1 3357 111 HISTONE H3 LYSINE 9 DI-METHYLATION AS AN EPIGENETIC SIGNATURE OF THE INTERFERON RESPONSE. EFFECTIVE ANTIVIRAL IMMUNITY DEPENDS ON THE ABILITY OF INFECTED CELLS OR CELLS TRIGGERED WITH VIRUS-DERIVED NUCLEIC ACIDS TO PRODUCE TYPE I INTERFERON (IFN), WHICH ACTIVATES TRANSCRIPTION OF NUMEROUS ANTIVIRAL GENES. HOWEVER, DISPROPORTIONATELY STRONG OR CHRONIC IFN EXPRESSION IS A COMMON CAUSE OF INFLAMMATORY AND AUTOIMMUNE DISEASES. WE DESCRIBE AN EPIGENETIC MECHANISM THAT DETERMINES CELL TYPE-SPECIFIC DIFFERENCES IN IFN AND IFN-STIMULATED GENE (ISG) EXPRESSION IN RESPONSE TO EXOGENOUS SIGNALS. WE IDENTIFY DI-METHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME2) AS A SUPPRESSOR OF IFN AND IFN-INDUCIBLE ANTIVIRAL GENE EXPRESSION. WE SHOW THAT LEVELS OF H3K9ME2 AT IFN AND ISG CORRELATE INVERSELY WITH THE SCOPE AND AMPLITUDE OF IFN AND ISG EXPRESSION IN FIBROBLASTS AND DENDRITIC CELLS. ACCORDINGLY, GENETIC ABLATION OR PHARMACOLOGICAL INACTIVATION OF LYSINE METHYLTRANSFERASE G9A, WHICH IS ESSENTIAL FOR THE GENERATION OF H3K9ME2, RESULTED IN PHENOTYPIC CONVERSION OF FIBROBLASTS INTO HIGHLY POTENT IFN-PRODUCING CELLS AND RENDERED THESE CELLS RESISTANT TO PATHOGENIC RNA VIRUSES. IN SUMMARY, OUR STUDIES IMPLICATE H3K9ME2 AND ENZYMES CONTROLLING ITS ABUNDANCE AS KEY REGULATORS OF INNATE ANTIVIRAL IMMUNITY. 2012 2 5429 29 REGULATION OF TYPE I INTERFERON RESPONSES. TYPE I INTERFERONS (IFNS) ACTIVATE INTRACELLULAR ANTIMICROBIAL PROGRAMMES AND INFLUENCE THE DEVELOPMENT OF INNATE AND ADAPTIVE IMMUNE RESPONSES. CANONICAL TYPE I IFN SIGNALLING ACTIVATES THE JANUS KINASE (JAK)-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) PATHWAY, LEADING TO TRANSCRIPTION OF IFN-STIMULATED GENES (ISGS). HOST, PATHOGEN AND ENVIRONMENTAL FACTORS REGULATE THE RESPONSES OF CELLS TO THIS SIGNALLING PATHWAY AND THUS CALIBRATE HOST DEFENCES WHILE LIMITING TISSUE DAMAGE AND PREVENTING AUTOIMMUNITY. HERE, WE SUMMARIZE THE SIGNALLING AND EPIGENETIC MECHANISMS THAT REGULATE TYPE I IFN-INDUCED STAT ACTIVATION AND ISG TRANSCRIPTION AND TRANSLATION. THESE REGULATORY MECHANISMS DETERMINE THE BIOLOGICAL OUTCOMES OF TYPE I IFN RESPONSES AND WHETHER PATHOGENS ARE CLEARED EFFECTIVELY OR CHRONIC INFECTION OR AUTOIMMUNE DISEASE ENSUES. 