1 997 101 CHRONIC STRESS-DRIVEN GLUCOCORTICOID RECEPTOR ACTIVATION PROGRAMS KEY CELL PHENOTYPES AND FUNCTIONAL EPIGENOMIC PATTERNS IN HUMAN FIBROBLASTS. CHRONIC ENVIRONMENTAL STRESS CAN PROFOUNDLY IMPACT CELL AND BODY FUNCTION. ALTHOUGH THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD, EPIGENETICS HAS EMERGED AS A KEY LINK BETWEEN ENVIRONMENT AND HEALTH. THE GENOMIC EFFECTS OF STRESS ARE THOUGHT TO BE MEDIATED BY THE ACTION OF GLUCOCORTICOID STRESS HORMONES, PRIMARILY CORTISOL IN HUMANS, WHICH ACT VIA THE GLUCOCORTICOID RECEPTOR (GR). TO DISSECT HOW CHRONIC STRESS-DRIVEN GR ACTIVATION INFLUENCES EPIGENETIC AND CELL STATES, HUMAN FIBROBLASTS UNDERWENT PROLONGED EXPOSURE TO PHYSIOLOGICAL STRESS LEVELS OF CORTISOL AND/OR A SELECTIVE GR ANTAGONIST. CORTISOL WAS FOUND TO DRIVE ROBUST CHANGES IN CELL PROLIFERATION, MIGRATION, AND MORPHOLOGY, WHICH WERE ABROGATED BY CONCOMITANT GR BLOCKADE. THE GR-DRIVEN CELL PHENOTYPES WERE ACCOMPANIED BY WIDESPREAD, YET GENOMIC CONTEXT-DEPENDENT, CHANGES IN DNA METHYLATION AND MRNA EXPRESSION, INCLUDING GENE LOCI WITH KNOWN ROLES IN CELL PROLIFERATION AND MIGRATION. THESE FINDINGS PROVIDE INSIGHTS INTO HOW CHRONIC STRESS-DRIVEN FUNCTIONAL EPIGENOMIC PATTERNS BECOME ESTABLISHED TO SHAPE KEY CELL PHENOTYPES. 2022 2 2641 28 EPIGENOMIC AND TRANSCRIPTOMIC ANALYSES REVEAL DIFFERENCES BETWEEN LOW-GRADE INFLAMMATION AND SEVERE EXHAUSTION IN LPS-CHALLENGED MURINE MONOCYTES. EMERGING STUDIES SUGGEST THAT MONOCYTES CAN BE TRAINED BY BACTERIAL ENDOTOXIN TO ADOPT DISTINCT MEMORY STATES RANGING FROM LOW-GRADE INFLAMMATION TO IMMUNE EXHAUSTION. WHILE LOW-GRADE INFLAMMATION MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, EXHAUSTED MONOCYTES WITH PATHOGENIC AND IMMUNE-SUPPRESSIVE CHARACTERISTICS MAY UNDERLIE THE PATHOGENESIS OF POLYMICROBIAL SEPSIS INCLUDING COVID-19. HOWEVER, DETAILED PROCESSES BY WHICH THE DYNAMIC ADAPTION OF MONOCYTES OCCUR REMAIN POORLY UNDERSTOOD. HERE WE EXPOSED MURINE BONE-MARROW DERIVED MONOCYTES TO CHRONIC LIPOPOLYSACCHARIDE (LPS) STIMULATION AT LOW-DOSE OR HIGH-DOSE, AS WELL AS A PBS CONTROL. THE CELLS WERE PROFILED FOR GENOME-WIDE H3K27AC MODIFICATION AND GENE EXPRESSION. THE GENE EXPRESSION OF TRAM-DEFICIENT AND IRAK-M-DEFICIENT MONOCYTES WITH LPS EXPOSURE WAS ALSO ANALYZED. WE DISCOVER THAT LOW-GRADE INFLAMMATION PREFERENTIALLY UTILIZES THE TRAM-DEPENDENT PATHWAY OF TLR4 SIGNALING, AND INDUCES THE EXPRESSION OF INTERFERON RESPONSE GENES. IN CONTRAST, HIGH DOSE LPS UNIQUELY UPREGULATES EXHAUSTION SIGNATURES WITH METABOLIC AND PROLIFERATIVE PATHWAYS. THE EXTENSIVE DIFFERENCES IN THE EPIGENOMIC LANDSCAPE BETWEEN LOW-DOSE AND HIGH-DOSE CONDITIONS SUGGEST THE IMPORTANCE OF EPIGENETIC REGULATIONS IN DRIVING DIFFERENTIAL RESPONSES. OUR DATA PROVIDE POTENTIAL TARGETS FOR FUTURE MECHANISTIC OR THERAPEUTIC STUDIES. 