1 6546 129 TRANSCRIPTOMIC AND EPIGENETIC PROFILING OF FIBROBLASTS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DEVASTATING, FIBROPROLIFERATIVE, CHRONIC LUNG DISORDER, IS ASSOCIATED WITH EXPANSION OF FIBROBLASTS/MYOFIBROBLASTS, WHICH LEADS TO EXCESSIVE PRODUCTION AND DEPOSITION OF EXTRACELLULAR MATRIX. IPF IS TYPICALLY CLINICALLY IDENTIFIED AS END-STAGE LUNG DISEASE, AFTER FIBROTIC PROCESSES ARE WELL-ESTABLISHED AND ADVANCED. FIBROBLASTS HAVE BEEN SHOWN TO BE CRITICALLY IMPORTANT IN THE DEVELOPMENT AND PROGRESSION OF IPF. WE HYPOTHESIZE THAT DIFFERENTIAL CHROMATIN ACCESS CAN DRIVE GENETIC DIFFERENCES IN IPF FIBROBLASTS RELATIVE TO HEALTHY FIBROBLASTS. TO THIS END, WE PERFORMED ASSAY OF TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING TO IDENTIFY DIFFERENTIALLY ACCESSIBLE REGIONS WITHIN THE GENOMES OF FIBROBLASTS FROM HEALTHY AND IPF LUNGS. MULTIPLE MOTIFS WERE IDENTIFIED TO BE ENRICHED IN IPF FIBROBLASTS COMPARED WITH HEALTHY FIBROBLASTS, INCLUDING BINDING MOTIFS FOR TWIST1 AND FOXA1. RNA SEQUENCING IDENTIFIED 93 GENES THAT COULD BE ANNOTATED TO DIFFERENTIALLY ACCESSIBLE REGIONS. PATHWAY ANALYSIS OF THE ANNOTATED GENES IDENTIFIED CELLULAR ADHESION, CYTOSKELETAL ANCHORING, AND CELL DIFFERENTIATION AS IMPORTANT BIOLOGICAL PROCESSES. IN ADDITION, SINGLE NUCLEOTIDE POLYMORPHISM ANALYSIS SHOWED THAT LINKAGE DISEQUILIBRIUM BLOCKS OF IPF RISK SINGLE NUCLEOTIDE POLYMORPHISMS WITH IPF-ACCESSIBLE REGIONS THAT HAVE BEEN IDENTIFIED TO BE LOCATED IN GENES THAT ARE IMPORTANT IN IPF, INCLUDING MUC5B, TERT, AND TOLLIP. VALIDATION STUDIES IN ISOLATED LUNG TISSUE CONFIRMED INCREASED EXPRESSION FOR TWIST1 AND FOXA1 IN ADDITION TO REVEALING SHANK2 AND CSPR2 AS NOVEL TARGETS. THUS, MODULATION OF DIFFERENTIAL CHROMATIN ACCESS MAY BE AN IMPORTANT MECHANISM IN THE PATHOGENESIS OF LUNG FIBROSIS. 2022 2 5456 30 RESEARCH ADVANCES ON DNA METHYLATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC COMPLEX LUNG DISEASE WITH NO SPECIFIC TREATMENT AND POOR PROGNOSIS, CHARACTERIZED BY THE PULMONARY PROGRESSIVE FIBROSIS AND DYSFUNCTIONS THAT LEAD TO RESPIRATORY FAILURE. SEVERAL FACTORS MAY IMPACT THE PROGRESS OF IPF, INCLUDING AGE, CIGARETTE SMOKING, AND DUSTS, OF WHICH GENETIC AND EPIGENETIC FACTORS MAINLY CONTRIBUTE TO LUNG TISSUE FIBROSIS. DNA METHYLATION IS ONE OF EPIGENETIC PROCESSES THAT OCCUR IN MANY DISEASES AND REGULATE CHROMOSOMAL AND EXTRACHROMOSOMAL DNA FUNCTIONS IN RESPONSE TO ENVIRONMENTAL EXPOSURES. THE METHYLATION PLAYS PIVOTAL ROLES IN REGULATION OF GENE EXPRESSION TO FACILITATE THE FORMATION OF FIBROBLASTIC FOCI AND LUNG FIBROSIS. THIS CHAPTER WILL DESCRIBE ALTERATIONS AND EFFECTS OF THE