2014 3 2055 31 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 4 170 39 ABNORMALITIES OF THE TYPE I INTERFERON SIGNALING PATHWAY IN LUPUS AUTOIMMUNITY. TYPE I INTERFERONS (IFNS), MOSTLY IFNALPHA AND IFNBETA, AND THE TYPE I IFN SIGNATURE ARE IMPORTANT IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AN AUTOIMMUNE CHRONIC CONDITION LINKED TO INFLAMMATION. BOTH IFNALPHA AND IFNBETA TRIGGER A SIGNALING CASCADE THAT, THROUGH THE ACTIVATION OF JAK1, TYK2, STAT1 AND STAT2, INITIATES GENE TRANSCRIPTION OF IFN STIMULATED GENES (ISGS). NOTEWORTHY, OTHER STAT FAMILY MEMBERS AND IFN RESPONSIVE FACTORS (IRFS) CAN ALSO CONTRIBUTE TO THE ACTIVATION OF THE IFN RESPONSE. ABERRANT TYPE I IFN SIGNALING, THEREFORE, CAN EXACERBATE SLE BY DEREGULATED HOMEOSTASIS LEADING TO UNNECESSARY PERSISTENCE OF THE BIOLOGICAL EFFECTS OF TYPE I IFNS. THE ETIOPATHOGENESIS OF SLE IS PARTIALLY KNOWN AND CONSIDERED MULTIFACTORIAL. FAMILY-BASED AND GENOME WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED GENETIC AND TRANSCRIPTIONAL ABNORMALITIES IN KEY MOLECULES DIRECTLY INVOLVED IN THE TYPE I IFN SIGNALING PATHWAY, NAMELY TYK2, STAT1 AND STAT4, AND IRF5. GAIN-OF-FUNCTION MUTATIONS THAT HEIGHTEN IFNALPHA/BETA PRODUCTION, WHICH IN TURN MAINTAINS TYPE I IFN SIGNALING, ARE FOUND IN OTHER PATHOLOGIES LIKE THE INTERFERONOPATHIES. HOWEVER, THE DISTINCTIVE CHARACTERISTICS HAVE YET TO BE DETERMINED. SIGNALING MOLECULES ACTIVATED IN RESPONSE TO TYPE I IFNS ARE UPREGULATED IN IMMUNE CELL SUBSETS AND AFFECTED TISSUES OF SLE PATIENTS. MOREOVER, TYPE I IFNS INDUCE CHROMATIN REMODELING LEADING TO A STATE PERMISSIVE TO TRANSCRIPTION, AND SLE PATIENTS HAVE INCREASED GLOBAL AND GENE-SPECIFIC EPIGENETIC MODIFICATIONS, SUCH AS HYPOMETHYLATION OF DNA AND HISTONE ACETYLATION. EPIGENOME WIDE ASSOCIATION STUDIES (EWAS) HIGHLIGHT IMPORTANT DIFFERENCES BETWEEN SLE PATIENTS AND HEALTHY CONTROLS IN INTERFERON STIMULATED GENES (ISGS). THE COMBINATION OF ENVIRONMENTAL AND GENETIC FACTORS MAY STIMULATE TYPE I IFN SIGNALING TRANSIENTLY AND PRODUCE LONG-LASTING DETRIMENTAL EFFECTS THROUGH EPIGENETIC ALTERATIONS. SUBSTANTIAL EVIDENCE FOR THE PATHOGENIC ROLE OF TYPE I IFNS IN SLE ADVOCATES THE CLINICAL USE OF NEUTRALIZING ANTI-TYPE I IFN RECEPTOR ANTIBODIES AS A THERAPEUTIC STRATEGY, WITH CLINICAL STUDIES ALREADY SHOWING PROMISING RESULTS. CURRENT AND FUTURE CLINICAL TRIALS WILL DETERMINE WHETHER DRUGS TARGETING MOLECULES OF THE TYPE I IFN SIGNALING PATHWAY, LIKE NON-SELECTIVE JAK INHIBITORS OR SPECIFIC TYK2 INHIBITORS, MAY BENEFIT PEOPLE LIVING WITH LUPUS. 