2022 3 4004 29 LOSS OF THE POLYCOMB MARK FROM BIVALENT PROMOTERS LEADS TO ACTIVATION OF CANCER-PROMOTING GENES IN COLORECTAL TUMORS. IN COLON TUMORS, THE TRANSCRIPTION OF MANY GENES BECOMES DEREGULATED BY POORLY DEFINED EPIGENETIC MECHANISMS THAT HAVE BEEN STUDIED MAINLY IN ESTABLISHED CELL LINES. IN THIS STUDY, WE USED FROZEN HUMAN COLON TISSUES TO ANALYZE PATTERNS OF HISTONE MODIFICATION AND DNA CYTOSINE METHYLATION IN CANCER AND MATCHED NORMAL MUCOSA SPECIMENS. DNA METHYLATION IS STRONGLY TARGETED TO BIVALENT H3K4ME3- AND H3K27ME3-ASSOCIATED PROMOTERS, WHICH LOSE BOTH HISTONE MARKS AND ACQUIRE DNA METHYLATION. HOWEVER, WE FOUND THAT LOSS OF THE POLYCOMB MARK H3K27ME3 FROM BIVALENT PROMOTERS WAS ACCOMPANIED OFTEN BY ACTIVATION OF GENES ASSOCIATED WITH CANCER PROGRESSION, INCLUDING NUMEROUS STEM CELL REGULATORS, ONCOGENES, AND PROLIFERATION-ASSOCIATED GENES. INDEED, WE FOUND MANY OF THESE SAME GENES WERE ALSO ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS WHERE CHRONIC INFLAMMATION PREDISPOSES THEM TO COLON CANCER. BASED ON OUR FINDINGS, WE PROPOSE THAT A LOSS OF POLYCOMB REPRESSION AT BIVALENT GENES COMBINED WITH AN ENSUING SELECTION FOR TUMOR-DRIVING EVENTS PLAYS A MAJOR ROLE IN CANCER PROGRESSION. 2014 4 2445 29 EPIGENETIC STATUS OF GDNF IN THE VENTRAL STRIATUM DETERMINES SUSCEPTIBILITY AND ADAPTATION TO DAILY STRESSFUL EVENTS. STRESSFUL EVENTS DURING ADULTHOOD ARE POTENT ADVERSE ENVIRONMENTAL FACTORS THAT CAN PREDISPOSE INDIVIDUALS TO PSYCHIATRIC DISORDERS, INCLUDING DEPRESSION; HOWEVER, MANY INDIVIDUALS EXPOSED TO STRESSFUL EVENTS CAN ADAPT AND FUNCTION NORMALLY. WHILE STRESS VULNERABILITY MAY INFLUENCE DEPRESSION, THE MOLECULAR MECHANISMS UNDERLYING THE SUSCEPTIBILITY AND ADAPTATION TO CHRONIC STRESS WITHIN THE BRAIN ARE POORLY UNDERSTOOD. IN THIS STUDY, TWO GENETICALLY DISTINCT MOUSE STRAINS THAT EXHIBIT DIFFERENT BEHAVIORAL RESPONSES TO CHRONIC STRESS WERE USED TO DEMONSTRATE HOW THE DIFFERENTIAL EPIGENETIC STATUS OF THE GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) GENE IN THE VENTRAL STRIATUM MODULATES SUSCEPTIBILITY AND ADAPTATION TO CHRONIC STRESS. OUR RESULTS SUGGEST THAT THE HISTONE MODIFICATIONS AND DNA METHYLATION OF THE GDNF PROMOTER HAVE CRUCIAL ROLES IN THE CONTROL OF BEHAVIORAL RESPONSES TO CHRONIC STRESS. OUR DATA PROVIDE INSIGHTS INTO THESE MECHANISMS, SUGGESTING THAT EPIGENETIC MODIFICATIONS OF GDNF, ALONG WITH GENETIC AND ENVIRONMENTAL FACTORS, CONTRIBUTE TO BEHAVIORAL RESPONSES TO STRESS. 