1 3757 113 INTEGRATED MECHANISMS OF CAMKII-DEPENDENT VENTRICULAR REMODELING. CAMKII HAS BEEN SHOWN TO BE ACTIVATED DURING DIFFERENT CARDIAC PATHOLOGICAL PROCESSES, AND CAMKII-DEPENDENT MECHANISMS CONTRIBUTE TO PATHOLOGICAL CARDIAC REMODELING, CARDIAC ARRHYTHMIAS, AND CONTRACTILE DYSFUNCTION DURING HEART FAILURE. ACTIVATION OF CAMKII DURING CARDIAC STRESS RESULTS IN A BROAD NUMBER OF BIOLOGICAL EFFECTS SUCH AS, ON THE ONE HAND, ACUTE EFFECTS DUE TO PHOSPHORYLATION OF DISTINCT CELLULAR PROTEINS AS ION CHANNELS AND CALCIUM HANDLING PROTEINS AND, ON THE OTHER HAND, INTEGRATIVE MECHANISMS BY CHANGING GENE EXPRESSION. THIS REVIEW FOCUSES ON TRANSCRIPTIONAL AND EPIGENETIC EFFECTS OF CAMKII ACTIVATION DURING CHRONIC CARDIAC REMODELING. MULTIPLE MECHANISMS HAVE BEEN DESCRIBED HOW CAMKII MEDIATES CHANGES IN CARDIAC GENE EXPRESSION. CAMKII HAS BEEN SHOWN TO DIRECTLY PHOSPHORYLATE COMPONENTS OF THE CARDIAC GENE REGULATION MACHINERY. CAMKII PHOSPHORYLATES SEVERAL TRANSCRIPTION FACTORS SUCH AS CREB THAT INDUCES THE ACTIVATION OF SPECIFIC GENE PROGRAMS. CAMKII ACTIVATES TRANSCRIPTIONAL REGULATORS ALSO INDIRECTLY BY PHOSPHORYLATING HISTONE DEACETYLASES, ESPECIALLY HDAC4, WHICH IN TURN INHIBITS TRANSCRIPTION FACTORS THAT DRIVE CARDIAC HYPERTROPHY, FIBROSIS, AND DYSFUNCTION. RECENT STUDIES DEMONSTRATE THAT CAMKII ALSO PHOSPHORYLATE DIRECTLY HISTONES, WHICH MAY CONTRIBUTE TO CHANGES IN GENE EXPRESSION. THESE FINDINGS OF CAMKII-DEPENDENT GENE REGULATION DURING CARDIAC REMODELING PROCESSES SUGGEST NOVEL STRATEGIES FOR CAMKII-DEPENDENT "TRANSCRIPTIONAL OR EPIGENETIC THERAPIES" TO CONTROL CARDIAC GENE EXPRESSION AND FUNCTION. MANIPULATION OF CAMKII-DEPENDENT SIGNALING PATHWAYS IN THE SETTINGS OF PATHOLOGICAL CARDIAC GROWTH, REMODELING, AND HEART FAILURE REPRESENTS AN AUSPICIOUS THERAPEUTIC APPROACH. 2014 2 2002 29 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 3 6226 15 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 4 5130 32 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 1902 34 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 6 2230 25 EPIGENETIC MODIFICATIONS OF KLOTHO EXPRESSION IN KIDNEY DISEASES. DEVELOPMENTS OF MANY RENAL DISEASES ARE SUBSTANTIALLY INFLUENCED BY EPIGENETIC MODIFICATIONS OF NUMEROUS GENES, MAINLY MEDIATED BY DNA METHYLATIONS, HISTONE MODIFICATIONS, AND MICRORNA INTERFERENCE; HOWEVER, NOT ALL GENE MODIFICATIONS CAUSALLY AFFECT THE DISEASE ONSET OR PROGRESSION. KLOTHO IS A CRITICAL GENE WHOSE REPRESSIONS IN VARIOUS PATHOLOGICAL CONDITIONS REPORTEDLY INVOLVE EPIGENETIC REGULATORY MECHANISMS. KLOTHO IS ALMOST UNEXCEPTIONALLY REPRESSED EARLY AFTER ACUTE