1 2387 120 EPIGENETIC REMODELING BY VITAMIN C POTENTIATES PLASMA CELL DIFFERENTIATION. ASCORBATE (VITAMIN C) IS AN ESSENTIAL MICRONUTRIENT IN HUMANS. THE SEVERE CHRONIC DEFICIENCY OF ASCORBATE, TERMED SCURVY, HAS LONG BEEN ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO INFECTIONS. HOW ASCORBATE AFFECTS THE IMMUNE SYSTEM AT THE CELLULAR AND MOLECULAR LEVELS REMAINED UNCLEAR. FROM A MICRONUTRIENT ANALYSIS, WE IDENTIFIED ASCORBATE AS A POTENT ENHANCER FOR ANTIBODY RESPONSE BY FACILITATING THE IL-21/STAT3-DEPENDENT PLASMA CELL DIFFERENTIATION IN MOUSE AND HUMAN B CELLS. THE EFFECT OF ASCORBATE IS UNIQUE AS OTHER ANTIOXIDANTS FAILED TO PROMOTE PLASMA CELL DIFFERENTIATION. ASCORBATE IS ESPECIALLY CRITICAL DURING EARLY B CELL ACTIVATION BY POISING THE CELLS TO PLASMA CELL LINEAGE WITHOUT AFFECTING THE PROXIMAL IL-21/STAT3 SIGNALING AND THE OVERALL TRANSCRIPTOME. AS A COFACTOR FOR EPIGENETIC ENZYMES, ASCORBATE FACILITATES TET2/3-MEDIATED DNA MODIFICATION AND DEMETHYLATION OF MULTIPLE ELEMENTS AT THE PRDM1 LOCUS. DNA DEMETHYLATION AUGMENTS STAT3 ASSOCIATION AT THE PRDM1 PROMOTER AND A DOWNSTREAM ENHANCER, THUS ENSURING EFFICIENT GENE EXPRESSION AND PLASMA CELL DIFFERENTIATION. THE RESULTS SUGGEST THAT AN ADEQUATE LEVEL OF ASCORBATE IS REQUIRED FOR ANTIBODY RESPONSE AND HIGHLIGHT HOW MICRONUTRIENTS MAY REGULATE THE ACTIVITY OF EPIGENETIC ENZYMES TO REGULATE GENE EXPRESSION. OUR FINDINGS IMPLY THAT EPIGENETIC ENZYMES CAN FUNCTION AS SENSORS TO GAUGE THE AVAILABILITY OF METABOLITES AND INFLUENCE CELL FATE DECISIONS. 2022 2 6399 37 THE ROLES AND MECHANISMS OF ACTIONS OF VITAMIN C IN BONE: NEW DEVELOPMENTS. VITAMIN C IS AN IMPORTANT ANTIOXIDANT AND COFACTOR THAT IS INVOLVED IN THE REGULATION OF DEVELOPMENT, FUNCTION, AND MAINTENANCE OF SEVERAL CELL TYPES IN THE BODY. DEFICIENCIES IN VITAMIN C CAN LEAD TO CONDITIONS SUCH AS SCURVY, WHICH, AMONG OTHER AILMENTS, CAUSES GINGIVIA, BONE PAIN, AND IMPAIRED WOUND HEALING. THIS REVIEW EXAMINES THE FUNCTIONAL IMPORTANCE OF VITAMIN C AS IT RELATES TO THE DEVELOPMENT AND MAINTENANCE OF BONE TISSUES. ANALYSIS OF SEVERAL EPIDEMIOLOGICAL STUDIES AND GENETIC MOUSE MODELS REGARDING THE EFFECT OF VITAMIN C SHOWS A POSITIVE EFFECT ON BONE HEALTH. OVERALL, VITAMIN C EXERTS A POSITIVE EFFECT ON TRABECULAR BONE FORMATION BY INFLUENCING EXPRESSION OF BONE MATRIX GENES IN OSTEOBLASTS. RECENT STUDIES ON THE MOLECULAR PATHWAY FOR VITAMIN C ACTIONS THAT INCLUDE DIRECT EFFECTS OF VITAMIN C ON TRANSCRIPTIONAL REGULATION OF TARGET GENES BY INFLUENCING THE ACTIVITY OF TRANSCRIPTION FACTORS AND BY EPIGENETIC MODIFICATION OF KEY GENES INVOLVED IN SKELETAL DEVELOPMENT AND MAINTENANCE ARE DISCUSSED. WITH AN UNDERSTANDING OF MECHANISMS INVOLVED IN THE UPTAKE AND METABOLISM OF VITAMIN C AND KNOWLEDGE OF PRECISE MOLECULAR PATHWAYS FOR VITAMIN C ACTIONS IN BONE CELLS, IT IS POSSIBLE THAT NOVEL THERAPEUTIC STRATEGIES CAN BE DEVELOPED OR EXISTING THERAPIES CAN BE MODIFIED FOR THE TREATMENT OF OSTEOPOROTIC FRACTURES. 