1 2218 92 EPIGENETIC MODIFICATIONS IN FIBROTIC DISEASES: IMPLICATIONS FOR PATHOGENESIS AND PHARMACOLOGICAL TARGETS. ORGAN FIBROSIS IS A COMPLEX AND CHRONIC DISORDER THAT RESULTS FROM A VARIETY OF ACUTE INJURIES AND CONTRIBUTES TO THIRTY PERCENT OF NATURALLY OCCURRING DEATHS WORLDWIDE. THE MAIN FEATURE OF ORGAN FIBROSIS IS THE EXCESSIVE ACCUMULATION AND DEPOSIT OF EXTRACELLULAR MATRIX, THEREBY LEADING TO ORGAN DYSFUNCTION, LOSS OF ELASTICITY, AND DEVELOPMENT OF A RIGID ORGAN. ACCUMULATING EVIDENCE SHOWS THAT EPIGENETIC REMODELING, INCLUDING ABERRANT DNA METHYLATION AND NONCODING RNA EXPRESSION AS WELL AS HISTONE POST-TRANSLATIONAL MODIFICATIONS, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS THROUGH THE REGULATION OF FIBROBLAST ACTIVATION, DIFFERENTIATION, AND APOPTOSIS, AS WELL AS COLLAGEN SYNTHESIS AND PROFIBROTIC GENE TRANSCRIPTION. IN THIS REVIEW, WE DISCUSS THE BASIC REGULATION OF DNA METHYLATION, NONCODING RNA EXPRESSION, AND HISTONE POST-TRANSLATIONAL MODIFICATION, AND THEIR PARTICIPATION IN THE PATHOGENESIS AND DEVELOPMENT OF ORGAN FIBROSIS. THIS REVIEW ALSO PROVIDES THE LATEST INSIGHTS INTO THE NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR FIBROSIS THROUGH MODULATION OF EPIGENETIC REMODELING. 2015 2 1597 37 DNA METHYLATION REGULATED GENE EXPRESSION IN ORGAN FIBROSIS. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM TO REGULATE GENE EXPRESSION. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND RNA INTERFERENCE, RESULTS IN HERITABLE CHANGES IN GENE EXPRESSION INDEPENDENT OF ALTERATIONS IN DNA SEQUENCE. EPIGENETIC REGULATION OFTEN OCCURS IN RESPONSE TO AGING AND ENVIRONMENT STIMULI, INCLUDING EXPOSURES AND DIET. STUDIES HAVE SHOWN THAT DNA METHYLATION IS CRITICAL IN THE PATHOGENESIS OF FIBROSIS INVOLVING MULTIPLE ORGAN SYSTEMS, CONTRIBUTING TO SIGNIFICANT MORBIDITY AND MORTALITY. ABERRANT DNA METHYLATION CAN SILENCE OR ACTIVATE GENE EXPRESSION PATTERNS THAT DRIVE THE FIBROSIS PROCESS. FIBROSIS IS A PATHOLOGICAL WOUND HEALING PROCESS IN RESPONSE TO CHRONIC INJURY. IT IS CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX PRODUCTION AND ACCUMULATION, WHICH EVENTUALLY AFFECTS ORGAN ARCHITECTURE AND RESULTS IN ORGAN FAILURE. FIBROSIS CAN AFFECT A WIDE RANGE OF ORGANS, INCLUDING THE HEART AND LUNGS, AND HAVE LIMITED THERAPEUTIC OPTIONS. DNA METHYLATION, LIKE OTHER EPIGENETIC PROCESS, IS REVERSIBLE, THEREFORE REGARDED AS ATTRACTIVE THERAPEUTIC INTERVENTIONS. ALTHOUGH EPIGENETIC MECHANISMS ARE HIGHLY INTERACTIVE AND OFTEN REINFORCING, THIS REVIEW DISCUSSES DNA METHYLATION-DEPENDENT MECHANISMS IN THE PATHOGENESIS OF ORGAN FIBROSIS, WITH FOCUS ON CARDIAC AND PULMONARY FIBROSIS. WE DISCUSS SPECIFIC PRO- AND ANTI-FIBROTIC GENES AND PATHWAYS REGULATED BY DNA METHYLATION IN ORGAN FIBROSIS; WE FURTHER HIGHLIGHT THE POTENTIAL BENEFITS AND SIDE-EFFECTS OF EPIGENETIC THERAPIES IN FIBROTIC DISORDERS. 