OR CHRONIC RENAL INJURIES AND ITS LEVELS INVERSELY CORRELATED WITH THE DISEASE PROGRESSION AND SEVERITY. MOREOVER, THE STRATEGIES OF KLOTHO DEREPRESSION VIA EPIGENETIC MODULATIONS BENEFICIALLY CHANGE THE PATHOLOGICAL COURSES BOTH IN VITRO AND IN VIVO. HENCE, KLOTHO IS NOT ONLY CONSIDERED A BIOMARKER OF THE RENAL DISEASE BUT ALSO A POTENTIAL OR EVEN AN IDEAL TARGET OF THERAPEUTIC EPIGENETIC INTERVENTION. HERE, WE SUMMARIZE AND DISCUSS STUDIES THAT INVESTIGATE THE KLOTHO REPRESSION AND INTERVENTION IN RENAL DISEASES FROM AN EPIGENETIC POINT OF VIEW. THESE INFORMATION MIGHT SHED NEW SIGHTS INTO THE EFFECTIVE THERAPEUTIC STRATEGIES TO PREVENT AND TREAT VARIOUS RENAL DISORDERS. 2021 7 1326 26 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 8 4204 37 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 9 3338 37 HISTONE DEACETYLASE INHIBITORS: THE EPIGENETIC THERAPEUTICS THAT REPRESS HYPOXIA-INDUCIBLE FACTORS. HISTONE DEACETYLASE INHIBITORS (HDACIS) HAVE BEEN ACTIVELY EXPLORED AS A NEW GENERATION OF CHEMOTHERAPEUTICS FOR CANCERS, GENERALLY KNOWN AS EPIGENETIC THERAPEUTICS. RECENT FINDINGS INDICATE THAT SEVERAL TYPES OF HDACIS REPRESS ANGIOGENESIS, A PROCESS ESSENTIAL FOR TUMOR METABOLISM AND PROGRESSION. ACCUMULATING EVIDENCE SUPPORTS THAT THIS REPRESSION IS MEDIATED BY DISRUPTING THE FUNCTION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1, HIF-2, AND COLLECTIVELY, HIF), WHICH ARE THE MASTER REGULATORS OF ANGIOGENESIS AND CELLULAR ADAPTATION TO HYPOXIA. SINCE HIF ALSO REGULATE GLUCOSE METABOLISM, CELL SURVIVAL, MICROENVIRONMENT REMODELING, AND OTHER ALTERATIONS COMMONLY REQUIRED FOR TUMOR PROGRESSION, THEY ARE CONSIDERED AS NOVEL TARGETS FOR CANCER CHEMOTHERAPY. THOUGH THE PRECISE BIOCHEMICAL MECHANISM UNDERLYING THE HDACI-TRIGGERED REPRESSION OF HIF FUNCTION REMAINS UNCLEAR, POTENTIAL CELLULAR FACTORS THAT MAY LINK THE INHIBITION OF DEACETYLASE ACTIVITY TO THE REPRESSION OF HIF FUNCTION HAVE BEEN PROPOSED. HERE WE REVIEW PUBLISHED DATA THAT INHIBITORS OF TYPE I/II HDACS REPRESS HIF FUNCTION BY EITHER REDUCING FUNCTIONAL HIF-1ALPHA LEVELS, OR REPRESSING HIF-ALPHA TRANSACTIVATION ACTIVITY. IN ADDITION, UNDERLYING MECHANISMS AND POTENTIAL PROTEINS INVOLVED IN THE REPRESSION WILL BE DISCUSSED. A THOROUGH UNDERSTANDING OF HDACI-INDUCED REPRESSION OF HIF FUNCTION MAY FACILITATE THE DEVELOPMENT OF FUTURE THERAPIES TO EITHER REPRESS OR PROMOTE ANGIOGENESIS FOR CANCER OR CHRONIC ISCHEMIC DISORDERS, RESPECTIVELY. 