1 2002 108 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 2 1326 23 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 3 2926 25 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 4 5130 24 POSTTRANSCRIPTIONAL GENE REGULATION: NOVEL PATHWAYS FOR GLUCOCORTICOIDS' ANTI-INFLAMMATORY ACTION. POSTTRANSCRIPTIONAL GENE REGULATION (PTR) IS A FUNDAMENTAL BIOLOGICAL PROCESS THAT INTEGRATES WITH THE MASTER TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION, IN WAYS THAT ONLY IN THE LAST DECADE HAVE BEEN INCREASINGLY UNDERSTOOD [1, 2]. WHILE EPIGENETIC AND TRANSCRIPTIONAL EVENTS SHAPE CELL RESPONSE QUALITATIVELY, DECIDING THE PATTERN OF GENE EXPRESSION TO 'SWITCH ON OR OFF' IN RESPONSE TO ENDOGENOUS OR ENVIRONMENTAL TRIGGERS, THE KEY TASK OF PTR IS TO ACT AS A 'RHEOSTAT' AND RAPIDLY ADAPT THE CELLULAR RESPONSE BY PROVIDING THE APPROPRIATE AMPLITUDE AND TIMING TO THE PROTEIN EXPRESSION PATTERNS [3, 4]. THE PIVOTAL ROLE OF THIS MECHANISM COMES TO THE FOREFRONT IN INFLAMMATORY AND IMMUNE RESPONSE, WHERE THE CHANGES IN AMPLITUDE AND DURATION IN THE EXPRESSION OF DANGEROUS AND PROTECTIVE GENES ARE IN DELICATE BALANCE, AND ARE CRITICAL IN DETERMINING EITHER THE SUCCESSFUL RESOLUTION OF THE IMMUNE RESPONSE OR ITS CHRONIC OVEREXPRESSION [5]. THIS BRIEF REVIEW INTRODUCES MEMBERS OF THE MAIN CLASSES OF MOLECULES MEDIATING THE CYTOPLASMIC ARM OF GENE REGULATION, NAMELY RNA-BINDING PROTEINS AND MICRO-RNA (MIRNA), AND SUMMARIZES EXPERIMENTAL DATA THAT UNDERSCORE THE ROLE OF THESE MOLECULES IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATION, AS WELL AS THEIR PROMISING VALUE AS MECHANISMS CONVEYING THE ANTI-INFLAMMATORY EFFECT OF SYNTHETIC GLUCOCORTICOIDS. 2012 5 1117 24 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT. 2017 6 4524 26 MULTIFACETED CONTROL OF DNA REPAIR PATHWAYS BY THE HYPOXIC TUMOR MICROENVIRONMENT. HYPOXIA, AS A PERVASIVE FEATURE IN THE MICROENVIRONMENT OF SOLID TUMORS, PLAYS A SIGNIFICANT ROLE IN CANCER PROGRESSION, METASTASIS, AND ULTIMATELY CLINICAL OUTCOME. ONE KEY CELLULAR CONSEQUENCE OF HYPOXIC STRESS IS THE REGULATION OF DNA REPAIR PATHWAYS, WHICH CONTRIBUTES TO THE GENOMIC INSTABILITY AND MUTATOR PHENOTYPE OBSERVED IN HUMAN CANCERS. TUMOR HYPOXIA CAN VARY IN SEVERITY AND DURATION, RANGING FROM ACUTE FLUCTUATING HYPOXIA ARISING FROM TEMPORARY BLOCKAGES IN THE IMMATURE MICROVASCULATURE, TO CHRONIC MODERATE HYPOXIA DUE TO SPARSE VASCULATURE, TO COMPLETE ANOXIA AT DISTANCES MORE THAN 150 MUM FROM THE NEAREST BLOOD VESSEL. PARALLELING THE INTRA-TUMOR HETEROGENEITY OF HYPOXIA, THE EFFECTS OF HYPOXIA ON DNA REPAIR OCCUR THROUGH DIVERSE MECHANISMS. ACUTELY, HYPOXIA ACTIVATES DNA DAMAGE SIGNALING PATHWAYS, PRIMARILY VIA POST-TRANSLATIONAL MODIFICATIONS. ON A LONGER