2015 3 6693 33 VARIABLE INDUCTION OF PRDM1 AND DIFFERENTIATION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH ANERGY. DESPITE ANTIGEN ENGAGEMENT AND INTACT B-CELL-RECEPTOR (BCR) SIGNALING, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS FAIL TO UNDERGO TERMINAL DIFFERENTIATION. WE HYPOTHESIZED THAT SUCH FAILURE MAY BE DUE TO ANERGY, AS CLL CELLS EXHIBIT VARIABLE LEVELS OF NONRESPONSIVENESS TO SURFACE IGM STIMULATION THAT IS REVERSIBLE IN VITRO. MOREOVER, ANERGY IS ASSOCIATED WITH REDUCED DIFFERENTIATION CAPACITY IN NORMAL B CELLS. WE INVESTIGATED RESPONSES OF CLL CELLS TO TWO POTENT DIFFERENTIATION-PROMOTING AGENTS, IL-21 AND CYTOSINE GUANINE DINUCLEOTIDE-ENRICHED OLIGO-DEOXYNUCLEOTIDES. THE INDUCTION OF PR DOMAIN-CONTAINING PROTEIN 1 (PRDM1; ALSO KNOWN AS BLIMP-1), A CRITICAL REGULATOR OF PLASMACYTIC DIFFERENTIATION, BY THESE AGENTS WAS CLOSELY CORRELATED BUT VARIED BETWEEN INDIVIDUAL CASES, DESPITE FUNCTIONALLY INTACT IL-21 RECEPTOR- AND TOLL-LIKE RECEPTOR 9-MEDIATED SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3, AND NUCLEAR FACTOR-KAPPAB PATHWAYS. PRDM1 INDUCTION WAS INVERSELY CORRELATED WITH THE EXTENT OF ANERGY AS MEASURED BY THE ABILITY TO MOBILIZE INTRACELLULAR CA(2+) FOLLOWING BCR CROSSLINKING. PRDM1 RESPONSIVENESS WAS ASSOCIATED WITH OTHER MARKERS OF DIFFERENTIATION AND PROLIFERATION BUT NOT WITH DIFFERENCES IN APOPTOSIS. THE ABILITY TO INDUCE PRDM1 DID CORRELATE WITH DIFFERENTIAL TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF THE PRDM1 GENE. THESE STUDIES EXTEND OUR UNDERSTANDING OF CLL PATHOBIOLOGY, DEMONSTRATING THAT REDUCED DIFFERENTIATION CAPACITY MAY BE A CONSEQUENCE OF ANERGY. EPIGENETIC DRUGS MAY OFFER POSSIBILITIES TO REACTIVATE PRDM1 EXPRESSION AS PART OF NOVEL DIFFERENTIATION THERAPY APPROACHES. 2014 4 559 30 BACH2 ENFORCES THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. DURING CHRONIC INFECTION AND CANCER, A SELF-RENEWING CD8(+) T CELL SUBSET MAINTAINS LONG-TERM IMMUNITY AND IS CRITICAL TO THE EFFECTIVENESS OF IMMUNOTHERAPY. THESE STEM-LIKE CD8(+) T CELLS DIVERGE FROM OTHER CD8(+) SUBSETS EARLY AFTER CHRONIC VIRAL INFECTION. HOWEVER, PATHWAYS GUARDING STEM-LIKE CD8(+) T CELLS AGAINST TERMINAL EXHAUSTION REMAIN UNCLEAR. HERE, WE SHOW THAT THE GENE ENCODING TRANSCRIPTIONAL REPRESSOR BACH2 IS TRANSCRIPTIONALLY AND EPIGENETICALLY ACTIVE IN STEM-LIKE CD8(+) T CELLS BUT NOT TERMINALLY EXHAUSTED CELLS EARLY AFTER INFECTION. BACH2 OVEREXPRESSION ENFORCED STEM-LIKE CELL FATE, WHEREAS BACH2 DEFICIENCY IMPAIRED STEM-LIKE CD8(+) T CELL DIFFERENTIATION. SINGLE-CELL TRANSCRIPTOMIC AND EPIGENOMIC APPROACHES REVEALED THAT BACH2 ESTABLISHED THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. IN ADDITION, BACH2 SUPPRESSED THE MOLECULAR PROGRAM DRIVING TERMINAL EXHAUSTION THROUGH TRANSCRIPTIONAL REPRESSION AND EPIGENETIC SILENCING. THUS, OUR STUDY REVEALS A NEW PATHWAY THAT ENFORCES COMMITMENT TO STEM-LIKE CD8(+) LINEAGE AND PREVENTS AN ALTERNATIVE TERMINALLY EXHAUSTED CELL FATE. 2021 5 6232 35 THE LONG NONCODING RNA MEG3 REGULATES MYOBLAST PLASTICITY AND MUSCLE REGENERATION THROUGH EPITHELIAL-MESENCHYMAL TRANSITION. FORMATION OF SKELETAL MUSCLE IS AMONG THE MOST STRIKING EXAMPLES OF CELLULAR PLASTICITY IN ANIMAL TISSUE DEVELOPMENT, AND WHILE MUSCLE PROGENITOR CELLS ARE REPROGRAMMED BY EPITHELIAL-MESENCHYMAL TRANSITION (EMT) TO MIGRATE DURING EMBRYONIC DEVELOPMENT, THE REGULATION OF EMT IN POST-NATAL MYOGENESIS REMAINS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT THE LONG NONCODING RNA (LNCRNA) MEG3 REGULATES EMT IN MYOBLAST DIFFERENTIATION AND SKELETAL MUSCLE REGENERATION. CHRONIC INHIBITION OF MEG3 IN C2C12 MYOBLASTS INDUCED EMT, AND SUPPRESSED CELL STATE TRANSITIONS REQUIRED FOR DIFFERENTIATION. FURTHERMORE, ADENOVIRAL MEG3 KNOCKDOWN COMPROMISED MUSCLE REGENERATION, WHICH WAS ACCOMPANIED BY ABNORMAL MESENCHYMAL GENE EXPRESSION AND INTERSTITIAL CELL PROLIFERATION. TRANSCRIPTOMIC AND PATHWAY ANALYSES OF MEG3-DEPLETED C2C12 MYOBLASTS AND INJURED SKELETAL