2021 5 2493 30 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 1479 26 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 7 730 34 CANCER CELLS RESISTANT TO IMMUNE CHECKPOINT BLOCKADE ACQUIRE INTERFERON-ASSOCIATED EPIGENETIC MEMORY TO SUSTAIN T CELL DYSFUNCTION. PROLONGED INTERFERON (IFN) SIGNALING IN CANCER CELLS CAN PROMOTE RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOW CANCER CELLS RETAIN EFFECTS OF PROLONGED IFN STIMULATION TO COORDINATE RESISTANCE IS UNCLEAR. WE SHOW THAT, ACROSS HUMAN AND/OR MOUSE TUMORS, IMMUNE DYSFUNCTION IS ASSOCIATED WITH CANCER CELLS ACQUIRING EPIGENETIC FEATURES OF INFLAMMATORY MEMORY. HERE, INFLAMMATORY MEMORY DOMAINS, MANY OF WHICH ARE INITIATED BY CHRONIC IFN-GAMMA, ARE MAINTAINED BY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)1 AND IFN REGULATORY FACTOR (IRF)3 AND LINK HISTONE 3 LYSINE 4 MONOMETHYLATION (H3K4ME1)-MARKED CHROMATIN ACCESSIBILITY TO INCREASED EXPRESSION OF A SUBSET OF IFN-STIMULATED GENES (ISGS). THESE ISGS INCLUDE THE RNA SENSOR OAS1 THAT AMPLIFIES TYPE I IFN (IFN-I) AND IMMUNE INHIBITORY GENES. ABROGATING CANCER CELL IFN-I SIGNALING RESTORES ANTI-PROGRAMMED CELL DEATH PROTEIN 1 (PD1) RESPONSE BY INCREASING IFN-GAMMA IN IMMUNE CELLS, PROMOTING DENDRITIC CELL AND CD8(+) T CELL INTERACTIONS, AND EXPANDING T CELLS TOWARD EFFECTOR-LIKE STATES RATHER THAN EXHAUSTED STATES. THUS, CANCER CELLS ACQUIRE INFLAMMATORY MEMORY TO AUGMENT A SUBSET OF ISGS THAT PROMOTE AND PREDICT IFN-DRIVEN IMMUNE DYSFUNCTION. 2023 8 1336 23 DESCRIBING A TRANSCRIPTION FACTOR DEPENDENT REGULATION OF THE MICRORNA TRANSCRIPTOME. WHILE THE TRANSCRIPTION REGULATION OF PROTEIN CODING GENES WAS EXTENSIVELY STUDIED, LITTLE IS KNOWN ON HOW TRANSCRIPTION FACTORS ARE INVOLVED IN TRANSCRIPTION OF NON-CODING RNAS, SPECIFICALLY OF MICRORNAS. HERE, WE PROPOSE A STRATEGY TO STUDY THE POTENTIAL ROLE OF TRANSCRIPTION FACTOR IN REGULATING TRANSCRIPTION OF MICRORNAS USING PUBLICALLY AVAILABLE DATA, COMPUTATIONAL RESOURCES AND HIGH THROUGHPUT DATA. WE USE THE H3K4ME3 EPIGENETIC SIGNATURE TO IDENTIFY MICRORNA PROMOTERS AND CHROMATIN IMMUNOPRECIPITATION (CHIP)-SEQUENCING DATA FROM THE ENCODE PROJECT TO IDENTIFY MICRORNA PROMOTERS THAT ARE ENRICHED WITH TRANSCRIPTION FACTOR BINDING SITES. BY TRANSFECTING CELLS OF INTEREST WITH SHRNA TARGETING A TRANSCRIPTION FACTOR OF INTEREST AND SUBJECTING THE CELLS TO MICRORNA ARRAY, WE STUDY THE EFFECT OF THIS TRANSCRIPTION FACTOR ON THE MICRORNA TRANSCRIPTOME. AS AN ILLUSTRATIVE EXAMPLE WE USE OUR STUDY ON THE EFFECT OF STAT3 ON THE MICRORNA TRANSCRIPTOME OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. 