINAR-TO-DUCTAL METAPLASIA. BACKGROUND AND PURPOSE: PANCREATITIS IS A COMMON INFLAMMATION OF THE PANCREAS WITH RISING INCIDENCE IN MANY COUNTRIES. DESPITE IMPROVEMENTS IN DIAGNOSTIC TECHNIQUES, THE DISEASE IS ASSOCIATED WITH HIGH RISK OF SEVERE MORBIDITY AND MORTALITY AND THERE IS AN URGENT NEED FOR NEW THERAPEUTIC INTERVENTIONS. IN THIS STUDY, WE EVALUATED WHETHER HISTONE DEACETYLASES (HDACS), KEY EPIGENETIC REGULATORS OF GENE TRANSCRIPTION, ARE INVOLVED IN THE DEVELOPMENT OF THE DISEASE. EXPERIMENTAL APPROACH: WE ANALYSED HDAC REGULATION DURING CERULEIN-INDUCED ACUTE, CHRONIC AND AUTOIMMUNE PANCREATITIS USING DIFFERENT TRANSGENIC MOUSE MODELS. THE FUNCTIONAL RELEVANCE OF CLASS I HDACS WAS TESTED WITH THE SELECTIVE INHIBITOR MS-275 IN VIVO UPON PANCREATITIS INDUCTION AND IN VITRO IN ACTIVATED MACROPHAGES AND PRIMARY ACINAR CELL EXPLANTS. KEY RESULTS: HDAC EXPRESSION AND ACTIVITY WERE UP-REGULATED IN A TIME-DEPENDENT MANNER FOLLOWING INDUCTION OF PANCREATITIS, WITH THE HIGHEST ABUNDANCE OBSERVED FOR CLASS I HDACS. CLASS I HDAC INHIBITION DID NOT PREVENT THE INITIAL ACINAR CELL DAMAGE. HOWEVER, IT EFFECTIVELY REDUCED THE INFILTRATION OF INFLAMMATORY CELLS, INCLUDING MACROPHAGES AND T CELLS, IN BOTH ACUTE AND CHRONIC PHASES OF THE DISEASE, AND DIRECTLY DISRUPTED MACROPHAGE ACTIVATION. IN ADDITION, MS-275 TREATMENT REDUCED DNA DAMAGE IN ACINAR CELLS AND LIMITED ACINAR DE-DIFFERENTIATION INTO ACINAR-TO-DUCTAL METAPLASIA IN A CELL-AUTONOMOUS MANNER BY IMPEDING THE EGF RECEPTOR SIGNALLING AXIS. CONCLUSIONS AND IMPLICATIONS: THESE RESULTS DEMONSTRATE THAT CLASS I HDACS ARE CRITICALLY INVOLVED IN THE DEVELOPMENT OF ACUTE AND CHRONIC FORMS OF PANCREATITIS AND SUGGEST THAT BLOCKADE OF CLASS I HDAC ISOFORMS IS A PROMISING TARGET TO IMPROVE THE OUTCOME OF THE DISEASE. 2017 17 2026 35 EPIGENETIC CHANGES IN BONE MARROW PROGENITOR CELLS INFLUENCE THE INFLAMMATORY PHENOTYPE AND ALTER WOUND HEALING IN TYPE 2 DIABETES. CLASSICALLY ACTIVATED (M1) MACROPHAGES ARE KNOWN TO PLAY A ROLE IN THE DEVELOPMENT OF CHRONIC INFLAMMATION ASSOCIATED WITH IMPAIRED WOUND HEALING IN TYPE 2 DIABETES (T2D); HOWEVER, THE MECHANISM RESPONSIBLE FOR THE DOMINANT PROINFLAMMATORY (M1) MACROPHAGE PHENOTYPE IN T2D WOUNDS IS UNKNOWN. SINCE EPIGENETIC ENZYMES CAN DIRECT MACROPHAGE PHENOTYPES, WE ASSESSED THE ROLE OF HISTONE METHYLATION IN BONE MARROW (BM) STEM/PROGENITOR CELLS IN THE PROGRAMMING OF MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE. WE HAVE FOUND THAT A REPRESSIVE HISTONE METHYLATION MARK, H3K27ME3, IS DECREASED AT THE PROMOTER OF THE IL-12 GENE IN BM PROGENITORS AND THIS EPIGENETIC SIGNATURE IS PASSED DOWN TO WOUND MACROPHAGES IN A MURINE MODEL OF GLUCOSE INTOLERANCE (DIET-INDUCED OBESE). THESE EPIGENETICALLY "PREPROGRAMMED" MACROPHAGES RESULT IN POISED MACROPHAGES IN PERIPHERAL TISSUE AND NEGATIVELY IMPACT WOUND REPAIR. WE FOUND THAT IN DIABETIC CONDITIONS THE H3K27 DEMETHYLASE JMJD3 DRIVES IL-12 PRODUCTION IN MACROPHAGES AND THAT IL-12 PRODUCTION CAN BE MODULATED BY INHIBITING JMJD3. USING HUMAN T2D TISSUE AND MURINE MODELS, WE HAVE IDENTIFIED A PREVIOUSLY UNRECOGNIZED MECHANISM BY WHICH MACROPHAGES ARE PROGRAMMED TOWARD A PROINFLAMMATORY PHENOTYPE, ESTABLISHING A PATTERN OF UNRESTRAINED INFLAMMATION ASSOCIATED WITH NONHEALING WOUNDS. HENCE, HISTONE DEMETHYLASE INHIBITOR-BASED THERAPY MAY REPRESENT A NOVEL TREATMENT OPTION FOR DIABETIC WOUNDS. 2015 18 4969 33 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 19 3720 36 INHIBITION OF CLASS I HISTONE DEACETYLASES ABROGATES TUMOR GROWTH FACTOR BETA EXPRESSION AND DEVELOPMENT OF FIBROSIS DURING CHRONIC PANCREATITIS. PANCREATIC FIBROSIS IS THE HALLMARK OF CHRONIC PANCREATITIS, A HIGHLY DEBILITATING DISEASE FOR WHICH THERE IS CURRENTLY NO CURE. THE KEY EVENT AT THE BASIS OF PANCREATIC FIBROSIS IS THE DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS BY ACTIVATED PANCREATIC STELLATE CELLS (PSCS). TRANSFORMING GROWTH FACTOR BETA (TGFBETA) IS A POTENT PROFIBROTIC FACTOR IN THE PANCREAS AS IT PROMOTES THE ACTIVATION OF PSC; THUS, PHARMACOLOGIC INTERVENTIONS THAT EFFECTIVELY REDUCE TGFBETA EXPRESSION HARBOR CONSIDERABLE THERAPEUTIC POTENTIAL IN THE TREATMENT OF CHRONIC PANCREATITIS. IN THIS STUDY, WE INVESTIGATED WHETHER TGFBETA EXPRESSION IS REDUCED BY PHARMACOLOGIC INHIBITION OF THE EPIGENETIC MODIFIERS HISTONE DEACETYLASES (HDACS). TO ADDRESS THIS AIM, CHRONIC PANCREATITIS WAS INDUCED IN C57BL/6 MICE WITH SERIAL INJECTIONS OF CERULEIN, AND THE SELECTIVE CLASS 1 HDAC INHIBITOR MS-275 WAS ADMINISTERED IN VIVO IN A PREVENTIVE AND THERAPEUTIC MANNER. BOTH MS-275 REGIMENS POTENTLY REDUCED DEPOSITION OF EXTRACELLULAR MATRIX AND DEVELOPMENT OF FIBROSIS IN THE PANCREAS AFTER 4 WEEKS OF CHRONIC PANCREATITIS. REDUCED PANCREATIC FIBROSIS WAS CONCOMITANT WITH LOWER EXPRESSION OF PANCREATIC TGFBETA AND CONSEQUENT