2011 5 1562 22 DNA METHYLATION OF ENHANCER ELEMENTS IN MYELOID NEOPLASMS: THINK OUTSIDE THE PROMOTERS? GENE REGULATION THROUGH DNA METHYLATION IS A WELL DESCRIBED PHENOMENON THAT HAS A PROMINENT ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL CELL-STATES. THIS EPIGENETIC MODIFICATION IS USUALLY GROUPED IN REGIONS DENOMINATED CPG ISLANDS, WHICH FREQUENTLY CO-LOCALIZE WITH GENE PROMOTERS, SILENCING THE TRANSCRIPTION OF THOSE GENES. RECENT GENOME-WIDE DNA METHYLATION STUDIES HAVE CHALLENGED THIS PARADIGM, DEMONSTRATING THAT DNA METHYLATION OF REGULATORY REGIONS OUTSIDE PROMOTERS IS ABLE TO INFLUENCE CELL-TYPE SPECIFIC GENE EXPRESSION PROGRAMS UNDER PHYSIOLOGIC OR PATHOLOGIC CONDITIONS. COUPLING GENOME-WIDE DNA METHYLATION ASSAYS WITH HISTONE MARK ANNOTATION HAS ALLOWED FOR THE IDENTIFICATION OF SPECIFIC EPIGENOMIC CHANGES THAT AFFECT ENHANCER REGULATORY REGIONS, REVEALING AN ADDITIONAL LAYER OF COMPLEXITY TO THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN THIS REVIEW, WE SUMMARIZE THE NOVEL EVIDENCE FOR THE MOLECULAR AND BIOLOGICAL REGULATION OF DNA METHYLATION IN ENHANCER REGIONS AND THE DYNAMISM OF THESE CHANGES CONTRIBUTING TO THE FINE-TUNING OF GENE EXPRESSION. WE ALSO ANALYZE THE CONTRIBUTION OF ENHANCER DNA METHYLATION ON THE EXPRESSION OF RELEVANT GENES IN ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOPROLIFERATIVE NEOPLASMS. THE CHARACTERIZATION OF THE ABERRANT ENHANCER DNA METHYLATION PROVIDES NOT ONLY A NOVEL PATHOGENIC MECHANISM FOR DIFFERENT TUMORS BUT ALSO HIGHLIGHTS NOVEL POTENTIAL THERAPEUTIC TARGETS FOR MYELOID DERIVED NEOPLASMS. 2019 6 5279 19 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 7 5750 21 SOCIAL DEFEAT STRESS IN ADULT MICE CAUSES ALTERATIONS IN GENE EXPRESSION, ALTERNATIVE SPLICING, AND THE EPIGENETIC LANDSCAPE OF H3K4ME3 IN THE PREFRONTAL CORTEX: AN IMPACT OF EARLY-LIFE STRESS. CHRONIC STRESS IS THE LEADING RISK FACTOR OF A BROAD RANGE OF SEVERE PSYCHOPATHOLOGIES. NONETHELESS, THE MOLECULAR MECHANISMS TRIGGERING THESE PATHOLOGICAL PROCESSES ARE NOT WELL UNDERSTOOD. IN OUR STUDY, WE INVESTIGATED THE EFFECTS OF 15-DAY SOCIAL DEFEAT STRESS (SDS) ON THE GENOME-WIDE LANDSCAPE OF TRIMETHYLATION AT THE 4TH LYSINE RESIDUE OF HISTONE H3 (H3K4ME3) AND ON THE TRANSCRIPTOME IN THE PREFRONTAL CORTEX OF MICE THAT WERE REARED NORMALLY (GROUP SDS) OR SUBJECTED TO MATERNAL SEPARATION EARLY IN LIFE (GROUP MS+SDS). THE MICE WITH THE HISTORY OF STRESS EARLY IN LIFE SHOWED INCREASED SUSCEPTIBILITY TO SDS IN ADULTHOOD AND DEMONSTRATED LONG-LASTING GENOME-WIDE ALTERATIONS IN GENE EXPRESSION AND SPLICING AS WELL AS IN THE H3K4ME3 EPIGENETIC LANDSCAPE IN THE PREFRONTAL CORTEX. THUS, THE HIGH-THROUGHPUT TECHNIQUES APPLIED HERE ALLOWED US TO SIMULTANEOUSLY DETECT, FOR THE FIRST TIME, GENOME-WIDE EPIGENETIC AND TRANSCRIPTIONAL CHANGES IN THE MURINE PREFRONTAL CORTEX THAT ARE ASSOCIATED WITH BOTH CHRONIC SDS AND INCREASED SUSCEPTIBILITY TO THIS STRESSOR. 2021 8 4093 23 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 9 1468 21 DISTINCT EPIGENETIC PROGRAMS REGULATE CARDIAC MYOCYTE DEVELOPMENT AND DISEASE IN THE HUMAN HEART IN VIVO. EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTOR NETWORKS ESSENTIAL FOR DIFFERENTIATION OF CARDIAC MYOCYTES HAVE BEEN UNCOVERED. HOWEVER, RESHAPING OF THE EPIGENOME OF THESE TERMINALLY DIFFERENTIATED CELLS DURING FETAL DEVELOPMENT, POSTNATAL MATURATION, AND IN DISEASE REMAINS UNKNOWN. HERE, WE INVESTIGATE THE DYNAMICS OF THE CARDIAC MYOCYTE EPIGENOME DURING DEVELOPMENT AND IN CHRONIC HEART FAILURE. WE FIND THAT PRENATAL DEVELOPMENT AND POSTNATAL MATURATION ARE CHARACTERIZED BY A COOPERATION OF ACTIVE CPG METHYLATION AND HISTONE MARKS AT CIS-REGULATORY AND GENIC REGIONS TO SHAPE THE CARDIAC MYOCYTE TRANSCRIPTOME. IN CONTRAST, PATHOLOGICAL GENE EXPRESSION IN TERMINAL HEART FAILURE IS ACCOMPANIED BY CHANGES IN ACTIVE HISTONE MARKS WITHOUT MAJOR ALTERATIONS IN CPG METHYLATION AND REPRESSIVE CHROMATIN MARKS. NOTABLY, CIS-REGULATORY REGIONS IN CARDIAC MYOCYTES ARE SIGNIFICANTLY ENRICHED FOR CARDIOVASCULAR DISEASE-ASSOCIATED VARIANTS. THIS STUDY UNCOVERS DISTINCT LAYERS OF EPIGENETIC REGULATION NOT ONLY DURING PRENATAL DEVELOPMENT AND POSTNATAL MATURATION BUT ALSO IN DISEASED HUMAN CARDIAC MYOCYTES. 