2016 9 3322 25 HISTONE ACETYLTRANSFERASE P300 INDUCES DE NOVO SUPER-ENHANCERS TO DRIVE CELLULAR SENESCENCE. ACCUMULATION OF SENESCENT CELLS DURING AGING CONTRIBUTES TO CHRONIC INFLAMMATION AND AGE-RELATED DISEASES. WHILE SENESCENCE IS ASSOCIATED WITH PROFOUND ALTERATIONS OF THE EPIGENOME, A SYSTEMATIC VIEW OF EPIGENETIC FACTORS IN REGULATING SENESCENCE IS LACKING. HERE, WE CURATED A LIBRARY OF SHORT HAIRPIN RNAS FOR TARGETED SILENCING OF ALL KNOWN EPIGENETIC PROTEINS AND PERFORMED A HIGH-THROUGHPUT SCREEN TO IDENTIFY KEY CANDIDATES WHOSE DOWNREGULATION CAN DELAY REPLICATIVE SENESCENCE OF PRIMARY HUMAN CELLS. THIS SCREEN IDENTIFIED MULTIPLE NEW PLAYERS INCLUDING THE HISTONE ACETYLTRANSFERASE P300 THAT WAS FOUND TO BE A PRIMARY DRIVER OF THE SENESCENT PHENOTYPE. P300, BUT NOT THE PARALOGOUS CBP, INDUCES A DYNAMIC HYPER-ACETYLATED CHROMATIN STATE AND PROMOTES THE FORMATION OF ACTIVE ENHANCER ELEMENTS IN THE NON-CODING GENOME, LEADING TO A SENESCENCE-SPECIFIC GENE EXPRESSION PROGRAM. OUR WORK ILLUSTRATES A CAUSAL ROLE OF HISTONE ACETYLTRANSFERASES AND ACETYLATION IN SENESCENCE AND SUGGESTS P300 AS A POTENTIAL THERAPEUTIC TARGET FOR SENESCENCE AND AGE-RELATED DISEASES. 2019 10 926 33 CHRONIC INFLAMMATION PATHWAY NF-KAPPAB COOPERATES WITH EPIGENETIC REPROGRAMMING TO DRIVE THE MALIGNANT PROGRESSION OF GLIOBLASTOMA. WITHOUT AN EFFECTIVE STRATEGY FOR TARGETED THERAPY, GLIOBLASTOMA IS STILL INCURABLE WITH A MEDIAN SURVIVAL OF ONLY 15 MONTHS. BOTH CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING ARE HALLMARKS OF CANCER. HOWEVER, THE MECHANISMS AND CONSEQUENCES OF THEIR COOPERATION IN GLIOBLASTOMA REMAIN UNKNOWN. HERE, WE DISCOVER THAT CHRONIC INFLAMMATION GOVERNS H3K27ME3 REPROGRAMMING IN GLIOBLASTOMA THROUGH THE CANONICAL NF-KAPPAB PATHWAY TO TARGET EZH2. BEING A CRUCIAL MEDIATOR OF CHRONIC INFLAMMATION, THE CANONICAL NF-KAPPAB SIGNALLING SPECIFICALLY DIRECTS THE EXPRESSION AND REDISTRIBUTION OF H3K27ME3 BUT NOT H3K4ME3, H3K9ME3 AND H3K36ME3. USING RNA-SEQ SCREENING TO FOCUS ON GENES ENCODING METHYLTRANSFERASES AND DEMETHYLASES OF HISTONE, WE IDENTIFY EZH2 AS A KEY METHYLTRANSFERASE TO CONTROL INFLAMMATION-TRIGGERED EPIGENETIC REPROGRAMMING IN GLIOMAGENESIS. MECHANISTICALLY, NF-KAPPAB SELECTIVELY DRIVES THE EXPRESSION OF EZH2 BY ACTIVATING ITS TRANSCRIPTION, CONSEQUENTLY RESULTING IN A GLOBAL CHANGE IN H3K27ME3 EXPRESSION AND DISTRIBUTION. FURTHERMORE, WE FIND THAT CO-ACTIVATION OF NF-KAPPAB AND EZH2 CONFERS THE POOREST CLINICAL OUTCOME, AND THAT THE RISK FOR GLIOBLASTOMA CAN BE ACCURATELY MOLECULARLY STRATIFIED BY NF-KAPPAB AND EZH2. IT IS NOTABLE THAT NF-KAPPAB CAN POTENTIALLY COOPERATE WITH EZH2 IN MORE THAN ONE WAY, AND MOST IMPORTANTLY, WE DEMONSTRATE A SYNERGISTIC EFFECT OF CANCER CELLS INDUCED BY COMBINATORY INHIBITION OF NF-KAPPAB AND EZH2, WHICH BOTH ARE FREQUENTLY OVER-ACTIVATED IN GLIOBLASTOMA. IN SUMMARY, WE UNCOVER A FUNCTIONAL COOPERATION BETWEEN CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING IN GLIOBLASTOMA, COMBINED TARGETING OF WHICH BY INHIBITORS GUARANTEED IN SAFETY AND AVAILABILITY FURNISHES A POTENT STRATEGY FOR EFFECTIVE TREATMENT OF THIS FATAL DISEASE. 