2011 10 5288 22 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 11 3207 33 HDACI: CELLULAR EFFECTS, OPPORTUNITIES FOR RESTORATIVE DENTISTRY. ACETYLATION OF HISTONE AND NON-HISTONE PROTEINS ALTERS GENE EXPRESSION AND INDUCES A HOST OF CELLULAR EFFECTS. THE ACETYLATION PROCESS IS HOMEOSTATICALLY BALANCED BY TWO GROUPS OF CELLULAR ENZYMES, HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). HAT ACTIVITY RELAXES THE STRUCTURE OF THE HUMAN CHROMATIN, RENDERING IT TRANSCRIPTIONALLY ACTIVE, THEREBY INCREASING GENE EXPRESSION. IN CONTRAST, HDAC ACTIVITY LEADS TO GENE SILENCING. THE ENZYMATIC BALANCE CAN BE 'TIPPED' BY HISTONE DEACETYLASE INHIBITORS (HDACI), LEADING TO AN ACCUMULATION OF ACETYLATED PROTEINS, WHICH SUBSEQUENTLY MODIFY CELLULAR PROCESSES INCLUDING STEM CELL DIFFERENTIATION, CELL CYCLE, APOPTOSIS, GENE EXPRESSION, AND ANGIOGENESIS. THERE IS A VARIETY OF NATURAL AND SYNTHETIC HDACI AVAILABLE, AND THEIR PLEIOTROPIC EFFECTS HAVE CONTRIBUTED TO DIVERSE CLINICAL APPLICATIONS, NOT ONLY IN CANCER BUT ALSO IN NON-CANCER AREAS, SUCH AS CHRONIC INFLAMMATORY DISEASE, BONE ENGINEERING, AND NEURODEGENERATIVE DISEASE. INDEED, IT APPEARS THAT HDACI-MODULATED EFFECTS MAY DIFFER BETWEEN 'NORMAL' AND TRANSFORMED CELLS, PARTICULARLY WITH REGARD TO REACTIVE OXYGEN SPECIES ACCUMULATION, APOPTOSIS, PROLIFERATION, AND CELL CYCLE ARREST. THE POTENTIAL BENEFICIAL EFFECTS OF HDACI FOR HEALTH, RESULTING FROM THEIR ABILITY TO REGULATE GLOBAL GENE EXPRESSION BY EPIGENETIC MODIFICATION OF DNA-ASSOCIATED PROTEINS, ALSO OFFER POTENTIAL FOR APPLICATION WITHIN RESTORATIVE DENTISTRY, WHERE THEY MAY PROMOTE DENTAL TISSUE REGENERATION FOLLOWING PULPAL DAMAGE. 2011 12 2308 27 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 13 4103 28 MECHANICAL CUES REGULATE HISTONE MODIFICATIONS AND CELL BEHAVIOR. CHANGE OF BIOPHYSICAL FACTORS IN TISSUE MICROENVIRONMENT IS AN IMPORTANT STEP IN A CHRONIC DISEASE DEVELOPMENT PROCESS. A MECHANICAL AND BIOCHEMICAL FACTOR FROM CELL LIVING MICRONICHE CAN REGULATE CELL EPIGENETIC DECORATION AND, THEREFORE, FURTHER INDUCE CHANGE OF GENE EXPRESSION. IN THIS REVIEW, WE WILL EMPHASIZE THE MECHANISM THAT BIOPHYSICAL MICROENVIRONMENT MANIPULATES CELL BEHAVIOR INCLUDING GENE EXPRESSION AND PROTEIN DECORATION, THROUGH MODIFYING HISTONE AMINO ACID RESIDUE MODIFICATION. THE INFLUENCE GIVEN BY DIFFERENT MECHANICAL FORCES, INCLUDING MECHANICAL STRETCH, SUBSTRATE SURFACE STIFFNESS, AND SHEAR STRESS, ON CELL FATE AND BEHAVIOR DURING CHRONIC DISEASE DEVELOPMENT INCLUDING TUMORIGENESIS WILL ALSO BE TEASED OUT. OVERALL, THE RECENT WORK SUMMARIZED IN THIS REVIEW CULMINATES ON THE HYPOTHESIS THAT A MECHANICAL FACTOR STIMULATES THE MODIFICATION ON HISTONE WHICH COULD FACILITATE DISEASE DETECTION AND POTENTIAL THERAPEUTIC TARGET. 