1 3729 146 INHIBITION OF TET1 PREVENTS THE DEVELOPMENT OF OSTEOARTHRITIS AND REVEALS THE 5HMC LANDSCAPE THAT ORCHESTRATES PATHOGENESIS. OSTEOARTHRITIS (OA) IS A DEGENERATIVE DISEASE OF THE JOINT, WHICH RESULTS IN PAIN, LOSS OF MOBILITY, AND, EVENTUALLY, JOINT REPLACEMENT. CURRENTLY, NO DISEASE-MODIFYING DRUGS EXIST, PARTLY BECAUSE OF THE MULTIPLE LEVELS AT WHICH CARTILAGE HOMEOSTASIS IS DISRUPTED. RECENT STUDIES HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC DYSREGULATION IN OA, SPARKING INTEREST IN THE EPIGENETIC MODULATION FOR THIS DISEASE. IN OUR PREVIOUS WORK, WE CHARACTERIZED A FIVEFOLD INCREASE IN CYTOSINE HYDROXYMETHYLATION (5HMC), AN OXIDIZED DERIVATIVE OF CYTOSINE METHYLATION (5MC) ASSOCIATED WITH GENE ACTIVATION, ACCUMULATING AT OA-ASSOCIATED GENES. TO TEST THE ROLE OF 5HMC IN OA, HERE, WE USED A MOUSE MODEL OF SURGICALLY INDUCED OA AND FOUND THAT OA ONSET WAS ACCOMPANIED BY A GAIN OF ~40,000 DIFFERENTIALLY HYDROXYMETHYLATED SITES BEFORE THE NOTABLE HISTOLOGICAL APPEARANCE OF DISEASE. WE DEMONSTRATED THAT TEN-ELEVEN-TRANSLOCATION ENZYME 1 (TET1) MEDIATES THE 5HMC DEPOSITION BECAUSE 98% OF SITES ENRICHED FOR 5HMC IN OA WERE LOST IN TET1(-/-) MICE. LOSS OF TET1-MEDIATED 5HMC PROTECTED THE TET1(-/-) MICE FROM OA DEVELOPMENT, INCLUDING DEGENERATION OF THE CARTILAGE SURFACE AND OSTEOPHYTE FORMATION, BY DIRECTLY PREVENTING THE ACTIVATION OF MULTIPLE OA PATHWAYS. LOSS OF TET1 IN HUMAN OA CHONDROCYTES REDUCED THE EXPRESSION OF THE MATRIX METALLOPROTEINASES MMP3 AND MMP13 AND MULTIPLE INFLAMMATORY CYTOKINES. INTRA-ARTICULAR INJECTIONS OF A DIOXYGENASES INHIBITOR, 2-HYDROXYGLUTARATE, ON MICE AFTER SURGICAL INDUCTION OF OA STALLED DISEASE PROGRESSION. TREATMENT OF HUMAN OA CHONDROCYTES WITH THE SAME INHIBITOR ALSO PHENOCOPIED TET1 LOSS. COLLECTIVELY, THESE DATA DEMONSTRATE THAT TET1-MEDIATED 5HMC DEPOSITION REGULATES MULTIPLE OA PATHWAYS AND CAN BE MODULATED FOR THERAPEUTIC INTERVENTION. 2020 2 5975 34 TET1 IS AN IMPORTANT TRANSCRIPTIONAL ACTIVATOR OF TNFALPHA EXPRESSION IN MACROPHAGES. ACTIVATION OF MACROPHAGES AND OVEREXPRESSION OF TNFALPHA IS ASSOCIATED WITH THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. HOWEVER, THE MECHANISMS LEADING TO TNFALPHA OVEREXPRESSION ARE STILL UNKNOWN. 5-METHYLOCYTOSINE (5-MC) IS AN EPIGENETIC MODIFICATION THAT IS ASSOCIATED WITH SILENCED GENES. RECENT STUDIES SHOWED THAT IT IS CONVERTED TO 5-HYDROXYLMETHYLOCYTOSINE (5-HMC) AND REACTIVATES GENE EXPRESSION THROUGH THE ACTION OF THE FAMILY OF TEN-ELEVEN-TRANSLOCATION (TET1-3) ENZYMES. IN THIS STUDY, WE SHOW THAT 5-HMC LEVELS ARE INCREASED GLOBALLY AND SPECIFICALLY IN THE TNFALPHA PROMOTER DURING THE DIFFERENTIATION OF MONOCYTES TO MACROPHAGES. IN ADDITION, THE LEVELS OF 5-HMC ARE INCREASED UPON LPS STIMULATION OF MACROPHAGES. FURTHERMORE, CRIPSR STABLE KNOCKOUT OF TET1 DECREASES THE EXPRESSION OF TNFALPHA AND OTHER PRO-INFLAMMATORY CYTOKINES. IN CONCLUSION, WE SHOWED THAT TET1 CONTRIBUTES TO THE ACTIVATION OF MACROPHAGES POSSIBLY THROUGH REGULATION OF 5-HYDROXYMETHYLATION IN THE PROMOTER OF PRO-INFLAMMATORY CYTOKINE GENES. THE TET1 ENZYME COULD BE A PROMISING THERAPEUTIC TARGET TO INHIBIT THE PERSISTENT INFLAMMATION CAUSED BY MACROPHAGES IN CHRONIC INFLAMMATORY DISEASES. 