2022 11 2228 25 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 12 911 29 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 13 5279 28 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 14 834 29 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 15 5547 26 ROLE OF EPIGENETIC MODIFICATION IN INTERFERON TREATMENT OF HEPATITIS B VIRUS INFECTION. HUMAN HEPATITIS B VIRUS (HBV) IS A SMALL, ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. CHRONIC HEPATITIS B (CHB) IS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA PATHOGENESIS. INTERFERONS (IFNS) HAVE BEEN USED FOR THE TREATMENT OF CHB FOR A LONG TIME, WITH ADVANTAGES INCLUDING LESS TREATMENT DURATION AND SUSTAINED VIROLOGICAL RESPONSE. PRESENTLY, VARIOUS EVIDENCE SUGGESTS THAT EPIGENETIC MODIFICATION OF THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) AND THE HOST GENOME IS CRUCIAL FOR THE REGULATION OF VIRAL ACTIVITY. THIS MODIFICATION INCLUDES HISTONE ACETYLATION, DNA METHYLATION, N6-METHYLADENOSINE, AND NON-CODING RNA MODIFICATION. IFN TREATMENT FOR CHB CAN STIMULATE MULTIPLE IFN-STIMULATED GENES FOR INHIBITING VIRUS REPLICATION. IFNS CAN ALSO AFFECT THE HBV LIFE CYCLE THROUGH EPIGENETIC MODULATION. IN THIS REVIEW, WE SUMMARIZED THE DIFFERENT MECHANISMS THROUGH WHICH IFN-ALPHA INHIBITS HBV REPLICATION, INCLUDING EPIGENETIC REGULATION. MOREOVER, THE MECHANISMS UNDERLYING IFN ACTIVITY ARE DISCUSSED, WHICH INDICATED ITS POTENTIAL AS A NOVEL TREATMENT FOR CHB. IT IS PROPOSED THAT EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION, DNA METHYLATION, M6A METHYLATION COULD BE THE TARGETS OF IFN, WHICH MAY OFFER A NOVEL APPROACH TO HBV TREATMENT. 2022 16 6176 33 THE HISTONE H3 LYSINE-27 DEMETHYLASE JMJD3 LINKS INFLAMMATION TO INHIBITION OF POLYCOMB-MEDIATED GENE SILENCING. EPIGENETIC CHROMATIN MARKS RESTRICT THE ABILITY OF DIFFERENTIATED CELLS TO CHANGE GENE EXPRESSION PROGRAMS IN RESPONSE TO ENVIRONMENTAL CUES AND TO TRANSDIFFERENTIATE. POLYCOMB GROUP (PCG) PROTEINS MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION IN A MANNER DEPENDENT ON HISTONE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3). HOWEVER, MACROPHAGES MIGRATED INTO INFLAMED TISSUES CAN TRANSDIFFERENTIATE, BUT IT IS UNKNOWN WHETHER INFLAMMATION ALTERS PCG-DEPENDENT SILENCING. HERE WE SHOW THAT THE JMJC-DOMAIN