2017 3 2341 31 EPIGENETIC REGULATION OF LIVER FIBROSIS. FIBROSIS IS A COMMON AND IMPORTANT PATHOLOGY ASSOCIATED WITH PROGRESSIVE CHRONIC LIVER DISEASES AND UNDERLIES THE DEVELOPMENT OF CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. RESEARCH INTO THE MOLECULAR REGULATION OF FIBROSIS HAS DISCOVERED THAT IT IS UNDER THE CONTROL OF A NUMBER OF EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND THE ACTIVITIES OF NON-CODING RNAS. A DEEPER UNDERSTANDING OF HOW EPIGENETIC REGULATORS SUCH AS DNA METHYLTRANSERASES, METHYL-DNA BINDING PROTEINS, HISTONE MODIFYING ENZYMES AND REGULATORY RNA MOLECULES IMPACT ON THE FIBROGENIC PROCESS IS EXPECTED TO RESULT IN NEW BIOMARKERS FOR DISEASE PROGRESSION AS WELL AS NOVEL THERAPEUTIC TARGETS. THE AIM OF THIS MINI-REVIEW IS TO BRIEFLY INTRODUCE THE READER TO THE MAJOR EPIGENETIC REGULATORS SO FAR IDENTIFIED AS BEING IMPLICATED IN FIBROSIS. 2015 4 2283 28 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 5 5533 29 ROLE AND MECHANISM OF DNA METHYLATION AND ITS INHIBITORS IN HEPATIC FIBROSIS. LIVER FIBROSIS IS A REPAIR RESPONSE TO INJURY CAUSED BY VARIOUS CHRONIC STIMULI THAT CONTINUALLY ACT ON THE LIVER. AMONG THEM, THE ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION INTO A MYOFIBROBLAST PHENOTYPE IS A KEY EVENT LEADING TO LIVER FIBROSIS, HOWEVER THE MECHANISM HAS NOT YET BEEN ELUCIDATED. THE MOLECULAR BASIS OF HSC ACTIVATION INVOLVES CHANGES IN THE REGULATION OF GENE EXPRESSION WITHOUT CHANGES IN THE GENOME SEQUENCE, NAMELY, VIA EPIGENETIC REGULATION. DNA METHYLATION IS A KEY FOCUS OF EPIGENETIC RESEARCH, AS IT AFFECTS THE EXPRESSION OF FIBROSIS-RELATED, METABOLISM-RELATED, AND TUMOR SUPPRESSOR GENES. INCREASING STUDIES HAVE SHOWN THAT DNA METHYLATION IS CLOSELY RELATED TO SEVERAL PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES INCLUDING HSC ACTIVATION AND LIVER FIBROSIS. THIS REVIEW AIMED TO DISCUSS THE MECHANISM OF DNA METHYLATION IN THE PATHOGENESIS OF LIVER FIBROSIS, EXPLORE DNA METHYLATION INHIBITORS AS POTENTIAL THERAPIES FOR LIVER FIBROSIS, AND PROVIDE NEW INSIGHTS ON THE PREVENTION AND CLINICAL TREATMENT OF LIVER FIBROSIS. 2023 6 3640 31 INCREASED EXTRACELLULAR MATRIX PROTEIN PRODUCTION IN CHRONIC DIABETIC COMPLICATIONS: IMPLICATIONS OF NON-CODING RNAS. MANAGEMENT OF CHRONIC DIABETIC COMPLICATIONS REMAINS A MAJOR MEDICAL CHALLENGE WORLDWIDE. ONE OF THE CHARACTERISTIC FEATURES OF ALL CHRONIC DIABETIC COMPLICATIONS IS AUGMENTED PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS. SUCH ECM PROTEINS ARE DEPOSITED IN ALL TISSUES AFFECTED BY CHRONIC COMPLICATIONS, ULTIMATELY CAUSING ORGAN DAMAGE AND DYSFUNCTION. A CONTRIBUTING FACTOR TO THIS PATHOGENETIC PROCESS IS GLUCOSE-INDUCED ENDOTHELIAL DAMAGE, WHICH INVOLVES PHENOTYPIC TRANSFORMATION OF ENDOTHELIAL CELLS (ECS). THIS PHENOTYPIC TRANSITION OF ECS, FROM A QUIESCENT STATE TO AN ACTIVATED DYSFUNCTIONAL STATE, CAN BE MEDIATED THROUGH ALTERATIONS IN THE SYNTHESIS OF CELLULAR PROTEINS. IN THIS REVIEW, WE DISCUSSED THE ROLES OF NON-CODING RNAS, SPECIFICALLY MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS), IN SUCH PROCESSES. WE FURTHER OUTLINED OTHER EPIGENETIC MECHANISMS REGULATING THE BIOGENESIS AND/OR FUNCTION OF NON-CODING RNAS. OVERALL, WE BELIEVE THAT BETTER UNDERSTANDING OF SUCH MOLECULAR PROCESSES MAY LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN THE FUTURE. 