2019 3 5796 38 STAT3 PROMOTES A YOUTHFUL EPIGENETIC STATE IN ARTICULAR CHONDROCYTES. EPIGENETIC MECHANISMS GUIDING ARTICULAR CARTILAGE REGENERATION AND AGE-RELATED DISEASE SUCH AS OSTEOARTHRITIS (OA) ARE POORLY UNDERSTOOD. STAT3 IS A CRITICAL AGE-PATTERNED TRANSCRIPTION FACTOR HIGHLY ACTIVE IN FETAL AND OA CHONDROCYTES, BUT THE CONTEXT-SPECIFIC ROLE OF STAT3 IN REGULATING THE EPIGENOME OF CARTILAGE CELLS REMAIN ELUSIVE. IN THIS STUDY, DNA METHYLATION PROFILING WAS PERFORMED ACROSS HUMAN CHONDROCYTE ONTOGENY TO BUILD AN EPIGENETIC CLOCK AND ESTABLISH AN ASSOCIATION BETWEEN CPG METHYLATION AND HUMAN CHONDROCYTE AGE. EXPOSURE OF ADULT CHONDROCYTES TO A SMALL MOLECULE STAT3 AGONIST DECREASED DNA METHYLATION, WHILE GENETIC ABLATION OF STAT3 IN FETAL CHONDROCYTES INDUCED GLOBAL HYPERMETHYLATION. CUT&RUN ASSAY AND SUBSEQUENT TRANSCRIPTIONAL VALIDATION REVEALED DNA METHYLTRANSFERASE 3 BETA (DNMT3B) AS ONE OF THE PUTATIVE STAT3 TARGETS IN CHONDROCYTE DEVELOPMENT AND OA. FUNCTIONAL ASSESSMENT OF HUMAN OA CHONDROCYTES SHOWED THE ACQUISITION OF PROGENITOR-LIKE IMMATURE PHENOTYPE BY A SIGNIFICANT SUBSET OF CELLS. FINALLY, CONDITIONAL DELETION OF STAT3 IN CARTILAGE CELLS INCREASED DNMT3B EXPRESSION IN ARTICULAR CHONDROCYTES IN THE KNEE JOINT IN VIVO AND RESULTED IN A MORE PROMINENT OA PROGRESSION IN A POST-TRAUMATIC OA (PTOA) MOUSE MODEL INDUCED BY DESTABILIZATION OF THE MEDIAL MENISCUS (DMM). TAKEN TOGETHER THESE DATA REVEAL A NOVEL ROLE FOR STAT3 IN REGULATING DNA METHYLATION IN CARTILAGE DEVELOPMENT AND DISEASE. OUR FINDINGS ALSO SUGGEST THAT ELEVATED LEVELS OF ACTIVE STAT3 IN OA CHONDROCYTES MAY INDICATE AN INTRINSIC ATTEMPT OF THE TISSUE TO REGENERATE BY PROMOTING A PROGENITOR-LIKE PHENOTYPE. HOWEVER, IT IS LIKELY THAT CHRONIC ACTIVATION OF THIS PATHWAY, INDUCED BY IL-6 CYTOKINES, IS DETRIMENTAL AND LEADS TO TISSUE DEGENERATION. 2023 4 1794 35 EFFECT OF DIABETES STATUS AND HYPERGLYCEMIA ON GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION. TYPE 2 DIABETES MELLITUS (T2DM) IS CHARACTERIZED BY OXIDATIVE STRESS THAT COULD LEAD TO CHRONIC MICRO- AND MACROVASCULAR COMPLICATIONS. WE HYPOTHESIZED THAT SOME OF THE TARGET ORGAN DAMAGE IS MEDIATED BY OXIDATIVE ALTERATIONS IN EPIGENETIC MECHANISMS INVOLVING DNA METHYLATION (5MC) AND DNA HYDROXYMETHYLATION (5HMC). WE ANALYZED GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION IN PERIPHERAL BLOOD CELLS IN WELL-CONTROLLED AND POORLY CONTROLLED PATIENTS WITH T2DM AND COMPARED THEM WITH HEALTHY CONTROLS. WE ALSO ANALYZED