DNA METHYLATION ON GENE EXPRESSION, THE POTENTIAL APPLICATION OF DNA METHYLATION AS A BIOMARKER, AND SIGNIFICANCE AS THERAPEUTIC TARGETS. THOSE UNDERSTANDING WILL PROVIDE US NEW INSIGHT INTO THE TREATMENT AND PROGNOSIS OF IPF. 2020 3 3308 37 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS. 2023 4 2169 38 EPIGENETIC MECHANISMS IN PARENCHYMAL LUNG DISEASES: BYSTANDERS OR THERAPEUTIC TARGETS? EPIGENETIC RESPONSES DUE TO ENVIRONMENTAL CHANGES ALTER CHROMATIN STRUCTURE, WHICH IN TURN MODIFIES THE PHENOTYPE, GENE EXPRESSION PROFILE, AND ACTIVITY OF EACH CELL TYPE THAT HAS A ROLE IN THE PATHOPHYSIOLOGY OF A DISEASE. PULMONARY DISEASES ARE ONE OF THE MAJOR CAUSES OF DEATH IN THE WORLD, INCLUDING LUNG CANCER, IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), PULMONARY HYPERTENSION (PH), LUNG TUBERCULOSIS, PULMONARY EMBOLISM, AND ASTHMA. SEVERAL LINES OF EVIDENCE INDICATE THAT EPIGENETIC MODIFICATIONS MAY BE ONE OF THE MAIN FACTORS TO EXPLAIN THE INCREASING INCIDENCE AND PREVALENCE OF LUNG DISEASES INCLUDING IPF AND COPD. INTERESTINGLY, ISOLATED FIBROBLASTS AND SMOOTH MUSCLE CELLS FROM PATIENTS WITH PULMONARY DISEASES SUCH AS IPF AND PH THAT WERE CULTURED EX VIVO MAINTAINED THE DISEASE PHENOTYPE. THE CELLS OFTEN SHOW A HYPER-PROLIFERATIVE, APOPTOSIS-RESISTANT PHENOTYPE WITH INCREASED EXPRESSION OF EXTRACELLULAR MATRIX (ECM) AND ACTIVATED FOCAL ADHESIONS SUGGESTING THE PRESENCE OF AN EPIGENETICALLY IMPRINTED PHENOTYPE. MOREOVER, MANY ABNORMALITIES OBSERVED IN MOLECULAR PROCESSES IN IPF PATIENTS ARE SHOWN TO BE EPIGENETICALLY REGULATED, SUCH AS INNATE IMMUNITY, CELLULAR SENESCENCE, AND APOPTOTIC CELL DEATH. DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION CONSTITUTE THE MOST COMMON EPIGENETIC MODIFICATION MECHANISMS. 2022 5 5575 40 ROLE OF MICRORNAS IN SIGNALING PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS: A FOCUS ON EPITHELIAL-MESENCHYMAL TRANSITION. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND PROGRESSIVE DISEASE WITH HIGH MORTALITY AND UNCLEAR ETIOLOGY. PREVIOUS EVIDENCE SUPPORTS THAT THE ORIGIN OF THIS DISEASE IS ASSOCIATED WITH EPIGENETIC ALTERATIONS, AGE, AND ENVIRONMENTAL FACTORS. IPF INITIATES WITH CHRONIC EPITHELIAL LUNG INJURIES, FOLLOWED BY BASAL MEMBRANE DESTRUCTION, WHICH PROMOTES THE ACTIVATION OF MYOFIBROBLASTS AND EXCESSIVE SYNTHESIS OF EXTRACELLULAR MATRIX (ECM) PROTEINS, AS WELL AS EPITHELIAL-MESENCHYMAL TRANSITION (EMT). DUE TO MIRNAS' ROLE AS REGULATORS OF APOPTOSIS, PROLIFERATION, DIFFERENTIATION, AND CELL-CELL INTERACTION PROCESSES, SOME STUDIES HAVE INVOLVED MIRNAS IN THE BIOGENESIS AND PROGRESSION OF IPF. IN THIS CONTEXT, THE ANALYSIS