TIMESCALE, HYPOXIA LEADS TO TRANSCRIPTIONAL AND/OR TRANSLATIONAL DOWNREGULATION OF MOST DNA REPAIR PATHWAYS INCLUDING DNA DOUBLE-STRAND BREAK REPAIR, MISMATCH REPAIR, AND NUCLEOTIDE EXCISION REPAIR. FURTHERMORE, EXTENDED HYPOXIA CAN LEAD TO LONG-TERM PERSISTENT SILENCING OF CERTAIN DNA REPAIR GENES, INCLUDING BRCA1 AND MLH1, REVEALING A MECHANISM BY WHICH TUMOR SUPPRESSOR GENES CAN BE INACTIVATED. THE DISCOVERIES OF THE HYPOXIC MODULATION OF DNA REPAIR PATHWAYS HAVE HIGHLIGHTED MANY POTENTIAL WAYS TO TARGET SUSCEPTIBILITIES OF HYPOXIC CANCER CELLS. IN THIS REVIEW, WE WILL DISCUSS THE MULTIFACETED HYPOXIC CONTROL OF DNA REPAIR AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVELS, AND WE WILL OFFER PERSPECTIVE ON THE FUTURE OF ITS CLINICAL IMPLICATIONS. 2015 7 2332 26 EPIGENETIC REGULATION OF INFLAMMATION IN INSULIN RESISTANCE. EPIGENETICS FOCUSES ON THE STUDY OF CHANGES IN GENE EXPRESSION BASED ON MODIFICATIONS THAT DO NOT INTERFERE WITH THE DNA SEQUENCE, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATION, AND NON-CODING RNA. EPIGENETIC CHANGES REGULATE THE EXPRESSION OF MANY GENES, INCLUDING INFLAMMATORY ONES. CHRONIC INFLAMMATION IS OFTEN ACCOMPANIED BY INSULIN RESISTANCE (IR), WHICH IS CHARACTERISTIC OF INTER ALIA TYPE 2 DIABETES. RECENTLY, IT HAS BEEN REPORTED THAT ALTERED EPIGENETIC SIGNATURE IN THE PROMOTER REGIONS OF INFLAMMATORY GENES MAY CONTRIBUTE TO THE DEVELOPMENT OF IR. THEREFORE, THE AIM OF THIS REVIEW IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC REGULATION OF INFLAMMATION IN IR. IT INCLUDES ORIGINAL PAPERS PUBLISHED FROM 2014 TO 2022. IT APPEARS THAT HYPOMETHYLATION OF THE SOCS3 GENE INCREASES THE RISK OF IR, WHILE THE ALTERATION OF H3K4ME IN THE NF-KB PROMOTER PROMOTES CHANGES IN INFLAMMATORY PHENOTYPE. FINALLY, IN HYPERGLYCEMIC STATES ASSOCIATED WITH IR, ALTERED LEVELS OF H3K4/K9M3 AND H3K9/K14AC RESULT IN INCREASED EXPRESSION OF THE INFLAMMATORY CYTOKINE IL-6. IN ADDITION, NUMEROUS MIRNAS HAVE BEEN IDENTIFIED THAT MAY BECOME A TARGET IN THE FIGHT AGAINST DISEASES RELATED TO INFLAMMATION AND IR. FUTURE STUDIES SHOULD EXAMINE THE EPIGENETIC MODIFICATIONS OF IR INFLAMMATORY MARKERS ASSOCIATED WITH ENVIRONMENTAL FACTORS. 2022 8 3527 28 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 9 2055 21 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 10 3403 24 HOW EPIGENETIC MODIFICATIONS DRIVE THE EXPRESSION AND MEDIATE THE ACTION OF PGC-1ALPHA IN THE REGULATION OF METABOLISM. EPIGENETIC CHANGES ARE A HALLMARK OF SHORT- AND LONG-TERM TRANSCRIPTIONAL REGULATION, AND HENCE INSTRUMENTAL IN THE CONTROL OF CELLULAR IDENTITY AND PLASTICITY. EPIGENETIC MECHANISMS LEADING TO CHANGES IN CHROMATIN STRUCTURE, ACCESSIBILITY FOR RECRUITMENT OF TRANSCRIPTIONAL COMPLEXES, AND