2022 14 6886 31 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 15 2176 28 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 16 2589 28 EPIGENETICS OF PROGRESSION OF CHRONIC KIDNEY DISEASE: FACT OR FANTASY? EPIGENETIC MODIFICATIONS ARE IMPORTANT IN THE NORMAL FUNCTIONING OF THE CELL, FROM REGULATING DYNAMIC EXPRESSION OF ESSENTIAL GENES AND ASSOCIATED PROTEINS TO REPRESSING THOSE THAT ARE UNNEEDED. EPIGENETIC CHANGES ARE ESSENTIAL FOR DEVELOPMENT AND FUNCTIONING OF THE KIDNEY, AND ABERRANT METHYLATION, HISTONE MODIFICATIONS, AND EXPRESSION OF MICRORNA COULD LEAD TO CHRONIC KIDNEY DISEASE (CKD). HERE, EPIGENETIC MODIFICATIONS MODULATE TRANSFORMING GROWTH FACTOR BETA SIGNALING, INFLAMMATION, PROFIBROTIC GENES, AND THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, PROMOTING RENAL FIBROSIS AND PROGRESSION OF CKD. IDENTIFICATION OF THESE EPIGENETIC CHANGES IS IMPORTANT BECAUSE THEY ARE POTENTIALLY REVERSIBLE AND MAY SERVE AS THERAPEUTIC TARGETS IN THE FUTURE TO PREVENT SUBSEQUENT RENAL FIBROSIS AND CKD. IN THIS REVIEW WE DISCUSS THE DIFFERENT TYPES OF EPIGENETIC CONTROL, METHODS TO STUDY EPIGENETIC MODIFICATIONS, AND HOW EPIGENETICS PROMOTES PROGRESSION OF CKD. 2013 17 6510 33 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS. 2015 18 6022 30 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 19 6130 29 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 20 2254 31 EPIGENETIC MODULATION: RESEARCH PROGRESS ON HISTONE ACETYLATION LEVELS IN MAJOR DEPRESSIVE DISORDERS. DEPRESSION IS A SERIOUS MENTAL ILLNESS AND A PREVALENT CONDITION WITH MULTIPLE AETIOLOGIES. THE IMPACT OF THE CURRENT THERAPEUTIC STRATEGIES IS LIMITED AND THE PATHOGENESIS OF THE ILLNESS IS NOT WELL UNDERSTOOD. ACCORDING TO PREVIOUS STUDIES, DEPRESSION ONSET IS INFLUENCED BY A VARIETY OF ENVIRONMENTAL AND GENETIC FACTORS, INCLUDING CHRONIC STRESS, ABERRANT CHANGES IN GENE EXPRESSION, AND HEREDITARY PREDISPOSITION. TRANSCRIPTIONAL REGULATION IN EUKARYOTES IS CLOSELY RELATED TO CHROMOSOME PACKING AND IS CONTROLLED BY HISTONE POST-TRANSLATIONAL MODIFICATIONS. THE DEVELOPMENT OF NEW ANTIDEPRESSANTS MAY PROCEED ALONG A NEW PATH WITH MEDICATIONS THAT TARGET EPIGENETICS. HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE A CLASS OF COMPOUNDS THAT INTERFERE WITH THE FUNCTION OF HISTONE DEACETYLASES (HDACS). THIS REVIEW EXPLORES THE RELATIONSHIP BETWEEN HDACS AND DEPRESSION AND FOCUSES ON THE CURRENT KNOWLEDGE ON THEIR REGULATORY MECHANISM IN DEPRESSION AND THE POTENTIAL THERAPEUTIC USE OF HDACIS WITH ANTIDEPRESSANT EFFICACY IN PRECLINICAL RESEARCH. FUTURE RESEARCH ON INHIBITORS IS ALSO PROPOSED AND DISCUSSED. 2023