AND DISCUSSION OF THE PROBABLE ASSOCIATION OF MIRNAS WITH THE SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF IPF WOULD IMPROVE OUR KNOWLEDGE OF THE ASSOCIATED MOLECULAR MECHANISMS, THEREBY FACILITATING ITS EVALUATION AS A THERAPEUTIC TARGET FOR THIS SEVERE LUNG DISEASE. IN THIS WORK, THE MOST RECENT PUBLICATIONS EVALUATING THE ROLE OF MIRNAS AS REGULATORS OR ACTIVATORS OF SIGNAL PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IPF WERE ANALYZED. THE SEARCH IN PUBMED WAS MADE USING THE FOLLOWING TERMS: "MIRNAS AND IDIOPATHIC PULMONARY FIBROSIS (IPF)"; "MIRNAS AND IPF AND SIGNALING PATHWAYS (SP)"; AND "MIRNAS AND IPF AND SP AND IPF PATHOGENESIS". ADDITIONALLY, WE FOCUS MAINLY ON THOSE WORKS WHERE THE SIGNALING PATHWAYS INVOLVED WITH EMT, FIBROBLAST DIFFERENTIATION, AND SYNTHESIS OF ECM COMPONENTS WERE ASSESSED. FINALLY, THE IMPORTANCE AND SIGNIFICANCE OF MIRNAS AS POTENTIAL THERAPEUTIC OR DIAGNOSTIC TOOLS FOR THE TREATMENT OF IPF ARE DISCUSSED. 2022 6 4294 36 MICRORNA REGULATORY NETWORKS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, AND FATAL SCARRING LUNG DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHANGES IN MICRORNA EXPRESSION. ACTIVATION OF TRANSFORMING GROWTH FACTOR (TGF-BETA) IS A KEY EVENT IN THE DEVELOPMENT OF IPF. RECENT REPORTS HAVE ALSO IDENTIFIED EPIGENETIC MODIFICATION AS AN IMPORTANT PLAYER IN THE PATHOGENESIS OF IPF. IN THIS REVIEW, WE SUMMARIZE THE MAIN RESULTS OF STUDIES THAT ADDRESS THE ROLE OF MICRORNAS IN IPF AND HIGHLIGHT THE SYNERGISTIC ACTIONS OF THESE MICRORNAS IN REGULATING TGF-BETA, THE PRIMARY FIBROGENIC MEDIATOR. WE OUTLINE EPIGENETIC REGULATION OF MICRORNAS BY METHYLATION. FUNCTIONAL STUDIES IDENTIFY MICRORNAS THAT ALTER PROLIFERATIVE AND MIGRATORY PROPERTIES OF FIBROBLASTS, AND INDUCE PHENOTYPIC CHANGES IN EPITHELIAL CELLS CONSISTENT WITH EPITHELIAL-MESENCHYMAL TRANSITION. THOUGH THESE STUDIES WERE PERFORMED IN ISOLATION, WE IDENTIFY MULTIPLE CO-OPERATIVE ACTIONS AFTER ASSEMBLING THE RESULTS INTO A NETWORK. CONSTRUCTION OF SUCH NETWORKS WILL HELP IDENTIFY DISEASE-PROPELLING HUBS THAT CAN BE TARGETED FOR THERAPEUTIC PURPOSES. 2015 7 4480 42 MOLECULAR PATHWAYS AND ROLE OF EPIGENETICS IN THE IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A FATAL LUNG DISEASE WITH UNKNOWN ETIOLOGICAL FACTORS THAT CAN PROGRESS TO OTHER DANGEROUS DISEASES LIKE LUNG CANCER. ENVIRONMENTAL AND GENETIC PREDISPOSITION ARE THE TWO MAJOR ETIOLOGICAL OR RISK FACTORS INVOLVED IN THE PATHOLOGY OF THE IPF. AMONG THE ENVIRONMENTAL RISK FACTORS, SMOKING IS ONE OF THE MAJOR CAUSES FOR THE DEVELOPMENT OF IPF. EPIGENETIC PATHWAYS LIKE NUCLEOSOMES