MICROARRAYS OF DNA METHYLATION AND GENE EXPRESSION OF OTHER IMPORTANT TISSUES IN THE CONTEXT OF DIABETES FROM THE GEO DATABASE REPOSITORY AND THEN COMPARED THESE RESULTS WITH OUR EXPERIMENTAL GENE EXPRESSION DATA. DNA METHYLATION AND, MORE IMPORTANTLY, DNA HYDROXYMETHYLATION LEVELS WERE INCREASED IN POORLY CONTROLLED PATIENTS COMPARED TO WELL-CONTROLLED AND HEALTHY INDIVIDUALS. BOTH 5MC AND 5HMC MEASUREMENTS WERE CORRELATED WITH THE PERCENTAGE OF GLYCATED HEMOGLOBIN, INDICATING A DIRECT IMPACT OF HYPERGLYCEMIA ON CHANGES OVER THE EPIGENOME. THE ANALYSIS OF METHYLATION MICROARRAYS WAS CONCORDANT, AND 5MC LEVELS WERE INCREASED IN THE PERIPHERAL BLOOD OF T2DM PATIENTS. HOWEVER, THE DNA METHYLATION LEVELS WERE THE OPPOSITE OF THOSE IN OTHER TISSUES, SUCH AS THE PANCREAS, ADIPOSE TISSUE AND SKELETAL MUSCLE. WE HYPOTHESIZE THAT A PROCESS OF DNA OXIDATION ASSOCIATED WITH HYPERGLYCEMIA MAY EXPLAIN THE DNA DEMETHYLATION IN WHICH THE ACTIVITY OF TEN-ELEVEN TRANSLOCATION (TET) PROTEINS IS NOT SUFFICIENT TO COMPLETE THE PROCESS. HIGH LEVELS OF GLUCOSE LEAD TO CELLULAR OXIDATION, WHICH TRIGGERS THE PROCESS OF DNA DEMETHYLATION AIDED BY TET ENZYMES, RESULTING IN EPIGENETIC DYSREGULATION OF THE DAMAGED TISSUES. 2017 5 141 35 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 6 3659 37 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 7 3527 35 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 8 2228 34 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 9 5067 34 PHYSICAL ACTIVITY AND DNA METHYLATION IN HUMANS. PHYSICAL ACTIVITY IS A STRONG STIMULUS INFLUENCING THE OVERALL PHYSIOLOGY OF THE HUMAN BODY. EXERCISES LEAD TO BIOCHEMICAL CHANGES IN VARIOUS TISSUES AND EXERT AN IMPACT ON GENE EXPRESSION. EXERCISE-INDUCED CHANGES IN GENE EXPRESSION MAY BE MEDIATED BY EPIGENETIC MODIFICATIONS, WHICH REARRANGE THE CHROMATIN STRUCTURE AND THEREFORE MODULATE ITS ACCESSIBILITY FOR TRANSCRIPTION FACTORS. ONE OF SUCH EPIGENETIC MARK IS DNA METHYLATION THAT INVOLVES AN ATTACHMENT OF A METHYL GROUP TO THE FIFTH CARBON OF CYTOSINE RESIDUE PRESENT IN CG DINUCLEOTIDES (CPG). DNA METHYLATION IS CATALYZED BY A FAMILY OF DNA METHYLTRANSFERASES. THIS REVERSIBLE DNA MODIFICATION RESULTS IN THE RECRUITMENT OF PROTEINS CONTAINING METHYL BINDING DOMAIN AND FURTHER TRANSCRIPTIONAL CO-REPRESSORS LEADING TO THE SILENCING OF GENE EXPRESSION. THE ACCUMULATION OF CPG DINUCLEOTIDES, REFERRED AS CPG ISLANDS, OCCURS AT THE PROMOTER REGIONS IN A GREAT MAJORITY OF HUMAN GENES. THEREFORE, CHANGES IN DNA METHYLATION PROFILE AFFECT THE TRANSCRIPTION OF MULTIPLE GENES. A GROWING BODY OF EVIDENCE INDICATES THAT EXERCISE TRAINING MODULATES DNA METHYLATION IN MUSCLES AND ADIPOSE TISSUE. SOME OF THESE EPIGENETIC MARKERS WERE ASSOCIATED WITH A REDUCED RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE INFLUENCE OF PHYSICAL ACTIVITY ON THE DNA METHYLATION STATUS IN HUMANS. 