2019 7 4668 33 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 8 607 31 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011 9 2164 32 EPIGENETIC MECHANISMS IN HEPATIC STELLATE CELL ACTIVATION DURING LIVER FIBROSIS AND CARCINOGENESIS. LIVER FIBROSIS IS AN ESSENTIAL COMPONENT OF CHRONIC LIVER DISEASE (CLD) AND HEPATOCARCINOGENESIS. THE FIBROTIC STROMA IS A CONSEQUENCE OF SUSTAINED LIVER DAMAGE COMBINED WITH EXACERBATED EXTRACELLULAR MATRIX (ECM) ACCUMULATION. IN THIS CONTEXT, ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) PLAYS A KEY ROLE IN BOTH INITIATION AND PERPETUATION OF FIBROGENESIS. THESE CELLS SUFFER PROFOUND REMODELING OF GENE EXPRESSION IN THIS PROCESS. THIS REVIEW IS FOCUSED ON THE EPIGENETIC ALTERATIONS PARTICIPATING IN THE TRANSDIFFERENTIATION OF HSCS FROM THE QUIESCENT TO ACTIVATED STATE. RECENT ADVANCES IN THE FIELD OF DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS (PTM) OF HISTONES (ACETYLATION AND METHYLATION) PATTERNS ARE DISCUSSED HERE, TOGETHER WITH ALTERED EXPRESSION AND ACTIVITY OF EPIGENETIC REMODELERS. WE ALSO CONSIDER RECENT ADVANCES IN TRANSLATIONAL APPROACHES, INCLUDING THE USE OF EPIGENETIC MARKS AS BIOMARKERS AND THE PROMISING ANTIFIBROTIC PROPERTIES OF EPIGENETIC DRUGS THAT ARE CURRENTLY BEING USED IN PATIENTS. 2019 10 2532 33 EPIGENETICS IN ATHEROSCLEROSIS AND INFLAMMATION. ATHEROSCLEROSIS IS A MULTIFACTORIAL DISEASE WITH A SEVERE BURDEN ON WESTERN SOCIETY. RECENT INSIGHTS INTO THE PATHOGENESIS OF ATHEROSCLEROSIS UNDERSCORE THE IMPORTANCE OF CHRONIC INFLAMMATION IN BOTH THE INITIATION AND PROGRESSION OF VASCULAR REMODELLING. EXPRESSION OF IMMUNOREGULATORY MOLECULES BY VASCULAR WALL COMPONENTS WITHIN THE ATHEROSCLEROTIC LESIONS IS ACCORDINGLY THOUGHT TO CONTRIBUTE TO THE ONGOING INFLAMMATORY PROCESS. BESIDES GENE REGULATORY PROTEINS (TRANSCRIPTION FACTORS), EPIGENETIC MECHANISMS ALSO PLAY AN ESSENTIAL AND FUNDAMENTAL ROLE IN THE TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION. THESE EPIGENETIC MECHANISMS CHANGE THE ACCESSIBILITY OF CHROMATIN BY DNA METHYLATION AND HISTONE MODIFICATIONS. EPIGENETIC MODULATORS ARE THUS CRITICALLY INVOLVED IN THE REGULATION OF VASCULAR, IMMUNE AND TISSUE-SPECIFIC GENE EXPRESSION WITHIN THE ATHEROSCLEROTIC LESION. IMPORTANTLY, EPIGENETIC PROCESSES ARE REVERSIBLE AND MAY PROVIDE AN EXCELLENT THERAPEUTIC TARGET. THE CONCEPT OF EPIGENETIC REGULATION IS GRADUALLY BEING RECOGNIZED AS AN IMPORTANT FACTOR IN THE PATHOGENESIS OF ATHEROSCLEROSIS. RECENT RESEARCH PROVIDES AN ESSENTIAL LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME. IN THIS REVIEW WE THEREFORE DISCUSS THE BASIS OF EPIGENETIC REGULATION - AND THE CONTRIBUTION THEREOF IN THE REGULATION OF INFLAMMATORY PROCESSES IN GENERAL AND DURING ATHEROSCLEROSIS IN PARTICULAR. MOREOVER WE HIGHLIGHT POTENTIAL THERAPEUTIC INTERVENTIONS BASED ON EPIGENETIC MECHANISMS. 