PROTEIN JMJD3 IS A H3K27ME DEMETHYLASE EXPRESSED IN MACROPHAGES IN RESPONSE TO BACTERIAL PRODUCTS AND INFLAMMATORY CYTOKINES. JMJD3 BINDS PCG TARGET GENES AND REGULATES THEIR H3K27ME3 LEVELS AND TRANSCRIPTIONAL ACTIVITY. THE DISCOVERY OF AN INDUCIBLE ENZYME THAT ERASES A HISTONE MARK CONTROLLING DIFFERENTIATION AND CELL IDENTITY PROVIDES A LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME, WHICH COULD BE THE BASIS FOR MACROPHAGE PLASTICITY AND MIGHT EXPLAIN THE DIFFERENTIATION ABNORMALITIES IN CHRONIC INFLAMMATION. 2007 17 5937 32 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 18 4768 28 NUCLEAR EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION IN LIVER CELLS. ALCOHOL INGESTION CAUSES ALTERATION IN SEVERAL CELLULAR MECHANISMS, AND LEADS TO INFLAMMATION, APOPTOSIS, IMMUNOLOGICAL RESPONSE DEFECTS, AND FIBROSIS. THESE PHENOMENA ARE ASSOCIATED WITH SIGNIFICANT CHANGES IN THE EPIGENETIC MECHANISMS, AND SUBSEQUENTLY, TO LIVER CELL MEMORY. THE UBIQUITIN-PROTEASOME PATHWAY IS ONE OF THE VITAL PATHWAYS IN THE CELL THAT BECOMES DYSFUNCTIONAL AS A RESULT OF CHRONIC ETHANOL CONSUMPTION. INHIBITION OF THE PROTEASOME ACTIVITY IN THE NUCLEUS CAUSES CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE MODIFYING ENZYMES, AND THEREFORE, AFFECTS EPIGENETIC MECHANISMS. ALCOHOL CONSUMPTION HAS BEEN ASSOCIATED WITH AN INCREASE IN HISTONE ACETYLATION AND A DECREASE IN HISTONE METHYLATION, WHICH LEADS TO GENE EXPRESSION CHANGES. DNA AND HISTONE MODIFICATIONS THAT RESULT FROM ETHANOL-INDUCED PROTEASOME INHIBITION ARE KEY PLAYERS IN REGULATING GENE EXPRESSION, ESPECIALLY GENES INVOLVED IN THE CELL CYCLE, IMMUNOLOGICAL RESPONSES, AND METABOLISM OF ETHANOL. THE PRESENT REVIEW HIGHLIGHTS THE CONSEQUENCES OF ETHANOL-INDUCED PROTEASOME INHIBITION IN THE NUCLEUS OF LIVER CELLS THAT ARE CHRONICALLY EXPOSED TO ETHANOL. 2009 19 5872 27 SUSTAINED TNF-ALPHA STIMULATION LEADS TO TRANSCRIPTIONAL MEMORY THAT GREATLY ENHANCES SIGNAL SENSITIVITY AND ROBUSTNESS. TRANSCRIPTIONAL MEMORY ALLOWS CERTAIN GENES TO RESPOND TO PREVIOUSLY EXPERIENCED SIGNALS MORE ROBUSTLY. HOWEVER, WHETHER AND HOW THE KEY PROINFLAMMATORY CYTOKINE TNF-ALPHA MEDIATES TRANSCRIPTIONAL MEMORY ARE POORLY UNDERSTOOD. USING HEK293F CELLS AS A MODEL SYSTEM, WE REPORT THAT SUSTAINED TNF-ALPHA STIMULATION INDUCES TRANSCRIPTIONAL MEMORY DEPENDENT ON TET ENZYMES. THE HYPOMETHYLATED STATUS OF TRANSCRIPTIONAL REGULATORY REGIONS CAN BE INHERITED, FACILITATING NF-KAPPAB BINDING AND MORE ROBUST SUBSEQUENT ACTIVATION. A HIGH INITIAL METHYLATION LEVEL AND CPG DENSITY AROUND KAPPAB SITES ARE