2021 10 5972 27 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 11 6419 35 THE TET2-UPF1 COMPLEX MODULATES MRNA STABILITY UNDER STRESS CONDITIONS. INTRODUCTION: ENVIRONMENTAL STRESS PROMOTES EPIGENETIC ALTERATIONS THAT IMPACT GENE EXPRESSION AND SUBSEQUENTLY PARTICIPATE IN THE PATHOLOGICAL PROCESSES OF THE DISORDER. AMONG EPIGENETIC REGULATIONS, TEN-ELEVEN TRANSLOCATION (TET) ENZYMES OXIDIZE 5-METHYLCYTOSINE (5MC) TO 5-HYDROXYMETHYLCYTOSINE (5HMC) IN DNA AND RNA AND FUNCTION AS CRITICAL PLAYERS IN THE PATHOGENESIS OF DISEASES. OUR PREVIOUS RESULTS SHOWED THAT CHRONIC STRESS INCREASES THE EXPRESSION OF CYTOPLASMIC TET2 IN THE HIPPOCAMPUS OF MICE EXPOSED TO CHRONIC MILD STRESS (CMS). WHETHER THE CYTOPLASMIC TET2 ALTERS RNA 5HMC MODIFICATION IN CHRONIC STRESS-RELATED PROCESSES REMAINS LARGELY UNKNOWN. METHODS: TO EXPLORE THE ROLE OF CYTOPLASMIC TET2 UNDER CMS CONDITIONS, WE ESTABLISHED CMS MICE MODEL AND DETECTED THE EXPRESSION OF RNA 5HMC BY DOT BLOT. WE VERIFIED THE INTERACTION OF TET2 AND ITS INTERACTING PROTEIN BY CO-IMMUNOPRECIPITATION COMBINED WITH MASS SPECTROMETRY AND SCREENED DOWNSTREAM TARGET GENES BY CLUSTER ANALYSIS OF TET2 AND UPSTREAM FRAMESHIFT 1 (UPF1) INTERACTING RNA. THE EXPRESSION OF PROTEIN WAS DETECTED BY WESTERN BLOT AND THE EXPRESSION OF THE SCREENED TARGET GENES WAS DETECTED BY QRT-PCR. RESULTS: IN THIS STUDY, WE FOUND THAT INCREASED CYTOPLASMIC TET2 EXPRESSION UNDER CMS CONDITIONS LEADS TO INCREASE IN TOTAL RNA 5HMC MODIFICATION. TET2 INTERACTED WITH THE KEY NON-SENSE-MEDIATED MRNA DECAY (NMD) FACTOR UPF1, REGULATED THE STABILITY OF STRESS-RELATED GENES SUCH AS UNC5B MRNA, AND MIGHT THEREBY AFFECT NEURODEVELOPMENT. DISCUSSION: IN SUMMARY, THIS STUDY REVEALED THAT TET2-MEDIATED RNA 5HMC MODIFICATION IS INVOLVED IN STRESS-RELATED MRNA STABILITY REGULATION AND MAY SERVE AS A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC STRESS-RELATED DISEASES SUCH AS DEPRESSION. 2023 12 2297 37 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 13 2493 35 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 14 4604 30 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 15 405 36 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1. 2015 16 3348 45 HISTONE DEACETYLASES MEET MICRORNA-ASSOCIATED MMP-9 EXPRESSION REGULATION IN GLUCOCORTICOID-SENSITIVE AND -RESISTANT CELL LINES. GLUCOCORTICOIDS ARE LARGELY USED IN THE TREATMENT OF INFLAMMATORY PATHOLOGIES AND/OR HEMATOLOGICAL MALIGNANCIES AND REGULATE THE EXPRESSION OF A VARIETY OF GENES INVOLVED IN INFLAMMATION OR METASTASIS SUCH AS MATRIX METALLOPROTEINASES (MMP). LONG-TERM EXPOSURE TO GLUCOCORTICOIDS CAN RESULT IN FAILURE OF RESPONSIVENESS, WHICH IS OFTEN ASSOCIATED WITH AN UNWANTED GENE EXPRESSION. EPIGENETIC MECHANISMS ARE INVOLVED IN GENE EXPRESSION MODULATED AFTER DEVELOPMENT OF GLUCOCORTICOID RESISTANCE BUT HOW THESE MECHANISMS