REDUCED PSC ACTIVATION. IN SEARCH OF THE CELL TYPES TARGETED BY THE INHIBITOR, WE FOUND THAT MS-275 TREATMENT ABROGATED THE EXPRESSION OF TGFBETA IN ACINAR CELLS STIMULATED BY CERULEIN TREATMENT. OUR STUDY DEMONSTRATES THAT MS-275 IS AN EFFECTIVE ANTIFIBROTIC AGENT IN THE CONTEXT OF EXPERIMENTAL CHRONIC PANCREATITIS AND THUS MAY CONSTITUTE A VALID THERAPEUTIC INTERVENTION FOR THIS SEVERE DISEASE. 2018 20 5946 32 TARGETING THE EPIGENOME IN THE TREATMENT OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC MODIFICATION OF GENE EXPRESSION BY METHYLATION OF DNA AND VARIOUS POST-TRANSLATIONAL MODIFICATIONS OF HISTONES MAY AFFECT THE EXPRESSION OF MULTIPLE INFLAMMATORY GENES. ACETYLATION OF HISTONES BY HISTONE ACETYLTRANSFERASES ACTIVATES INFLAMMATORY GENES, WHEREAS HISTONE DEACETYLATION RESULTS IN INFLAMMATORY GENE REPRESSION. CORTICOSTEROIDS EXERT THEIR ANTIINFLAMMATORY EFFECTS PARTLY BY INDUCING ACETYLATION OF ANTIINFLAMMATORY GENES, BUT MAINLY BY RECRUITING HISTONE DEACETYLASE-2 (HDAC2) TO ACTIVATED INFLAMMATORY GENES. HDAC2 DEACETYLATES ACETYLATED GLUCOCORTICOID RECEPTORS SO THAT THEY CAN SUPPRESS ACTIVATED INFLAMMATORY GENES IN ASTHMA. IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), THERE IS RESISTANCE TO THE ANTIINFLAMMATORY ACTIONS OF CORTICOSTEROIDS, WHICH IS EXPLAINED BY REDUCED ACTIVITY AND EXPRESSION OF HDAC2. THIS CAN BE REVERSED BY A PLASMID VECTOR, WHICH RESTORES HDAC2 LEVELS, BUT MAY ALSO BE ACHIEVED BY LOW CONCENTRATIONS OF THEOPHYLLINE. OXIDATIVE STRESS CAUSES CORTICOSTEROID RESISTANCE BY REDUCING HDAC2 ACTIVITY AND EXPRESSION BY ACTIVATION OF PHOSPHOINOSITIDE-3-KINASE-DELTA, RESULTING IN HDAC2 PHOSPHORYLATION VIA A CASCADE OF KINASES. THEOPHYLLINE REVERSES CORTICOSTEROID RESISTANCE BY DIRECTLY INHIBITING OXIDANT-ACTIVATED PI3KDELTA AND IS MIMICKED BY PI3KDELTA KNOCKOUT OR BY SELECTIVE INHIBITORS. OTHER TREATMENTS MAY ALSO INTERACT IN THIS PATHWAY, MAKING IT POSSIBLE TO REVERSE CORTICOSTEROID RESISTANCE IN PATIENTS WITH COPD, AS WELL AS IN SMOKERS WITH ASTHMA AND SOME PATIENTS WITH SEVERE ASTHMA IN WHOM SIMILAR MECHANISMS OPERATE. OTHER HISTONE MODIFICATIONS, INCLUDING METHYLATION, TYROSINE NITRATION, AND UBIQUITINATION MAY ALSO AFFECT HISTONE FUNCTION AND INFLAMMATORY GENE EXPRESSION, AND BETTER UNDERSTANDING OF THESE EPIGENETIC PATHWAYS COULD LED TO NOVEL ANTIINFLAMMATORY THERAPIES, PARTICULARLY IN CORTICOSTEROID-RESISTANT INFLAMMATION. 2009