2018 10 3072 34 GENOME-WIDE DNA METHYLATION REPROGRAMMING IN RESPONSE TO INORGANIC ARSENIC LINKS INHIBITION OF CTCF BINDING, DNMT EXPRESSION AND CELLULAR TRANSFORMATION. CHRONIC LOW DOSE INORGANIC ARSENIC (IAS) EXPOSURE LEADS TO CHANGES IN GENE EXPRESSION AND EPITHELIAL-TO-MESENCHYMAL TRANSFORMATION. DURING THIS TRANSFORMATION, CELLS ADOPT A FIBROBLAST-LIKE PHENOTYPE ACCOMPANIED BY PROFOUND GENE EXPRESSION CHANGES. WHILE MANY MECHANISMS HAVE BEEN IMPLICATED IN THIS TRANSFORMATION, STUDIES THAT FOCUS ON THE ROLE OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE JUST EMERGING. DNA METHYLATION CONTROLS GENE EXPRESSION IN PHYSIOLOGIC AND PATHOLOGIC STATES. SEVERAL STUDIES SHOW ALTERATIONS IN DNA METHYLATION PATTERNS IN IAS-MEDIATED PATHOGENESIS, BUT THESE STUDIES FOCUSED ON SINGLE GENES. WE PRESENT A COMPREHENSIVE GENOME-WIDE DNA METHYLATION ANALYSIS USING METHYL-SEQUENCING TO MEASURE CHANGES BETWEEN NORMAL AND IAS-TRANSFORMED CELLS. ADDITIONALLY, THESE DIFFERENTIAL METHYLATION CHANGES CORRELATED POSITIVELY WITH CHANGES IN GENE EXPRESSION AND ALTERNATIVE SPLICING. INTERESTINGLY, MOST OF THESE DIFFERENTIALLY METHYLATED GENES FUNCTION IN CELL ADHESION AND COMMUNICATION PATHWAYS. TO GAIN INSIGHT INTO HOW GENOMIC DNA METHYLATION PATTERNS ARE REGULATED DURING IAS-MEDIATED CARCINOGENESIS, WE SHOW THAT IAS PROBABLY TARGETS CTCF BINDING AT THE PROMOTER OF DNA METHYLTRANSFERASES, REGULATING THEIR EXPRESSION. THESE FINDINGS REVEAL HOW CTCF BINDING REGULATES DNA METHYLTRANSFERASE TO REPROGRAM THE METHYLOME IN RESPONSE TO AN ENVIRONMENTAL TOXIN. 2017 11 3952 23 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 12 2252 27 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 13 6533 26 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 14 2598 22 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013 15 5872 23 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 16 925 22 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 17 5438 14 REMOVAL OF EPIGENETIC REPRESSIVE MARK ON INFLAMMATORY GENES IN FAT LIVER. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE. THE DETAILED EPIGENOMIC CHANGES DURING FAT ACCUMULATION IN LIVER ARE NOT CLEAR YET. HERE, WE PERFORMED CHIP-SEQ ANALYSIS IN THE LIVER TISSUES OF HIGH-FAT DIET AND REGULAR CHOW DIET MICE AND INVESTIGATED THE DYNAMIC LANDSCAPES OF H3K27AC AND H3K9ME3 MARKS ON CHROMATIN. WE FIND THAT THE ACTIVATED TYPICAL ENHANCERS MARKED WITH H3K27AC ARE ENRICHED ON LIPID METABOLIC PATHWAYS IN FAT LIVER; HOWEVER, SUPER ENHANCERS DO NOT CHANGE MUCH. THE REGIONS COVERED WITH H3K9ME3 REPRESSIVE MARK SEEM TO UNDERGO GREAT CHANGES, AND ITS PEAK NUMBER AND INTENSITY BOTH DECREASE IN FAT LIVER. THE ENHANCERS LOCATED IN LOST H3K9ME3 REGIONS ARE ENRICHED IN LIPID METABOLISM AND INFLAMMATORY PATHWAYS; AND MOTIF ANALYSIS SHOWS THAT THEY ARE POTENTIAL TARGETS FOR TRANSCRIPTION FACTORS INVOLVED IN METABOLIC AND INFLAMMATORY PROCESSES. OUR STUDY HAS REVEALED THAT H3K9ME3 MAY PLAY AN IMPORTANT ROLE DURING THE PATHOGENESIS OF NAFLD THROUGH REGULATING THE ACCESSIBILITY OF ENHANCERS. 