MUSCLE REVEALED A SIGNIFICANT DYSREGULATION OF EMT-RELATED GENES, AND IDENTIFIED TGFBETA AS A KEY UPSTREAM REGULATOR. IMPORTANTLY, INHIBITION OF TGFBETAR1 AND ITS DOWNSTREAM EFFECTORS, AND THE EMT TRANSCRIPTION FACTOR SNAI2, RESTORED MANY ASPECTS OF MYOGENIC DIFFERENTIATION IN MEG3-DEPLETED MYOBLASTS IN VITRO WE FURTHER DEMONSTRATE THAT REDUCTION OF MEG3-DEPENDENT EZH2 ACTIVITY RESULTS IN EPIGENETIC ALTERATIONS ASSOCIATED WITH TGFBETA ACTIVATION. THUS, MEG3 REGULATES MYOBLAST IDENTITY TO FACILITATE PROGRESSION INTO DIFFERENTIATION. 2021 6 438 25 ANTIGEN-DRIVEN EGR2 EXPRESSION IS REQUIRED FOR EXHAUSTED CD8(+) T CELL STABILITY AND MAINTENANCE. CHRONIC STIMULATION OF CD8(+) T CELLS TRIGGERS EXHAUSTION, A DISTINCT DIFFERENTIATION STATE WITH DIMINISHED EFFECTOR FUNCTION. EXHAUSTED CELLS EXIST IN MULTIPLE DIFFERENTIATION STATES, FROM STEM-LIKE PROGENITORS THAT ARE THE KEY MEDIATORS OF THE RESPONSE TO CHECKPOINT BLOCKADE, THROUGH TO TERMINALLY EXHAUSTED CELLS. DUE TO ITS CLINICAL RELEVANCE, THERE IS SUBSTANTIAL INTEREST IN DEFINING THE PATHWAYS THAT CONTROL DIFFERENTIATION AND MAINTENANCE OF THESE SUBSETS. HERE, WE SHOW THAT CHRONIC ANTIGEN INDUCES THE ANERGY-ASSOCIATED TRANSCRIPTION FACTOR EGR2 SELECTIVELY WITHIN PROGENITOR EXHAUSTED CELLS IN BOTH CHRONIC LCMV AND TUMOURS. EGR2 ENABLES TERMINAL EXHAUSTION AND STABILIZES THE EXHAUSTED TRANSCRIPTIONAL STATE BY BOTH DIRECT EGR2-DEPENDENT CONTROL OF KEY EXHAUSTION-ASSOCIATED GENES, AND INDIRECT MAINTENANCE OF THE EXHAUSTED EPIGENETIC STATE. WE SHOW THAT EGR2 IS A REGULATOR OF EXHAUSTION THAT EPIGENETICALLY AND TRANSCRIPTIONALLY MAINTAINS THE DIFFERENTIATION COMPETENCY OF PROGENITOR EXHAUSTED CELLS. 2021 7 4761 33 NRF2 SENSITIZES FERROPTOSIS THROUGH L-2-HYDROXYGLUTARATE-MEDIATED CHROMATIN MODIFICATIONS IN SICKLE CELL DISEASE. SICKLE CELL DISEASE (SCD) IS A CHRONIC HEMOLYTIC AND SYSTEMIC HYPOXIA CONDITION WITH CONSTANT OXIDATIVE STRESS AND SIGNIFICANT METABOLIC ALTERATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE CORRELATION BETWEEN METABOLIC ALTERATIONS AND THE PATHOPHYSIOLOGICAL SYMPTOMS. HERE, WE REPORT THAT NRF2, A MASTER REGULATOR OF CELLULAR ANTIOXIDANT RESPONSES, REGULATES THE PRODUCTION OF THE METABOLITE L-2-HYDROXYGLUTARATE (L2HG) TO MEDIATE EPIGENETIC HISTONE HYPERMETHYLATION FOR GENE EXPRESSION INVOLVED IN METABOLIC, OXIDATIVE, AND FERROPTOTIC STRESS RESPONSES IN SCD. MECHANISTICALLY, NRF2 WAS FOUND TO REGULATE THE EXPRESSION OF L2HG DEHYDROGENASE (L2HGDH) TO MEDIATE L2HG PRODUCTION UNDER HYPOXIA. GENE EXPRESSION PROFILE ANALYSIS INDICATED THAT REACTIVE OXYGEN SPECIES (ROS) AND FERROPTOSIS RESPONSES WERE THE MOST SIGNIFICANTLY AFFECTED SIGNALING PATHWAYS AFTER NRF2 ABLATION IN SCD. NRF2 SILENCING AND L2HG SUPPLEMENTATION SENSITIZE HUMAN SICKLE ERYTHROID CELLS TO ROS AND FERROPTOSIS STRESS. THE ABSENCE OF NRF2 AND ACCUMULATION OF L2HG SIGNIFICANTLY AFFECT HISTONE METHYLATION FOR CHROMATIN STRUCTURE MODIFICATION AND REDUCE THE ASSEMBLY OF TRANSCRIPTION COMPLEXES ON DOWNSTREAM TARGET GENES TO REGULATE ROS AND FERROPTOSIS RESPONSES. FURTHERMORE, PHARMACOLOGICAL ACTIVATION OF NRF2 WAS FOUND TO HAVE PROTECTIVE EFFECTS AGAINST ROS AND FERROPTOSIS STRESS IN SCD MICE. OUR DATA SUGGEST A NOVEL MECHANISM BY WHICH NRF2 REGULATES L2HG LEVELS TO MEDIATE SCD SEVERITY THROUGH ROS AND FERROPTOSIS STRESS RESPONSES, SUGGESTING THAT TARGETING NRF2 IS A VIABLE THERAPEUTIC STRATEGY FOR AMELIORATING SCD SYMPTOMS. 