CORRELATED WITH THE FUNCTIONAL POTENTIAL OF TRANSCRIPTIONAL MEMORY MODULES. INTERESTINGLY, THE CALCB GENE, ENCODING THE PROVEN MIGRAINE THERAPEUTIC TARGET CGRP, EXHIBITS THE BEST TRANSCRIPTIONAL MEMORY. A NEIGHBORING PRIMATE-SPECIFIC ENDOGENOUS RETROVIRUS STIMULATES MORE RAPID, MORE STRONG, AND AT LEAST 100-FOLD MORE SENSITIVE CALCB INDUCTION IN SUBSEQUENT TNF-ALPHA STIMULATION. OUR STUDY REVEALS THAT TNF-ALPHA-MEDIATED TRANSCRIPTIONAL MEMORY IS GOVERNED BY ACTIVE DNA DEMETHYLATION AND GREATLY SENSITIZES MEMORY GENES TO MUCH LOWER DOSES OF INFLAMMATORY CUES. 2020 20 6100 33 THE EMERGING ROLE OF EPIGENETIC MODIFIERS IN REPAIR OF DNA DAMAGE ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES (ROS), WHICH CAN CONTRIBUTE TO THE INITIATION AND DEVELOPMENT OF MANY DIFFERENT HUMAN CANCERS. ABERRANT EPIGENETIC ALTERATIONS THAT CAUSE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES ARE ALSO IMPLICATED IN MANY DISEASES ASSOCIATED WITH INFLAMMATION, INCLUDING CANCER. HOWEVER, IT IS NOT CLEAR HOW ALTERED EPIGENETIC GENE SILENCING IS INITIATED DURING CHRONIC INFLAMMATION. THE HIGH LEVEL OF ROS AT SITES OF INFLAMMATION IS KNOWN TO INDUCE OXIDATIVE DNA DAMAGE IN SURROUNDING EPITHELIAL CELLS. FURTHERMORE, DNA DAMAGE IS KNOWN TO TRIGGER SEVERAL RESPONSES, INCLUDING RECRUITMENT OF DNA REPAIR PROTEINS, TRANSCRIPTIONAL REPRESSION, CHROMATIN MODIFICATIONS AND OTHER CELL SIGNALING EVENTS. RECRUITMENT OF EPIGENETIC MODIFIERS TO CHROMATIN IN RESPONSE TO DNA DAMAGE RESULTS IN TRANSIENT COVALENT MODIFICATIONS TO CHROMATIN SUCH AS HISTONE UBIQUITINATION, ACETYLATION AND METHYLATION AND DNA METHYLATION. DNA DAMAGE ALSO ALTERS NON-CODING RNA EXPRESSION. ALL OF THESE ALTERATIONS HAVE THE POTENTIAL TO ALTER GENE EXPRESSION AT SITES OF DAMAGE. TYPICALLY, THESE MODIFICATIONS AND GENE TRANSCRIPTION ARE RESTORED BACK TO NORMAL ONCE THE REPAIR OF THE DNA DAMAGE IS COMPLETED. HOWEVER, CHRONIC INFLAMMATION MAY INDUCE SUSTAINED DNA DAMAGE AND DNA DAMAGE RESPONSES THAT RESULT IN THESE TRANSIENT COVALENT CHROMATIN MODIFICATIONS BECOMING MITOTICALLY STABLE EPIGENETIC ALTERATIONS. UNDERSTANDING HOW EPIGENETIC ALTERATIONS ARE INITIATED DURING CHRONIC INFLAMMATION WILL ALLOW US TO DEVELOP PHARMACEUTICAL STRATEGIES TO PREVENT OR TREAT CHRONIC INFLAMMATION-INDUCED CANCER. THIS REVIEW WILL FOCUS ON TYPES OF DNA DAMAGE AND EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES, THE TYPES OF DNA DAMAGE AND TRANSIENT COVALENT CHROMATIN MODIFICATIONS INDUCED BY INFLAMMATION AND OXIDATIVE DNA DAMAGE AND HOW THESE MODIFICATIONS MAY RESULT IN EPIGENETIC ALTERATIONS. 2019