2023 18 2069 29 EPIGENETIC CONTROL OF SKELETAL MUSCLE REGENERATION: INTEGRATING GENETIC DETERMINANTS AND ENVIRONMENTAL CHANGES. DURING EMBRYONIC DEVELOPMENT, PLURIPOTENT CELLS ARE GENETICALLY COMMITTED TO SPECIFIC LINEAGES BY THE EXPRESSION OF CELL-TYPE-SPECIFIC TRANSCRIPTIONAL ACTIVATORS THAT DIRECT THE FORMATION OF SPECIALIZED TISSUES AND ORGANS IN RESPONSE TO DEVELOPMENTAL CUES. CHROMATIN-MODIFYING PROTEINS ARE EMERGING AS ESSENTIAL COMPONENTS OF THE EPIGENETIC MACHINERY, WHICH ESTABLISHES THE NUCLEAR LANDSCAPE THAT ULTIMATELY DETERMINES THE FINAL IDENTITY AND FUNCTIONAL SPECIALIZATION OF ADULT CELLS. RECENT EVIDENCE HAS REVEALED THAT DISCRETE POPULATIONS OF ADULT CELLS CAN RETAIN THE ABILITY TO ADOPT ALTERNATIVE CELL FATES IN RESPONSE TO ENVIRONMENTAL CUES. THESE CELLS INCLUDE CONVENTIONAL ADULT STEM CELLS AND A STILL POORLY DEFINED COLLECTION OF CELL TYPES ENDOWED WITH FACULTATIVE PHENOTYPE AND FUNCTIONAL PLASTICITY. UNDER PHYSIOLOGICAL CONDITIONS OR ADAPTIVE STATES, THESE CELLS COOPERATE TO SUPPORT TISSUE AND ORGAN HOMEOSTASIS, AND TO PROMOTE GROWTH OR COMPENSATORY REGENERATION. HOWEVER, DURING CHRONIC DISEASES AND AGING THESE CELLS CAN ADOPT A PATHOLOGICAL PHENOTYPE AND MEDIATE MALADAPTIVE RESPONSES, SUCH AS THE FORMATION OF FIBROTIC SCARS AND FAT DEPOSITION THAT PROGRESSIVELY REPLACES STRUCTURAL AND FUNCTIONAL UNITS OF TISSUES AND ORGANS. THE MOLECULAR DETERMINANTS OF THESE PHENOTYPIC TRANSITIONS ARE ONLY EMERGING FROM RECENT STUDIES THAT REVEAL HOW DYNAMIC CHROMATIN STATES CAN GENERATE FLEXIBLE EPIGENETIC LANDSCAPES, WHICH CONFER ON CELLS THE ABILITY TO RETAIN PARTIAL PLURIPOTENCY AND ADAPT TO ENVIRONMENTAL CHANGES. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE ROLE OF THE EPIGENETIC MACHINERY AS A 'FILTER' BETWEEN GENETIC COMMITMENT AND ENVIRONMENTAL SIGNALS IN CELL TYPES THAT CAN ALTERNATIVELY PROMOTE SKELETAL MUSCLE REGENERATION OR FIBRO-ADIPOGENIC DEGENERATION. 