2023 8 790 22 CELLULAR AND MOLECULAR MECHANISMS OF CD8(+) T CELL DIFFERENTIATION, DYSFUNCTION AND EXHAUSTION. T CELLS FOLLOW A TRIPHASIC DISTINCT PATHWAY OF ACTIVATION, PROLIFERATION AND DIFFERENTIATION BEFORE BECOMING FUNCTIONALLY AND PHENOTYPICALLY "EXHAUSTED" IN SETTINGS OF CHRONIC INFECTION, AUTOIMMUNITY AND IN CANCER. EXHAUSTED T CELLS PROGRESSIVELY LOSE CANONICAL EFFECTOR FUNCTIONS, EXHIBIT ALTERED TRANSCRIPTIONAL NETWORKS AND EPIGENETIC SIGNATURES AND GAIN CONSTITUTIVE EXPRESSION OF A BROAD COINHIBITORY RECEPTOR SUITE. THIS REVIEW OUTLINES RECENT ADVANCES IN OUR UNDERSTANDING OF EXHAUSTED T CELL BIOLOGY AND EXAMINES CELLULAR AND MOLECULAR MECHANISMS BY WHICH A STATE OF DYSFUNCTION OR EXHAUSTION IS ESTABLISHED, AND MECHANISMS BY WHICH EXHAUSTED T CELLS MAY STILL CONTRIBUTE TO PATHOGEN OR TUMOUR CONTROL. FURTHER, THIS REVIEW DESCRIBES OUR UNDERSTANDING OF EXHAUSTED T CELL HETEROGENEITY AND OUTLINES THE MECHANISMS BY WHICH CHECKPOINT BLOCKADE DIFFERENTIALLY ENGAGES EXHAUSTED T CELL SUBSETS TO OVERCOME EXHAUSTION AND RECOVER T CELL FUNCTION. 2020 9 3516 37 IDO1 AND INFLAMMATORY NEOVASCULARIZATION: BRINGING NEW BLOOD TO TUMOR-PROMOTING INFLAMMATION. IN PARALLEL WITH THE GENETIC AND EPIGENETIC CHANGES THAT ACCUMULATE IN TUMOR CELLS, CHRONIC TUMOR-PROMOTING INFLAMMATION ESTABLISHES A LOCAL MICROENVIRONMENT THAT FOSTERS THE DEVELOPMENT OF MALIGNANCY. WHILE KNOWLEDGE OF THE SPECIFIC FACTORS THAT DISTINGUISH TUMOR-PROMOTING FROM NON-TUMOR-PROMOTING INFLAMMATION REMAINS INCHOATE, NEVERTHELESS, AS HIGHLIGHTED IN THIS SERIES ON THE 'HALLMARKS OF CANCER', IT IS CLEAR THAT TUMOR-PROMOTING INFLAMMATION IS ESSENTIAL TO NEOPLASIA AND METASTATIC PROGRESSION MAKING IDENTIFICATION OF SPECIFIC FACTORS CRITICAL. STUDIES OF IMMUNOMETABOLISM AND INFLAMOMETABOLISM HAVE REVEALED A ROLE FOR THE TRYPTOPHAN CATABOLIZING ENZYME IDO1 AS A CORE ELEMENT IN TUMOR-PROMOTING INFLAMMATION. AT ONE LEVEL, IDO1 EXPRESSION PROMOTES IMMUNE TOLERANCE TO TUMOR ANTIGENS, THEREBY HELPING TUMORS EVADE ADAPTIVE IMMUNE CONTROL. ADDITIONALLY, RECENT FINDINGS INDICATE THAT IDO1 ALSO PROMOTES TUMOR NEOVASCULARIZATION BY SUBVERTING LOCAL INNATE IMMUNITY. THIS NEWLY RECOGNIZED FUNCTION FOR IDO1 IS MEDIATED BY A UNIQUE MYELOID CELL POPULATION TERMED IDVCS (IDO1-DEPENDENT VASCULARIZING CELLS). INITIALLY IDENTIFIED IN METASTATIC LESIONS, IDVCS MAY EXERT BROADER EFFECTS ON PATHOLOGIC NEOVASCULARIZATION IN VARIOUS DISEASE SETTINGS. MECHANISTICALLY, INDUCTION OF IDO1 EXPRESSION IN IDVCS BY THE INFLAMMATORY CYTOKINE IFNGAMMA BLOCKS THE ANTAGONISTIC EFFECT OF IFNGAMMA ON NEOVASCULARIZATION BY STIMULATING THE EXPRESSION OF IL6, A POWERFUL PRO-ANGIOGENIC CYTOKINE. BY CONTRIBUTING TO VASCULAR ACCESS, THIS NEWLY ASCRIBED FUNCTION FOR IDO1 ALIGNS WITH ITS INVOLVEMENT IN OTHER CANCER HALLMARK FUNCTIONALITIES, (TUMOR-PROMOTING INFLAMMATION, IMMUNE ESCAPE, ALTERED CELLULAR METABOLISM, METASTASIS), WHICH MAY STEM FROM AN UNDERLYING ROLE IN NORMAL PHYSIOLOGICAL FUNCTIONS SUCH AS WOUND HEALING AND PREGNANCY. UNDERSTANDING THE NUANCES OF HOW IDO1 INVOLVEMENT IN THESE CANCER HALLMARK FUNCTIONALITIES VARIES BETWEEN DIFFERENT TUMOR SETTINGS WILL BE CRUCIAL TO THE FUTURE DEVELOPMENT OF SUCCESSFUL IDO1-DIRECTED THERAPIES. 