REMODELING, DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA MEDIATED GENES PLAY A CRUCIAL ROLE IN DEVELOPMENT OF IPF. MUTATIONS IN THE GENES MAKE THE EPIGENETIC FACTORS AS IMPORTANT DRUG TARGETS IN IPF. TRANSCRIPTIONAL CHANGES DUE TO ENVIRONMENTAL FACTORS ARE ALSO INVOLVED IN THE PROGRESSION OF IPF. THE MUTATIONS IN HUMAN TELOMERASE REVERSE TRANSCRIPTASE (HTERT) HAVE SHOWN DECREASED LIFE EXPECTANCY IN IPF PATIENTS. THE TERT-GENE IS HIGHLY EXPRESSED IN CHRONIC SMOKERS AND MAKES THE ROLE OF EPIGENETICS EVIDENT. DRUG LIKE NINTEDANIB ACTS THROUGH VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS (VEGFR), WHILE DRUG PIRFENIDONE ACTS THROUGH TRANSFORMING GROWTH FACTOR (TGF), WHICH IS USEFUL IN IPF. GEFITINIB, A TYROSINE KINASE INHIBITOR OF EGFR, IS USEFUL AS AN ANTI-FIBROSIS AGENT IN PRECLINICAL MODELS. NEWER DRUGS SUCH AS CELGENE-CC90001 AND FIBROGEN-FG-3019 ARE CURRENTLY UNDER INVESTIGATIONS ACTS THROUGH THE MODULATING EPIGENETIC MECHANISMS. THUS, THE STUDY ON EPIGENETICS OPENS A WIDE WINDOW FOR THE DISCOVERY OF NEWER DRUGS. THIS STUDY PROVIDES AN ELEMENTARY ANALYSIS OF MULTIPLE REGULATORS OF EPIGENETICS AND THEIR ROLES ASSOCIATED WITH THE PATHOLOGY OF IPF. FURTHER, THIS REVIEW ALSO INCLUDES EPIGENETIC DRUGS UNDER DEVELOPMENT IN PRECLINICAL AND CLINICAL STAGES. 2022 8 6223 42 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 9 5484 42 REVEALING THE PATHOGENIC AND AGING-RELATED MECHANISMS OF THE ENIGMATIC IDIOPATHIC PULMONARY FIBROSIS. AN INTEGRAL MODEL. A GROWING BODY OF EVIDENCE INDICATES THAT ABERRANT ACTIVATION OF ALVEOLAR EPITHELIAL CELLS AND FIBROBLASTS IN AN AGING LUNG PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS (IPF). HOWEVER, THE BIOPATHOLOGICAL PROCESSES LINKING AGING WITH IPF AND THE MECHANISMS RESPONSIBLE FOR THE ABNORMAL ACTIVATION OF EPITHELIAL CELLS AND FIBROBLASTS HAVE NOT BEEN ELUCIDATED. MANY OF THE HALLMARKS OF AGING (E.G., GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, AND CELLULAR SENESCENCE) HAVE BEEN PROPOSED AS ESSENTIAL MECHANISMS FOR THE DEVELOPMENT OF IPF; HOWEVER, THESE DISTURBANCES ARE NOT RESTRICTED TO IPF AND ALSO OCCUR IN OTHER AGING-RELATED LUNG DISORDERS, PRIMARILY CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THEREFORE, AN UNANSWERED QUESTION IS WHY A CURRENT/FORMER SMOKER OF ABOUT 60 YEARS OF AGE WITH SHORTER TELOMERES, ALVEOLAR EPITHELIAL SENESCENCE, EXCESSIVE OXIDATIVE STRESS, AND MITOCHONDRIAL DYSFUNCTION DEVELOPS IPF AND NOT COPD; IN OTHER WORDS, WHAT MAKES OLD LUNGS SPECIFICALLY SUSCEPTIBLE TO DEVELOP IPF? IN THIS PERSPECTIVE, WE PROPOSE AN INTEGRAL MODEL IN WHICH THE COMBINATION OF SOME GENE VARIANTS AND/OR GENE