2010 11 4738 33 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 12 2933 37 GENESIS OF THE MYOFIBROBLAST IN LUNG INJURY AND FIBROSIS. TISSUE INJURY INCITES A REPAIR RESPONSE WITH A KEY MESENCHYMAL COMPONENT THAT PROVIDES THE ESSENTIAL CONNECTIVE TISSUE FOR SUBSEQUENT REGENERATION OR PATHOLOGICAL FIBROSIS. THE FIBROBLAST IS THE MAJOR MESENCHYMAL CELL TYPE TO BE IMPLICATED IN THIS CONNECTIVE TISSUE RESPONSE, AND IT IS IN ITS ACTIVATED OR DIFFERENTIATED FORM THAT IT PARTICIPATES IN THE REPAIR PROCESS. THE MYOFIBROBLAST REPRESENTS SUCH AN ACTIVATED MESENCHYMAL CELL AND IS A KEY SOURCE OF EXTRACELLULAR MATRIX AND INFLAMMATORY/FIBROGENIC CYTOKINES AS WELL AS PARTICIPATING IN WOUND CONTRACTION. ALTHOUGH SUCCESSFUL HEALING RESULTS IN GRADUAL DISAPPEARANCE OF MYOFIBROBLASTS, THEIR PERSISTENCE IS ASSOCIATED WITH CHRONIC AND PROGRESSIVE FIBROSIS. THUS, ELUCIDATION OF THE MECHANISM INVOLVED IN THE GENESIS OF THE MYOFIBROBLAST SHOULD PROVIDE INSIGHT INTO BOTH PATHOGENESIS OF CHRONIC FIBROTIC DISEASES AND THERAPEUTIC STRATEGIES FOR THEIR MANAGEMENT AND CONTROL. ALTHOUGH THE FIBROBLAST IS A WELL-DOCUMENTED PROGENITOR CELL FOR THE MYOFIBROBLAST, RECENT STUDIES HAVE SUGGESTED ADDITIONAL PRECURSOR CELLS THAT HAVE THE POTENTIAL TO GIVE RISE TO THE MYOFIBROBLAST. MANY OF THE STUDIES FOCUSED ON MECHANISMS AND FACTORS THAT REGULATE INDUCTION OF ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, A KEY AND COMMONLY USED MARKER OF THE MYOFIBROBLAST. THESE REVEAL COMPLEX AND MULTIFACTORIAL MECHANISMS INVOLVING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND IMPLICATING DIVERSE CELL-SIGNALING PATHWAYS, INCLUDING THOSE ACTIVATED BY THE POTENT FIBROGENIC CYTOKINE TRANSFORMING GROWTH FACTOR BETA. DESPITE THESE EXTENSIVE STUDIES, MANY ASPECTS REMAIN POORLY UNDERSTOOD, WITH THE SUGGESTION THAT ADDITIONAL NOVEL MECHANISMS REMAIN TO BE DISCOVERED. FUTURE STUDIES WITH THE HELP OF NEWLY DEVELOPED TECHNICAL ADVANCEMENTS SHOULD EXPEDITE DISCOVERY IN THIS DIRECTION. 2012 13 4336 24 MICRORNAS: THE UNDERLYING MEDIATORS OF PATHOGENETIC PROCESSES IN VASCULAR COMPLICATIONS OF DIABETES. DIABETES MELLITUS CAUSES CHRONIC COMPLICATIONS PRIMARILY AFFECTING THE VASCULATURE OF VARIOUS ORGANS, RISKING PATIENTS FOR RENAL FAILURE, VISION LOSS AND HEART FAILURE. A NEWLY DISCOVERED CLASS OF MOLECULES, MICRORNAS, MAY BE IMPORTANT IN THE GENESIS OF THESE PATHOLOGIC PROCESSES. MICRORNAS REGULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL BY INHIBITING TARGET MESSENGER RNA TRANSLATION. IN DISEASE STATES, HOWEVER, THE