2023 10 6121 26 THE EPIGENETIC LANDSCAPE OF T CELL EXHAUSTION. EXHAUSTED T CELLS IN CANCER AND CHRONIC VIRAL INFECTION EXPRESS DISTINCTIVE PATTERNS OF GENES, INCLUDING SUSTAINED EXPRESSION OF PROGRAMMED CELL DEATH PROTEIN 1 (PD-1). HOWEVER, THE REGULATION OF GENE EXPRESSION IN EXHAUSTED T CELLS IS POORLY UNDERSTOOD. HERE, WE DEFINE THE ACCESSIBLE CHROMATIN LANDSCAPE IN EXHAUSTED CD8(+) T CELLS AND SHOW THAT IT IS DISTINCT FROM FUNCTIONAL MEMORY CD8(+) T CELLS. EXHAUSTED CD8(+) T CELLS IN HUMANS AND A MOUSE MODEL OF CHRONIC VIRAL INFECTION ACQUIRE A STATE-SPECIFIC EPIGENETIC LANDSCAPE ORGANIZED INTO FUNCTIONAL MODULES OF ENHANCERS. GENOME EDITING SHOWS THAT PD-1 EXPRESSION IS REGULATED IN PART BY AN EXHAUSTION-SPECIFIC ENHANCER THAT CONTAINS ESSENTIAL RAR, T-BET, AND SOX3 MOTIFS. FUNCTIONAL ENHANCER MAPS MAY OFFER TARGETS FOR GENOME EDITING THAT ALTER GENE EXPRESSION PREFERENTIALLY IN EXHAUSTED CD8(+) T CELLS. 2016 11 4177 35 MEMORY T CELL, EXHAUSTION, AND TUMOR IMMUNITY. CD8(+)T CELLS ARE IMPORTANT IN PROTECTIVE IMMUNITY AGAINST INTRACELLULAR PATHOGENS AND TUMORS. IN CHRONIC INFECTIONS OR CANCER, CD8(+)T CELLS ARE CONSTANTLY EXPOSED TO ANTIGENS AND INFLAMMATORY SIGNALS. SUCH EXCESSIVE AND CONSTITUTIVE SIGNALS LEAD TO THE DETERIORATION OF T CELL FUNCTION, CALLED 'EXHAUSTION'. EXHAUSTED T CELLS ARE CHARACTERIZED BY LOW PROLIFERATION IN RESPONSE TO ANTIGEN STIMULATION, PROGRESSIVE LOSS OF EFFECTOR FUNCTION (CYTOKINE PRODUCTION AND KILLING FUNCTION), EXPRESSION OF MULTIPLE INHIBITORY RECEPTORS SUCH AS PD-1, TIM3, AND LAG3, AND METABOLIC ALTERATIONS FROM OXIDATIVE PHOSPHORYLATION TO GLYCOLYSIS. THESE DYSFUNCTIONS ARE ASSOCIATED WITH ALTERED TRANSCRIPTIONAL PROGRAMS AND EPIGENETIC REGULATIONS AND RECENT STUDIES SUGGESTED THAT NR4A AND TOX TRANSCRIPTION FACTORS ARE DEEPLY INVOLVED IN EXHAUSTION PHENOTYPES. HOWEVER, AN INCREASE THE EARLY MEMORY T CELLS INCLUDING STEM CELL MEMORY T (T(SCM)) CELLS IS CRITICAL FOR T CELL PERSISTENCE AND EFFICIENT TUMOR KILLING ESPECIALLY FOR ADOPTIVE CANCER IMMUNOTHERAPY SUCH AS CAR-T CELL THERAPY. AN INCREASING AMOUNT OF EVIDENCE SUPPORTS THE THERAPEUTIC POTENTIAL OF TARGETING EXHAUSTED T CELLS AND T(SCM) CELLS. WE HAVE BEGUN TO UNDERSTAND THE MOLECULAR MECHANISMS OF T CELL EXHAUSTION AND EARLY MEMORY FORMATION, AND THE CLINICAL APPLICATION OF CONVERTING EXHAUSTED T CELLS TO REJUVENATED EARLY MEMORY T CELLS IS THE GOAL OF OUR STUDY. 2020 12 770 23 CD8(+) T CELL DYSFUNCTION BY TOX INTOXICATION: A PROTUMORIGENIC EVENT IN THE TUMOR MICROENVIRONMENT. ACCUMULATING EVIDENCE SUGGESTS THE ROLE OF CELLULAR COMPONENTS IN ACHIEVING ANTITUMOR TO PROTUMOR MICROENVIRONMENTS. AMONG THE VARIOUS TYPES OF CELLS WITHIN THE TUMOR NICHE, THE STATE OF CD8(+) T CELLS APPARENTLY CHANGES FROM CYTOTOXIC T EFFECTOR CELLS AND MEMORY T CELLS TO EXHAUSTED CD8(+) T CELLS. THESE CHANGES IN THE PHENOTYPE OF CD8(+) T CELLS PROMOTE THE PROTUMOR MICROENVIRONMENT. RECENTLY, COMPREHENSIVE EXPERIMENTAL DATA DELINEATED THE ROLE OF THYMOCYTE SELECTION-ASSOCIATED HIGH-MOBILITY GROUP-BOX PROTEIN (TOX), WHICH REGULATES THE TRANSCRIPTIONAL PROCESS AND EPIGENETIC REMODELING, WITH IMPLICATIONS IN TUMOR AND CHRONIC VIRAL INFECTIONS. THIS PERSPECTIVE SUMMARIZES THE MOLECULAR MECHANISMS THAT LINK CD8(+) T CELLS, TOX, AND TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING AS WELL AS FUTURE DIRECTIONS FOR DETERMINING NEW AVENUES OF CANCER THERAPEUTICS. 