EXPRESSION IN THE AGING LUNG RESULTS IN THE LOSS OF EPITHELIAL INTEGRITY AND CONSEQUENTLY IN THE FAILURE OF THE ALVEOLI TO CORRECTLY RESPOND TO INJURY AND TO FACE THE STRESS ASSOCIATED WITH MECHANICAL STRETCH. AFTERWARD, A DISTINCTIVE EPIGENETIC "REPROGRAMMING" THAT AFFECTS BOTH EPITHELIAL CELLS AND FIBROBLASTS PROVOKES, AMONG OTHERS, THE RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND THE ABERRANT ACTIVATION AND MISCOMMUNICATION BETWEEN BOTH CELL TYPES, RESULTING IN THE EXAGGERATED PRODUCTION AND ACCUMULATION OF EXTRACELLULAR MATRIX AND THE SUBSEQUENT DESTRUCTION OF THE LUNG ARCHITECTURE. 2014 10 172 37 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 11 4228 28 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 12 4450 41 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 13 348 50 ALTERED DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN PARENCHYMAL BUT NOT AIRWAY FIBROBLASTS ISOLATED FROM INDIVIDUALS WITH COPD. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A HETEROGENEOUS DISEASE OF THE LUNGS THAT IS CURRENTLY THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. GENETIC FACTORS ACCOUNT FOR ONLY A SMALL AMOUNT OF COPD RISK, BUT EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HAVE THE POTENTIAL TO MEDIATE THE INTERACTIONS BETWEEN AN INDIVIDUAL'S GENETICS AND ENVIRONMENTAL EXPOSURE. DNA METHYLATION IS HIGHLY CELL TYPE-SPECIFIC, AND INDIVIDUAL CELL TYPE STUDIES OF DNA METHYLATION IN COPD ARE SPARSE. FIBROBLASTS ARE PRESENT WITHIN THE AIRWAY AND PARENCHYMA OF THE LUNG AND CONTRIBUTE TO THE ABERRANT DEPOSITION OF EXTRACELLULAR MATRIX IN COPD. NO ASSESSMENT OR COMPARISON OF GENOME-WIDE DNA METHYLATION PROFILES IN THE AIRWAY AND PARENCHYMAL FIBROBLASTS FROM INDIVIDUALS WITH AND WITHOUT COPD HAS BEEN UNDERTAKEN. THESE DATA PROVIDE VALUABLE INSIGHT INTO THE MOLECULAR MECHANISMS CONTRIBUTING TO COPD AND THE DIFFERING PATHOLOGIES OF SMALL AIRWAYS DISEASE AND EMPHYSEMA IN COPD. METHODS: GENOME-WIDE DNA METHYLATION WAS EVALUATED AT OVER 485,000 CPG SITES USING THE ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY IN THE AIRWAY (NON-COPD N = 8, COPD N = 7) AND PARENCHYMAL FIBROBLASTS (NON-COPD N = 17, COPD N = 29) ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD. TARGETED GENE EXPRESSION WAS ASSESSED BY QPCR IN MATCHED RNA SAMPLES. RESULTS: DIFFERENTIALLY METHYLATED DNA REGIONS WERE IDENTIFIED BETWEEN CELLS ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD IN BOTH AIRWAY AND PARENCHYMAL FIBROBLASTS. ONLY IN PARENCHYMAL FIBROBLASTS WAS DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH DIFFERENTIAL GENE EXPRESSION. A SECOND ANALYSIS OF DIFFERENTIAL