EXPRESSION OF MICRORNAS OFTEN IS ALTERED, RESULTING IN FURTHER ALTERED EXPRESSION (MOSTLY OVEREXPRESSION) OF DOWNSTREAM TARGET GENES. INTERESTINGLY, RESTORING MICRORNA EXPRESSION TO NORMAL LEVELS CAN CORRECT DOWNSTREAM EFFECTS AND PREVENT DIABETES-ASSOCIATED CHANGES. INVESTIGATIONS INTO MICRORNA INVOLVED IN VARIOUS PATHOGENETIC PROCESSES MEDIATING DIABETIC NEPHROPATHY, RETINOPATHY AND CARDIOMYOPATHY ARE HIGHLIGHTED IN THIS REVIEW. FUTURE DIRECTIONS OF MICRORNA IN THERAPEUTICS AND DIAGNOSTICS ARE ALSO DISCUSSED. IT IS OUR INTENT TO HELP THE READER APPRECIATE THE DIVERSE INTERACTIONS MICRORNAS HAVE IN CELLULAR SIGNALLING AND HOW UNDERSTANDING EPIGENETIC ELEMENTS, SUCH AS MICRORNAS, POTENTIALLY CAN YIELD NEW THERAPEUTIC STRATEGIES. 2013 14 3826 34 INVESTIGATION OF EPIGENETICS IN KIDNEY CELL BIOLOGY. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN DNA OR ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN THE PROCESSES OF KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATIONS VIA EPIGENETIC REGULATORS AND INTERACTION VIA TRANSCRIPTION FACTORS, AND NONCODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, NEPHRITIC AND NEPHROTIC SYNDROMES, PYELONEPHRITIS AND POLYCYSTIC KIDNEY DISEASES ARE DRIVEN BY ABERRANT ACTIVITY IN NUMEROUS SIGNALING PATHWAYS IN EVEN INDIVIDUAL KIDNEY CELL. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, NONCODING RNAS, AND PROTEIN POSTTRANSLATIONAL MODIFICATIONS, COULD DISRUPT ESSENTIAL PATHWAYS THAT PROTECT THE RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND ESTABLISHMENT OF OTHER RENAL ASSOCIATED SYNDROMES, WHICH HAVE BEEN RECOGNIZED AS ONE OF THE CRITICAL MECHANISMS FOR REGULATING FUNCTIONAL CHANGES THAT DRIVE AND MAINTAIN THE KIDNEY DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE THE EPIGENETIC MECHANISMS IN KIDNEY CELL BIOLOGY AND EPIGENETIC BASIS OF KIDNEY DEVELOPMENT, AND INTRODUCE EPIGENETIC TECHNIQUES THAT CAN BE USED IN INVESTIGATING THE MOLECULAR MECHANISM OF KIDNEY CELL BIOLOGY AND KIDNEYS DISEASES, PRIMARILY FOCUSING ON THE INTEGRATION OF DNA METHYLATION AND CHROMATIN IMMUNOPRECIPITATION TECHNOLOGIES INTO KIDNEY DISEASE ASSOCIATED STUDIES. FUTURE STUDIES USING THESE EMERGING TECHNOLOGIES WILL ELUCIDATE HOW ALTERATIONS IN THE RENAL CELL EPIGENOME COOPERATE WITH GENETIC ABERRATIONS FOR KIDNEY DISEASE INITIATION AND PROGRESSION. INCORPORATING EPIGENOMIC TESTING INTO THE CLINICAL RESEARCH IS ESSENTIAL TO FUTURE STUDIES WITH EPIGENETICS BIOMARKERS AND PRECISION MEDICINE USING EMERGING EPIGENETIC THERAPIES. 