INTERACTION OF ENHANCERS AND PROMOTERS ALL CONTRIBUTE TO ACUTE AND CHRONIC ADAPTATIONS OF CELLS, TISSUES AND ORGANS TO INTERNAL AND EXTERNAL PERTURBATIONS. SIMILARLY, THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA) IS ACTIVATED BY STIMULI THAT ALTER THE CELLULAR ENERGETIC DEMAND, AND SUBSEQUENTLY CONTROLS COMPLEX TRANSCRIPTIONAL NETWORKS RESPONSIBLE FOR CELLULAR PLASTICITY. IT THUS IS OF NO SURPRISE THAT PGC-1ALPHA IS UNDER THE CONTROL OF EPIGENETIC MECHANISMS, AND CONSTITUTES A MEDIATOR OF EPIGENETIC CHANGES IN VARIOUS TISSUES AND CONTEXTS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE LINK BETWEEN EPIGENETICS AND PGC-1ALPHA IN HEALTH AND DISEASE. 2019 11 6226 14 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 12 4992 18 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 13 2338 24 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 14 2119 22 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 15 3418 22 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 16 5872 26 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 17 4204 27 METABOLISM, EPIGENETICS, AND CAUSAL INFERENCE IN HEART FAILURE. EUKARYOTES MUST BALANCE THE METABOLIC AND CELL DEATH ACTIONS OF MITOCHONDRIA VIA CONTROL OF GENE EXPRESSION AND CELL FATE BY CHROMATIN, THEREBY FUNCTIONALLY BINDING THE METABOLOME AND EPIGENOME. THIS INTERACTION HAS FAR-REACHING IMPLICATIONS FOR CHRONIC DISEASES IN HUMANS, THE MOST COMMON OF WHICH ARE THOSE OF THE CARDIOVASCULAR SYSTEM. THE MOST DEVASTATING CONSEQUENCE OF CARDIOVASCULAR DISEASE, HEART FAILURE, IS NOT A SINGLE DISEASE, DIAGNOSIS, OR ENDPOINT. HUMAN AND ANIMAL STUDIES HAVE REVEALED THAT, REGARDLESS OF ETIOLOGY AND SYMPTOMS, HEART FAILURE IS UNIVERSALLY ASSOCIATED WITH ABNORMAL METABOLISM AND GENE EXPRESSION - TO FRAME THIS AS CAUSE OR CONSEQUENCE, HOWEVER, MAY BE TO WRONGFOOT THE QUESTION. THIS ESSAY AIMS TO CHALLENGE CURRENT THINKING ON METABOLIC-EPIGENETIC CROSSTALK IN HEART FAILURE, PRESENTING HYPOTHESES FOR HOW CHRONIC DISEASES ARISE, TAKE HOLD, AND PERSIST. WE UNPACK ASSUMPTIONS ABOUT THE ORDER OF OPERATIONS FOR GENE EXPRESSION AND METABOLISM, EXPLORING RECENT FINDINGS IN NONCARDIAC SYSTEMS THAT LINK METABOLIC INTERMEDIATES DIRECTLY TO CHROMATIN REMODELING. LASTLY, WE DISCUSS POTENTIAL MECHANISMS BY WHICH CHROMATIN MAY SERVE AS A SUBSTRATE FOR METABOLIC MEMORY, AND HOW CHANGES IN CELLULAR TRANSCRIPTOMES (AND HENCE IN CELLULAR BEHAVIOR) IN RESPONSE TO STRESS CORRESPOND TO GLOBAL CHANGES IN CHROMATIN ACCESSIBILITY AND STRUCTURE. 