DNA METHYLATION VARIABILITY IDENTIFIED 359 INDIVIDUAL DIFFERENTIALLY VARIABLE CPG SITES IN PARENCHYMAL FIBROBLASTS. NO DIFFERENTIALLY VARIABLE CPG SITES WERE IDENTIFIED IN THE AIRWAY FIBROBLASTS. FIVE DIFFERENTIALLY VARIABLE-METHYLATED CPG SITES, ASSOCIATED WITH THREE GENES, WERE SUBSEQUENTLY ASSESSED FOR GENE EXPRESSION DIFFERENCES. TWO GENES (OAT AND GRIK2) DISPLAYED SIGNIFICANTLY INCREASED GENE EXPRESSION IN CELLS ISOLATED FROM INDIVIDUALS WITH COPD. CONCLUSIONS: DIFFERENTIAL AND VARIABLE DNA METHYLATION WAS ASSOCIATED WITH COPD STATUS IN THE PARENCHYMAL FIBROBLASTS BUT NOT AIRWAY FIBROBLASTS. ABERRANT DNA METHYLATION WAS ASSOCIATED WITH ALTERED GENE EXPRESSION IMPARTING BIOLOGICAL FUNCTION TO DNA METHYLATION CHANGES. CHANGES IN DNA METHYLATION ARE THEREFORE IMPLICATED IN THE MOLECULAR MECHANISMS UNDERLYING COPD PATHOGENESIS AND MAY REPRESENT NOVEL THERAPEUTIC TARGETS. 2018 14 1587 34 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS. 2016 15 5324 43 PULMONARY MICRORNA PROFILING: IMPLICATIONS IN UPPER LOBE PREDOMINANT LUNG DISEASE. BACKGROUND: NUMEROUS PULMONARY DISEASES MANIFEST WITH UPPER LOBE PREDOMINANCE INCLUDING CYSTIC FIBROSIS, SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND TUBERCULOSIS. ZONAL HYPOXIA, CHARACTERISTIC OF THESE PULMONARY MALADIES, AND OXYGEN STRESS IN GENERAL IS KNOWN TO EXERT PROFOUND EFFECTS ON VARIOUS IMPORTANT ASPECTS OF CELL BIOLOGY. LUNG MACROPHAGES ARE MAJOR PARTICIPANTS IN THE PULMONARY INNATE IMMUNE RESPONSE AND REGIONAL DIFFERENCES IN MACROPHAGE RESPONSIVENESS TO HYPOXIA MAY CONTRIBUTE IN THE DEVELOPMENT OF LUNG DISEASE. MICRORNAS ARE UBIQUITOUS REGULATORS OF HUMAN BIOLOGY AND EMERGING EVIDENCE INDICATES ALTERED MICRORNA EXPRESSION MODULATES RESPIRATORY DISEASE PROCESSES. THE OBJECTIVE OF THIS STUDY IS TO GAIN INSIGHT INTO THE EPIGENETIC AND CELLULAR MECHANISMS INFLUENCING REGIONAL DIFFERENCES IN LUNG DISEASE BY INVESTIGATING EFFECT OF HYPOXIA ON REGIONAL MICRORNA EXPRESSION IN THE LUNG. ALL STUDIES WERE PERFORMED USING PRIMARY ALVEOLAR MACROPHAGES (N = 10) OR BRONCHOALVEOLAR LAVAGE FLUID (N = 16) ISOLATED FROM HUMAN SUBJECTS. MICRORNA WAS ASSAYED VIA THE NANOSTRING NCOUNTER MICRORNA ASSAY. RESULTS: DIVERGENT MOLECULAR PATTERNS OF MICRORNA EXPRESSION WERE OBSERVED IN ALTERNATE LUNG LOBES, SPECIFICALLY NOTED WAS DISPARATE EXPRESSION OF MIR-93 AND MIR-4454 IN ALVEOLAR MACROPHAGES ALONG WITH ALTERED EXPRESSION OF MIR-451A AND MIR-663A IN BRONCHOALVEOLAR LAVAGE FLUID. GENE ONTOLOGY WAS USED TO IDENTIFY POTENTIAL DOWNSTREAM TARGETS OF DIVERGENT MICRORNAS. TARGETS INCLUDE CYTOKINES AND MATRIX METALLOPROTEINASES, MOLECULES THAT COULD HAVE A