2013 19 2107 20 EPIGENETIC FACTORS IN SCHIZOPHRENIA: MECHANISMS AND EXPERIMENTAL APPROACHES. SCHIZOPHRENIA IS A CHRONIC MENTAL DISORDER THAT IS STILL POORLY UNDERSTOOD DESPITE DECADES OF STUDY. MANY FACTORS HAVE BEEN FOUND TO CONTRIBUTE TO THE PATHOGENESIS, INCLUDING NEURODEVELOPMENTAL DISTURBANCE, GENETIC RISK, AND ENVIRONMENTAL INSULT, BUT NO SINGLE ROOT CAUSE HAS EMERGED. WHILE EVIDENCE FROM TWIN STUDIES SUGGESTS A STRONG HERITABLE COMPONENT, FEW INDIVIDUAL LOCI HAVE BEEN IDENTIFIED IN GENOMEWIDE SCREENS, SUGGESTING A ROLE FOR EPIGENETIC EFFECTS. RATHER, LARGE NUMBERS OF WEAKLY ACTING LOCI MAY CUMULATIVELY INCREASE DISEASE RISK, INCLUDING SEVERAL MAPPING TO EPIGENETIC PATHWAYS. IN THIS REVIEW, WE DISCUSS MECHANISMS OF EPIGENETIC REGULATION AND EVIDENCE FOR AN EPIGENETIC CONTRIBUTION TO DISEASE PHENOTYPE. WE FURTHER DESCRIBE THE RANGE OF EXPERIMENTAL TOOLS CURRENTLY AVAILABLE TO STUDY EPIGENETIC EFFECTS ASSOCIATED WITH THE DISEASE. 2019 20 1202 26 COULD DNA HYDROXYMETHYLATION BE CRUCIAL IN INFLUENCING STEROID HORMONE SIGNALING IN ENDOMETRIAL BIOLOGY AND ENDOMETRIOSIS? ENDOMETRIOSIS AFFECTS 10% OF REPRODUCTIVE-AGED WOMEN. IT IS CHARACTERIZED BY THE GROWTH OF THE ENDOMETRIUM, OUTSIDE THE UTERUS AND IS ASSOCIATED WITH INFERTILITY AND CHRONIC ABDOMINAL PAIN. LACK OF NONINVASIVE DIAGNOSTIC TOOLS AND EARLY SCREENING TESTS RESULTS IN DELAYED TREATMENT AND SUBSEQUENTLY INCREASED DISEASE SEVERITY. ENDOMETRIOSIS IS A DISEASE ASSOCIATED WITH A DEREGULATED HORMONAL RESPONSE, THEREFORE, UNDERSTANDING THE MOLECULAR MECHANISMS THAT GOVERN THIS HORMONAL INTERPLAY IS OF PARAMOUNT IMPORTANCE. DNA METHYLATION IS AN EPIGENETIC MARK THAT REGULATES GENE EXPRESSION AND IS OFTEN ASSOCIATED WITH GENES THAT CODE FOR STEROID RECEPTORS AND ENZYMES ASSOCIATED WITH ESTROGEN SYNTHESIS AND METABOLISM IN ENDOMETRIOSIS. DNA HYDROXYMETHYLATION, WHICH IS STRUCTURALLY SIMILAR TO METHYLATION BUT FUNCTIONALLY DIFFERENT, IS A BIOLOGICALLY CRITICAL MECHANISM THAT IS ALSO KNOWN TO REGULATE GENE EXPRESSION. TEN ELEVEN TRANSLOCATION (TET) PROTEINS MEDIATE HYDROXYMETHYLATION. HOWEVER, THE ROLE OF DNA HYDROXYMETHYLATION OR TETS IN THE ENDOMETRIUM REMAINS RELATIVELY UNEXPLORED. CURRENTLY, THE "GOLD STANDARD" TECHNIQUE USED TO STUDY METHYLATION PATTERNS IS BISULFITE GENOMIC SEQUENCING. THIS TECHNIQUE ALSO DETECTS HYDROXYMETHYLATION BUT FAILS TO DISTINGUISH BETWEEN THE TWO, THEREBY LIMITING OUR UNDERSTANDING OF THESE TWO PROCESSES. THE PRESENCE OF TETS IN THE MALE AND FEMALE REPRODUCTIVE TRACT AND ITS CONTRIBUTION TO ENDOMETRIAL CANCER MAKES IT AN IMPORTANT FACTOR TO STUDY IN ENDOMETRIOSIS. THIS REVIEW SUMMARIZES THE ROLE OF DNA METHYLATION IN ABERRANT STEROID HORMONE SIGNALING AND HYPOTHESIZES THAT HYDROXYMETHYLATION COULD BE A FACTOR INFLUENCING HORMONAL INSTABILITY SEEN IN ENDOMETRIOSIS. 2020