TAKE PLACE MUST BE FURTHER STUDIED. THE EFFECTS OF HDAC INHIBITORS (HDACI) IN A CONTEXT OF GLUCOCORTICOID RESISTANCE ARE STILL NOT WELL UNDERSTOOD AND NEED TO BE FURTHER INVESTIGATED. WE HYPOTHESIZED THAT ACQUIRED GLUCOCORTICOID RESISTANCE ASSOCIATED TO HDACI COULD DISTURBS EPIGENETIC LANDSCAPE, ESPECIALLY MIR EXPRESSION, LEADING TO A MODULATION OF MMP-9 GENE EXPRESSION AND/OR PROTEIN SECRETION, DESCRIBED AS LARGELY INVOLVED IN BONE REMODELING AND TUMOR INVASION IN MULTIPLE MYELOMA. TO THIS AIM, WE USED SENSITIVE RPMI-8226 CELL LINE AND ITS DEXAMETHASONE- AND METHYLPREDNISOLONE-RESISTANT DERIVATIVES. THE RESISTANT CELL LINES DISPLAYED AN 'OPEN CHROMATIN' AND AN MMP-9 OVEREXPRESSION COMPARATIVELY TO THE SENSITIVE CELL LINE. HDACI TREATMENT WITH MS-275 INCREASED EVEN MORE MMP-9 OVEREXPRESSION NOT ONLY AT AN MRNA LEVEL BUT ALSO AT THE PROTEIN LEVEL. WE SHOWED THAT MMP-9 EXPRESSION REGULATION WAS NOT DIRECTLY LINKED WITH HAT/HDAC BALANCE ALTERATIONS BUT RATHER WITH THE DEREGULATION OF MMP-9-TARGETING MIRS. THEN, WE FIRST DEMONSTRATED THAT MIR?149 DOWNREGULATION WAS DIRECTLY INVOLVED IN THE MMP-9 OVEREXPRESSION FOLLOWING A CHRONIC GLUCOCORTICOID EXPOSURE AND THAT MS-275 COULD AMPLIFY THIS OVEREXPRESSION BY INHIBITION OF MIR?149 EXPRESSION AND MIR?520C OVEREXPRESSION. TAKEN TOGETHER, THESE RESULTS INDICATE THAT THE USE OF HDACI IN A CONTEXT OF ACQUIRED GLUCOCORTICOID RESISTANCE COULD MODIFY THE EPIGENETIC LANDSCAPE, HIGHLIGHTING THE IMPORTANCE OF TAKING THE GLUCOCORTICOID RESPONSE STATUS INTO CONSIDERATION IN TREATMENT WITH HDACI. 2017 17 2508 35 EPIGENETICS AND OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS. THE DEVELOPMENT OF DISEASE-MODIFYING THERAPY FOR OA CURRENTLY FACES MAJOR OBSTACLES LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE FUNCTION OF JOINT TISSUE CELLS REMAIN UNCLEAR. PREVIOUS STUDIES HAVE FOUND THAT THE ALTERATIONS IN GENE EXPRESSION OF SPECIFIC TRANSCRIPTION FACTORS (TFS), PRO- OR ANTI-INFLAMMATORY CYTOKINES, MATRIX PROTEINASES AND EXTRACELLULAR MATRIX (ECM) PROTEINS IN ARTICULAR CARTILAGE MAY BE INVOLVED IN THE DEVELOPMENT OF OA. HOWEVER, THE REGULATORY MECHANISMS FOR THE EXPRESSION OF THOSE GENES IN OA CHONDROCYTES ARE LARGELY UNKNOWN. THE RECENT ADVANCES IN EPIGENETIC STUDIES HAVE SHED LIGHTS ON THE IMPORTANCE OF EPIGENETIC REGULATION OF GENE EXPRESSION IN THE DEVELOPMENT OF OA. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE RECENT STUDIES ON THE REGULATORY ROLES OF VARIOUS EPIGENETIC MECHANISMS IN THE EXPRESSION OF GENES FOR SPECIFIC TFS, CYTOKINES, ECM PROTEINS AND MATRIX PROTEINASES, AS WELL THE SIGNIFICANCE OF THESE EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF OA. 2015 18 834 33 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 19 3795 36 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 20 6533 37 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