2019 15 2542 36 EPIGENETICS IN KIDNEY DISEASES. EPIGENETICS EXAMINES HERITABLE CHANGES IN DNA AND ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATION VIA EPIGENETIC REGULATORS AND NON-CODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS ARE MULTISTEP PROCESSES ASSOCIATED WITH NUMEROUS MOLECULAR ALTERATIONS EVEN IN INDIVIDUAL KIDNEY CELLS. EPIGENETIC ALTERATIONS, INCLUDING ANOMALOUS DNA METHYLATION, ABERRANT HISTONE ALTERATIONS AND CHANGES OF MICRORNA EXPRESSION ALL CONTRIBUTE TO KIDNEY PATHOGENESIS. THESE CHANGES ALTER THE GENOME-WIDE EPIGENETIC SIGNATURES AND DISRUPT ESSENTIAL PATHWAYS THAT PROTECT RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND DEVELOPMENT OF OTHER RENAL ASSOCIATED SYNDROMES. MOLECULAR CHANGES IMPACT CELLULAR FUNCTION WITHIN KIDNEY CELLS AND ITS MICROENVIRONMENT TO DRIVE AND MAINTAIN DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE EPIGENETIC MECHANISMS IN FOUR KIDNEY DISEASES INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS. WE PRIMARILY FOCUS ON CURRENT KNOWLEDGE ABOUT THE GENOME-WIDE PROFILING OF DNA METHYLATION AND HISTONE MODIFICATION, AND EPIGENETIC REGULATION ON SPECIFIC GENE(S) IN THE PATHOPHYSIOLOGY OF THESE DISEASES AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENT FOR PREVENTION AND THERAPY. INCORPORATING EPIGENOMIC TESTING INTO CLINICAL RESEARCH IS ESSENTIAL TO ELUCIDATE NOVEL EPIGENETIC BIOMARKERS AND DEVELOP PRECISION MEDICINE USING EMERGING THERAPIES. 2021 16 2381 32 EPIGENETIC REGULATION OF WOUND HEALING AND FIBROSIS. PURPOSE OF REVIEW: WOUND HEALING IS A NORMAL PHYSIOLOGICAL RESPONSE TO TISSUE INJURY WHICH CAN OCCUR IN ANY ORGAN. MECHANISMS THAT ORCHESTRATE WOUND HEALING IN DIFFERENT ORGANS ARE SURPRISINGLY GENERIC, INVOLVING GENERATION OF FIBROBLASTS AND MYOFIBROBLASTS BY DIFFERENTIATION PROCESSES THAT REQUIRE EXTENSIVE ALTERATIONS IN GENE EXPRESSION. THIS PROCESS AND INDEED PHENOTYPE OF CELLS ARE ORCHESTRATED BY THE COMBINED INFLUENCES OF MOLECULAR COMPONENTS OF EPIGENOME INCLUDING DNA METHYLATION, VAST ARRAY OF POSTTRANSLATIONAL MODIFICATIONS OF THE HISTONE PROTEIN CONSTITUENTS OF CHROMATIN AND REGULATORY NONCODING RNAS OF WHICH MICRORNAS (MIRS) ARE THE MOST EXTENSIVELY STUDIED. RECENT FINDINGS: NUMEROUS STUDIES FROM THE LAST 12 MONTHS SHOW ALL THE THREE EPIGENETIC MECHANISMS TO BE REGULATING GENERATION AND APOPTOSIS OF MYOFIBROBLASTS IN ORGANS AFFECTED BY PERTURBED WOUND HEALING. FURTHERMORE, THESE MECHANISMS ARE INVOLVED IN FIBROTIC DISEASE ITSELF, WITH SOME MIRS AND EPIGENETIC DRUGS BEING TESTED FOR THEIR THERAPEUTIC POTENTIAL. SUMMARY: FIELDS OF WOUND HEALING AND FIBROSIS WILL BE ENRICHED OVER THE NEXT DECADE BY PLETHORA OF NEW INFORMATION REGARDING EPIGENETIC CONTROL MECHANISMS WHICH WILL HOPEFULLY PROVIDE NEW ADVANCES IN DIAGNOSTICS AND PROGNOSTICS. WITH THE DESIGN OF EVER MORE SPECIFIC EPIGENETIC DRUGS, WE MAY IMPROVE OUR ABILITY TO THERAPEUTICALLY OPTIMIZE WOUND HEALING AND PREVENT FIBROSIS IN CHRONIC DISEASE AND AGEING. 