2021 13 2307 31 EPIGENETIC REGULATION OF CELLULAR FUNCTIONS IN WOUND HEALING. STRINGENT SPATIOTEMPORAL REGULATION OF THE WOUND HEALING PROCESS INVOLVING MULTIPLE CELL TYPES IS ASSOCIATED WITH EPIGENETIC MECHANISMS OF GENE REGULATION, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND CHROMATIN REMODELLING, AS WELL AS NON-CODING RNAS. HERE, WE DISCUSS THE EPIGENETIC CHANGES THAT OCCUR DURING WOUND HEALING AND THE RAPIDLY EXPANDING UNDERSTANDING OF HOW THESE MECHANISMS AFFECT HEALING RESOLUTION IN BOTH ACUTE AND CHRONIC WOUND MILIEU. WE PROVIDE A FOCUSSED OVERVIEW OF CURRENT RESEARCH INTO EPIGENETIC REGULATORS THAT CONTRIBUTE TO WOUND HEALING BY SPECIFIC CELL TYPE. WE HIGHLIGHT THE ROLE OF EPIGENETIC REGULATORS IN THE MOLECULAR PATHOPHYSIOLOGY OF CHRONIC WOUND CONDITIONS. THE UNDERSTANDING OF HOW EPIGENETIC REGULATORS CAN AFFECT CELLULAR FUNCTIONS DURING NORMAL AND IMPAIRED WOUND HEALING COULD LEAD TO NOVEL THERAPEUTIC APPROACHES, AND WE OUTLINE QUESTIONS THAT CAN PROVIDE GUIDANCE FOR FUTURE RESEARCH ON EPIGENETIC-BASED INTERVENTIONS TO PROMOTE HEALING. DISSECTING THE DYNAMIC INTERPLAY BETWEEN CELLULAR SUBTYPES INVOLVED IN WOUND HEALING AND EPIGENETIC PARAMETERS DURING BARRIER REPAIR WILL DEEPEN OUR UNDERSTANDING OF HOW TO IMPROVE HEALING OUTCOMES IN PATIENTS AFFECTED BY CHRONIC NON-HEALING WOUNDS. 2021 14 4196 29 METABOLIC PLASTICITY AND REGULATION OF T CELL EXHAUSTION. THE METABOLIC REPROGRAMMING DURING T CELL ACTIVATION AND DIFFERENTIATION AFFECTS T CELL FATE AND IMMUNE RESPONSES. CELL METABOLISM MAY SERVE AS THE DRIVING FORCE THAT INDUCES EPIGENETIC MODIFICATIONS, CONTRIBUTING TO REGULATING T CELL DIFFERENTIATION. PERSISTENT PATHOGEN INFECTION LEADS TO T CELL EXHAUSTION, WHICH IS COMPOSED OF TWO MAIN SUBSETS AND WITH DISTINCT METABOLIC CHARACTERISTICS. THE PROGENITOR EXHAUSTED T CELLS UTILIZE MITOCHONDRIAL FATTY ACID OXIDATION (FAO) AND OXIDATIVE PHOSPHORYLATION (OXPHOS) FOR ENERGY, WHILE TERMINALLY EXHAUSTED T CELLS MAINLY RELY ON GLYCOLYTIC METABOLISM WITH IMPAIRED GLYCOLYSIS AND OXPHOS. HERE, WE COMPILED THE LATEST RESEARCH ON HOW T CELL METABOLISM DEFINES DIFFERENTIATION, FOCUSING ON T CELL EXHAUSTION DURING CHRONIC INFECTIONS. IN ADDITION, METABOLIC-RELATED FACTORS INCLUDING ANTIGEN STIMULATION SIGNALS STRENGTH, CYTOKINES AND EPIGENETICS AFFECTING T CELL EXHAUSTION WERE ALSO REVIEWED. FURTHERMORE, THE INTERVENTION STRATEGIES ON METABOLISM AND EPIGENETICS TO REVERSE T CELL EXHAUSTION WERE DISCUSSED IN DETAIL, WHICH MAY CONTRIBUTE TO ACHIEVING THE GOAL OF PREVENTION AND TREATMENT OF T CELL EXHAUSTION. 2022 15 1866 34 EMERGING CROSSTALK BETWEEN LONG NON-CODING RNAS AND NRF2 SIGNALING. DIVERSE STIMULI TRIGGER NRF2 SIGNALING, WHICH IN TURN TRANSCRIPTIONALLY REGULATES AN ARRAY OF DOWNSTREAM TARGETS, PROVIDING FOR MULTIPLE LAYERS OF CONTROL. WHILE NRF2 ACTIVITY LARGELY IS GOVERNED BY POSTTRANSLATIONAL MODIFICATION OF CRITICAL THIOL RESIDUES IN THE PROTEIN PARTNER AND REDOX SENSOR KEAP1, FINE-TUNING IS PROVIDED BY ADDITIONAL MECHANISMS - INCLUDING EPIGENETIC REGULATION. HEREIN, WE REVIEW THE EMERGING SIGNIFICANCE OF LONG NON-CODING RNAS (LNCRNA) AS DOWNSTREAM TARGETS AND UPSTREAM REGULATORS OF THE NRF2 SIGNALING PATHWAY. AMONG THE ~16000 LNCRNAS IN GENCODE, SOME HAVE BEEN VALIDATED AS TRANSCRIPTIONALLY REGULATED BY NRF2 (E.G., LUCAT1, NMRAL2P, ODRUL, ROR AND TUG1), AND OTHERS HAVE BEEN IDENTIFIED AS UPSTREAM REGULATORS OF NRF2 EXPRESSION (E.G., HOTAIR, MALAT1, MEG1, NRAL AND UCA1). BIOINFORMATIC ANALYSES OF ANNOTATED HUMAN LNCRNAS IDENTIFIED PUTATIVE NRF2 BINDING SITES IN THE PROMOTER REGIONS OF 13,285 LNCRNAS. FURTHER INVESTIGATION IS WARRANTED TO VALIDATE THE MANY NOVEL LNCRNAS AS BONA FIDE NRF2-REGULATED TARGETS, AND THEIR ROLES IN NRF2 SIGNALING. NRF2 IS CONSIDERED A PROMISING THERAPEUTIC CANDIDATE FOR CANCER AND OTHER CHRONIC DISEASES; THUS, TARGETING THE ASSOCIATED LNCRNAS MIGHT PROVIDE FOR A MORE REFINED FINE-TUNING OF THE SYSTEM, DEPENDING ON CELLULAR AND PATHOPHYSIOLOGICAL CONTEXT. 