2020 18 5548 20 ROLE OF EPIGENETIC REPROGRAMMING OF HOST GENES IN BACTERIAL PATHOGENESIS. THE GENOMES ARE REGULARLY TARGETED BY EPIGENETIC REGULATORY MECHANISMS (DNA METHYLATION, HISTONE MODIFICATIONS, BINDING OF REGULATORY PROTEINS) IN INFECTED CELLS. IN ADDITION, PROTEINS ENCODED BY MICROBIAL GENOMES MAY DISTURB THE ACTION OF A SET OF CELLULAR PROMOTERS BY INTERACTING WITH THE SAME EPI-REGULATORY MACHINERY. THE OUTCOME OF THIS MAY RESULT IN EPIGENETIC DYSREGULATION AND SUBSEQUENT CELLULAR DYSFUNCTIONS THAT MAY MANIFEST IN OR CONTRIBUTE TO THE DEVELOPMENT OF PATHOLOGICAL CHANGES. HOW EPIGENETIC METHYLATION DECORATIONS ON DNA AND HISTONES ARE STARTED AND ESTABLISHED REMAINS LARGELY UNKNOWN. THE INHERITED NATURE OF THESE PROCESSES IN REGULATION OF GENES SUGGESTS THAT THEY COULD PLAY KEY ROLES IN CHRONIC DISEASES ASSOCIATED WITH MICROBIAL PERSISTENCE; THEY MIGHT ALSO EXPLAIN SO-CALLED HIT-AND-RUN PHENOMENA IN INFECTIOUS DISEASE PATHOGENESIS. MICROBES INFECTING MAMMALS MAY CAUSE DISEASES BY CAUSING HYPER-METHYLATION OF KEY CELLULAR PROMOTERS AT CPG DI-NUCLEOTIDES AND MAY INDUCE PATHOLOGICAL CHANGES BY EPIGENETIC REPROGRAMMING OF HOST CELLS THEY ARE INTERACTING WITH ELUCIDATION OF THE EPIGENETIC CONSEQUENCES OF MICROBE-HOST INTERACTIONS MAY HAVE IMPORTANT THERAPEUTIC IMPLICATIONS BECAUSE EPIGENETIC PROCESSES CAN BE REVERTED AND ELIMINATION OF MICROBES INDUCING PATHO-EPIGENETIC CHANGES MAY PREVENT DISEASE DEVELOPMENT. 2013 19 6100 24 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 20 2308 25 EPIGENETIC REGULATION OF CHEMOKINE (CC-MOTIF) LIGAND 2 IN INFLAMMATORY DISEASES. APPROPRIATE RESPONSES TO INFLAMMATION ARE CONDUCIVE TO PATHOGEN ELIMINATION AND TISSUE REPAIR, WHILE UNCONTROLLED INFLAMMATORY REACTIONS ARE LIKELY TO RESULT IN THE DAMAGE OF TISSUES. CHEMOKINE (CC-MOTIF) LIGAND 2 (CCL2) IS THE MAIN CHEMOKINE AND ACTIVATOR OF MONOCYTES, MACROPHAGES, AND NEUTROPHILS. CCL2 PLAYED A KEY ROLE IN AMPLIFYING AND ACCELERATING THE INFLAMMATORY CASCADE AND IS CLOSELY RELATED TO CHRONIC NON-CONTROLLABLE INFLAMMATION (CIRRHOSIS, NEUROPATHIC PAIN, INSULIN RESISTANCE, ATHEROSCLEROSIS, DEFORMING ARTHRITIS, ISCHEMIC INJURY, CANCER, ETC.). THE CRUCIAL REGULATORY ROLES OF CCL2 MAY PROVIDE POTENTIAL TARGETS FOR THE TREATMENT OF INFLAMMATORY DISEASES. THEREFORE, WE PRESENTED A REVIEW OF THE REGULATORY MECHANISMS OF CCL2. GENE EXPRESSION IS LARGELY AFFECTED BY THE STATE OF CHROMATIN. DIFFERENT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, POST-TRANSLATIONAL MODIFICATION OF HISTONES, HISTONE VARIANTS, ATP-DEPENDENT CHROMATIN REMODELLING, AND NON-CODING RNA, COULD AFFECT THE 'OPEN' OR 'CLOSED' STATE OF DNA, AND THEN SIGNIFICANTLY AFFECT THE EXPRESSION OF TARGET GENES. SINCE MOST EPIGENETIC MODIFICATIONS ARE PROVEN TO BE REVERSIBLE, TARGETING THE EPIGENETIC MECHANISMS OF CCL2 IS EXPECTED TO BE A PROMISING THERAPEUTIC STRATEGY FOR INFLAMMATORY DISEASES. THIS REVIEW FOCUSES ON THE EPIGENETIC REGULATION OF CCL2 IN INFLAMMATORY DISEASES. 2023