2013 17 5932 32 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 18 6244 26 THE MECHANISMS OF HSC ACTIVATION AND EPIGENETIC REGULATION OF HSCS PHENOTYPES. EPIGENETICS IS A DYNAMICALLY EXPANDING FIELD OF SCIENCE ENTAILING NUMEROUS REGULATORY MECHANISMS CONTROLLING CHANGES OF GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL FACTORS. OVER THE RECENT YEARS THERE HAS BEEN A GREAT INTEREST IN EPIGENETIC MARKS AS A POTENTIAL DIAGNOSTIC AND PROGNOSTIC TOOL OR FUTURE TARGET FOR TREATMENT OF VARIOUS HUMAN DISEASES. THERE IS AN INCREASING BODY OF PUBLISHED RESEARCH TO SUGGEST THAT EPIGENETIC EVENTS REGULATE PROGRESSION OF CHRONIC LIVER DISEASE. EXPERIMENTAL MANIPULATION OF EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION, HISTONE ACETYLATION / METHYLATION AND THE ACTIVITIES OF PROTEINS THAT EITHER ANNOTATE OR INTERPRET THESE EPIGENETIC MARKS CAN HAVE PROFOUND EFFECTS ON THE ACTIVATION AND PHENOTYPE OF HSC, KEY CELLS RESPONSIBLE FOR ONSET AND PROGRESSION OF LIVER FIBROSIS. THIS REVIEW PRESENTS RECENT ADVANCES IN EPIGENETIC ALTERATIONS, WHICH COULD PROVIDE MECHANISTIC INSIGHT INTO THE PATHOGENESIS OF CHRONIC LIVER DISEASE AND PROVIDE NOVEL CLINICAL APPLICATIONS. 2014 19 5805 34 STRATEGIES TO PREVENT AND REVERSE LIVER FIBROSIS IN HUMANS AND LABORATORY ANIMALS. LIVER FIBROSIS RESULTS FROM CHRONIC DAMAGE TO THE LIVER IN CONJUNCTION WITH VARIOUS PATHWAYS AND IS MEDIATED BY A COMPLEX MICROENVIRONMENT. BASED ON CLINICAL OBSERVATIONS, IT IS NOW EVIDENT THAT FIBROSIS IS A DYNAMIC, BIDIRECTIONAL PROCESS WITH AN INHERENT CAPACITY FOR RECOVERY AND REMODELING. THE MAJOR MECHANISMS INVOLVED IN LIVER FIBROSIS INCLUDE THE REPETITIVE INJURY OF HEPATOCYTES, THE ACTIVATION OF THE INFLAMMATORY RESPONSE AFTER INJURY STIMULATION, AND THE ACTIVATION AND PROLIFERATION OF HEPATIC STELLATE CELLS (HSCS), WHICH REPRESENTS THE MAJOR EXTRACELLULAR MATRIX (ECM)-PRODUCING CELLS, STIMULATED BY HEPATOCYTE INJURY AND INFLAMMATION. THE MICROENVIRONMENT IN THE LIVER IS SYNERGISTICALLY REGULATED ABNORMAL ECM DEPOSITION, SCAR FORMATION, ANGIOGENESIS, AND FIBROGENESIS. MOREOVER, RECENT STUDIES HAVE CLARIFIED NOVEL MECHANISM IN FIBROSIS SUCH AS EPIGENETIC REGULATION OF HSCS, THE LEPTIN AND PPARGAMMA PATHWAYS, THE COAGULATION SYSTEM, AND EVEN AUTOPHAGY. UNCOVERING THE MECHANISMS OF LIVER FIBROGENESIS PROVIDES A BASIS TO DEVELOP POTENTIAL THERAPIES TO REVERSE AND TREAT THE FIBROTIC RESPONSE, THEREBY IMPROVING THE OUTCOMES OF PATIENTS WITH CHRONIC LIVER DISEASE. ALTHOUGH BOTH SCIENTIFIC AND CLINICAL CHALLENGES REMAIN, EMERGING STUDIES ATTEMPT TO REVEAL THE IDEAL ANTI-FIBROTIC DRUG THAT COULD BE EASILY DELIVERED TO THE LIVER WITH HIGH SPECIFICITY AND LOW TOXICITY. THIS REVIEW HIGHLIGHTS THE MECHANISMS, INCLUDING NOVEL PATHWAYS UNDERLYING FIBROGENESIS THAT MAY BE TRANSLATED INTO PREVENTIVE AND TREATMENT STRATEGIES, REVIEWS BOTH CURRENT AND NOVEL AGENTS THAT TARGET SPECIFIC PATHWAYS OR MULTIPLE TARGETS, AND DISCUSSES NOVEL DRUG DELIVERY SYSTEMS SUCH AS NANOTECHNOLOGY THAT CAN BE APPLIED IN THE TREATMENT OF LIVER FIBROSIS. IN ADDITION, WE ALSO DISCUSS SOME CURRENT TREATMENT STRATEGIES THAT ARE BEING APPLIED IN ANIMAL MODELS AND IN CLINICAL TRIALS. 2015 20 6223 37 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020