2020 16 568 29 BATF REGULATES PROGENITOR TO CYTOLYTIC EFFECTOR CD8(+) T CELL TRANSITION DURING CHRONIC VIRAL INFECTION. DURING CHRONIC VIRAL INFECTION, CD8(+) T CELLS DEVELOP INTO THREE MAJOR PHENOTYPICALLY AND FUNCTIONALLY DISTINCT SUBSETS: LY108(+)TCF-1(+) PROGENITORS, LY108(-)CX(3)CR1(-) TERMINALLY EXHAUSTED CELLS AND THE RECENTLY IDENTIFIED CX(3)CR1(+) CYTOTOXIC EFFECTOR CELLS. NEVERTHELESS, HOW CX(3)CR1(+) EFFECTOR CELL DIFFERENTIATION IS TRANSCRIPTIONALLY AND EPIGENETICALLY REGULATED REMAINS ELUSIVE. HERE, WE IDENTIFY DISTINCT GENE REGULATORY NETWORKS AND EPIGENETIC LANDSCAPES UNDERPINNING THE FORMATION OF THESE SUBSETS. NOTABLY, OUR DATA DEMONSTRATE THAT CX(3)CR1(+) EFFECTOR CELLS BEAR A STRIKING SIMILARITY TO SHORT-LIVED EFFECTOR CELLS DURING ACUTE INFECTION. GENETIC DELETION OF TBX21 SIGNIFICANTLY DIMINISHED FORMATION OF THE CX(3)CR1(+) SUBSET. IMPORTANTLY, WE FURTHER IDENTIFY A PREVIOUSLY UNAPPRECIATED ROLE FOR THE TRANSCRIPTION FACTOR BATF IN MAINTAINING A PERMISSIVE CHROMATIN STRUCTURE THAT ALLOWS THE TRANSITION FROM TCF-1(+) PROGENITORS TO CX(3)CR1(+) EFFECTOR CELLS. BATF DIRECTLY BOUND TO REGULATORY REGIONS NEAR TBX21 AND KLF2, MODULATING THEIR ENHANCER ACCESSIBILITY TO FACILITATE THE TRANSITION. THESE MECHANISTIC INSIGHTS CAN POTENTIALLY BE HARNESSED TO OVERCOME T CELL EXHAUSTION DURING CHRONIC INFECTION AND CANCER. 2021 17 3054 21 GENOME-WIDE CRISPR SCREENS OF T CELL EXHAUSTION IDENTIFY CHROMATIN REMODELING FACTORS THAT LIMIT T CELL PERSISTENCE. T CELL EXHAUSTION LIMITS ANTITUMOR IMMUNITY, BUT THE MOLECULAR DETERMINANTS OF THIS PROCESS REMAIN POORLY UNDERSTOOD. USING A CHRONIC STIMULATION ASSAY, WE PERFORMED GENOME-WIDE CRISPR-CAS9 SCREENS TO SYSTEMATICALLY DISCOVER REGULATORS OF T CELL EXHAUSTION, WHICH IDENTIFIED AN ENRICHMENT OF EPIGENETIC FACTORS. IN VIVO CRISPR SCREENS IN MURINE AND HUMAN TUMOR MODELS DEMONSTRATED THAT PERTURBATION OF THE INO80 AND BAF CHROMATIN REMODELING COMPLEXES IMPROVED T CELL PERSISTENCE IN TUMORS. IN VIVO PERTURB-SEQ REVEALED DISTINCT TRANSCRIPTIONAL ROLES OF EACH COMPLEX AND THAT DEPLETION OF CANONICAL BAF COMPLEX MEMBERS, INCLUDING ARID1A, RESULTED IN THE MAINTENANCE OF AN EFFECTOR PROGRAM AND DOWNREGULATION OF EXHAUSTION-RELATED GENES IN TUMOR-INFILTRATING T CELLS. FINALLY, ARID1A DEPLETION LIMITED THE ACQUISITION OF EXHAUSTION-ASSOCIATED CHROMATIN ACCESSIBILITY AND LED TO IMPROVED ANTITUMOR IMMUNITY. IN SUMMARY, WE PROVIDE AN ATLAS OF THE GENETIC REGULATORS OF T CELL EXHAUSTION AND DEMONSTRATE THAT MODULATION OF EPIGENETIC STATE CAN IMPROVE T CELL RESPONSES IN CANCER IMMUNOTHERAPY. 2022 18 1670 30 DRAWING A LINE BETWEEN HISTONE DEMETHYLASE KDM5A AND KDM5B: THEIR ROLES IN DEVELOPMENT AND TUMORIGENESIS. DISTINCT EPIGENETIC MODIFIERS ENSURE COORDINATED CONTROL OVER GENES THAT GOVERN A MYRIAD OF CELLULAR PROCESSES. GROWING EVIDENCE SHOWS THAT DYNAMIC REGULATION OF HISTONE METHYLATION IS CRITICAL FOR ALMOST ALL STAGES OF DEVELOPMENT. NOTABLY, THE KDM5 SUBFAMILY OF HISTONE LYSINE-SPECIFIC DEMETHYLASES PLAYS ESSENTIAL ROLES IN THE PROPER DEVELOPMENT AND DIFFERENTIATION OF TISSUES, AND ABERRANT REGULATION OF KDM5 PROTEINS DURING DEVELOPMENT CAN LEAD TO CHRONIC DEVELOPMENTAL DEFECTS AND EVEN CANCER. IN THIS REVIEW, WE ADOPT A UNIQUE PERSPECTIVE REGARDING THE CONTEXT-DEPENDENT ROLES OF KDM5A AND KDM5B IN DEVELOPMENT AND TUMORIGENESIS. IT IS WELL KNOWN THAT THESE TWO PROTEINS SHOW A HIGH DEGREE OF SEQUENCE HOMOLOGY, WITH OVERLAPPING FUNCTIONS. HOWEVER, WE PROVIDE DEEPER INSIGHTS INTO THEIR SUBSTRATE SPECIFICITY AND DISTINCTIVE FUNCTION IN GENE REGULATION THAT AT TIMES DIVERT FROM EACH OTHER. WE ALSO HIGHLIGHT BOTH THE POSSIBILITY OF TARGETING KDM5A AND KDM5B TO IMPROVE CANCER TREATMENT AND THE LIMITATIONS THAT MUST BE OVERCOME TO INCREASE THE EFFICACY OF CURRENT DRUGS. 2022 19 6530 34 TRANSCRIPTIONAL REGULATION AND T CELL EXHAUSTION. PURPOSE OF REVIEW: THIS REVIEW HIGHLIGHTS THE CONTROL OF TRANSCRIPTIONAL NETWORKS, INCLUDING INDUCTION OF INHIBITORY RECEPTORS, BY T CELL-SPECIFIC TRANSCRIPTION FACTORS IN EXHAUSTED T CELLS THAT ACCUMULATE IN CHRONIC VIRAL INFECTIONS INCLUDING HIV. RECENT FINDINGS: TRANSCRIPTIONAL PROFILING HAS ESTABLISHED DISTINCT MOLECULAR PHENOTYPES FOR EXHAUSTED CD4 AND CD8 T CELLS IN CHRONIC VIRAL INFECTION MODELS. THERE EXISTS A SUBSET OF TRANSCRIPTION FACTORS ASSOCIATED WITH EXHAUSTION, NOTABLY BLIMP-1, BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE AND HELIOS. EPIGENETIC PHENOMENA ARE LIKELY IMPORTANT IN REGULATING GENE EXPRESSION NETWORKS DURING EXHAUSTION AS ILLUSTRATED BY PROGRAMMED DEATH 1 PROMOTER METHYLATION PATTERNS. SUMMARY: FOLLOWING CHRONIC VIRAL INFECTIONS, CD4 AND CD8 T CELLS DEFINED FUNCTIONALLY AND PHENOTYPICALLY AS EXHAUSTED HAVE DISTINCT TRANSCRIPTIONAL PROFILES. THESE STUDIES HAVE IDENTIFIED A CORE SET OF TRANSCRIPTION FACTORS THAT HAVE BEEN IMPLICATED IN PROMOTING EXHAUSTION. HOWEVER, NO SINGLE FACTOR APPEARS TO BE AN EXHAUSTION DETERMINING FACTOR, SUGGESTING THAT T CELL EXHAUSTION REFLECTS A COMBINATORIAL MECHANISM WITH MULTIPLE TRANSCRIPTION FACTORS INTERACTING TO INFLUENCE THE DEVELOPMENT OF FUNCTIONALLY EXHAUSTED T CELLS AS WELL AS DIFFERENT T EFFECTOR POPULATIONS. 2014 20 3362 35 HISTONE LYSINE DEMETHYLASE KDM5B MAINTAINS CHRONIC MYELOID LEUKEMIA VIA MULTIPLE EPIGENETIC ACTIONS. THE HISTONE LYSINE DEMETHYLASE KDM5 FAMILY IS IMPLICATED IN NORMAL DEVELOPMENT AND STEM CELL MAINTENANCE BY EPIGENETIC MODULATION OF HISTONE METHYLATION STATUS. DEREGULATION OF THE KDM5 FAMILY HAS BEEN REPORTED IN VARIOUS TYPES OF CANCERS, INCLUDING HEMATOLOGICAL MALIGNANCIES. HOWEVER, THEIR TRANSCRIPTIONAL REGULATORY ROLES IN THE CONTEXT OF LEUKEMIA REMAIN UNCLEAR. HERE, WE FIND THAT KDM5B IS STRONGLY EXPRESSED IN NORMAL CD34(+) HEMATOPOIETIC STEM/PROGENITOR CELLS AND CHRONIC MYELOID LEUKEMIA (CML) CELLS. KNOCKDOWN OF KDM5B IN K562 CML CELLS REDUCED LEUKEMIA COLONY-FORMING POTENTIAL. TRANSCRIPTOME PROFILING OF KDM5B KNOCKDOWN K562 CELLS REVEALED THE DEREGULATION OF GENES INVOLVED IN MYELOID DIFFERENTIATION AND TOLL-LIKE RECEPTOR SIGNALING. THROUGH THE INTEGRATION OF TRANSCRIPTOME AND CHIP-SEQ PROFILING DATA, WE SHOW THAT KDM5B IS ENRICHED AT THE BINDING SITES OF THE GATA AND AP-1 TRANSCRIPTION FACTOR FAMILIES, SUGGESTING THEIR COLLABORATIONS IN THE REGULATION OF TRANSCRIPTION. EVEN THOUGH THE BINDING OF KDM5B SUBSTANTIALLY OVERLAPPED WITH H3K4ME1 OR H3K4ME3 MARK AT GENE PROMOTERS, ONLY A SMALL SUBSET OF THE KDM5B TARGETS SHOWED DIFFERENTIAL EXPRESSION IN ASSOCIATION WITH THE HISTONE DEMETHYLATION ACTIVITY. BY CHARACTERIZING THE INTERACTING PROTEINS IN K562 CELLS, WE DISCOVERED THAT KDM5B RECRUITS PROTEIN COMPLEXES INVOLVED IN THE MRNA PROCESSING MACHINERY, IMPLYING AN ALTERNATIVE EPIGENETIC ACTION MEDIATED BY KDM5B IN GENE REGULATION. OUR STUDY HIGHLIGHTS THE ONCOGENIC FUNCTIONS OF KDM5B IN CML CELLS AND SUGGESTS THAT KDM5B IS VITAL TO THE TRANSCRIPTIONAL REGULATION VIA MULTIPLE EPIGENETIC MECHANISMS. 2020