SIGNIFICANT IMPACT ON PULMONARY INFLAMMATION AND FIBROSIS. CONCLUSIONS: OUR FINDINGS SHOW VARIANT REGIONAL MICRORNA EXPRESSION ASSOCIATED WITH HYPOXIA IN ALVEOLAR MACROPHAGES AND BAL FLUID IN THE LUNG-UPPER VS LOWER LOBE. FUTURE STUDIES SHOULD ADDRESS WHETHER THESE SPECIFIC MICRORNAS MAY ACT INTRACELLULARLY, IN A PARACRINE/ENDOCRINE MANNER TO DIRECT THE INNATE IMMUNE RESPONSE OR MAY ULTIMATELY BE INVOLVED IN PULMONARY HOST-TO-PATHOGEN TRANS-KINGDOM CROSS-TALK. 2017 16 6431 33 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION. 2018 17 6839 29 [LUNG CANCER AND ITS EPIGENETICS ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE THE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE. DEVELOPMENT OF LUNG CANCER INVOLVES BOTH GENETIC AND ENVIRONMENT FACTORS. IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC MECHANISM IS CLOSELY INVOLVED IN PATHOGENESIS OF LUNG CANCER. CHARACTERIZED BY AN ABNORMAL PERSISTENT INFLAMMATORY RESPONSE TO NOXIOUS ENVIRONMENTAL STIMULATION, COPD HAS SHOWN TO INCREASE THE SUSCEPTIBILITY FOR LUNG TUMORIGENESIS IN PREVIOUS RESEARCH. CURRENT RESEARCH ON EPIGENETICS OF LUNG CANCER AND COPD HAS FOCUSED ON ABERRANT DNA METHYLATION, HISTONE ACETYLATION AND NON-CODING RNAS REGULATION. THE ABERRANT DNA METHYLATION ASSOCIATED WITH LUNG CANCER AND COPD HAS INCLUDED OVEREXPRESSION OF DNA METHYLTRANSFERASE, GLOBAL DNA HYPOMETHYLATION AND DNA HYPERMETHYLATION IN PROMOTER REGIONS, WHILE HISTONE ACETYLATION AND HISTONE METHYLATION ARE THE MAJOR CHANGES FOR HISTONE MODIFICATION, IN WHICH HISTONE ACETYLTRANSFERASES, HISTONE DEACETYLASES, HISTONE METHYLTRANSFERASES AND HISTONE DEMETHYLASES PLAY THE MOST IMPORTANT ROLES. RNA INTERFERENCE AND MICRORNAS ARE BOTH HOT TOPICS OF RESEARCH ON NON-CODING RNAS REGULATION. UNDERSTANDING OF CONCURRENT EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF LUNG CANCER AND COPD MAY FACILITATE IDENTIFICATION OF SPECIFIC THERAPEUTIC TARGETS AND DEVELOPMENT OF EFFECTIVE TREATMENT. 2013 18 1508 38 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 19 2059 33 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE LUNG. EPIGENETICS IS TRADITIONALLY DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. THERE ARE THREE MAIN CLASSES OF EPIGENETIC MARKS--DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS, AND NONCODING RNAS--EACH OF WHICH MAY BE INFLUENCED BY THE ENVIRONMENT, DIET, DISEASES, AND AGEING. IMPORTANTLY, EPIGENETIC MARKS HAVE BEEN SHOWN TO INFLUENCE IMMUNE CELL MATURATION AND ARE ASSOCIATED WITH THE RISK OF DEVELOPING VARIOUS FORMS OF CANCER, INCLUDING LUNG CANCER. MOREOVER, THERE IS EMERGING EVIDENCE THAT THESE EPIGENETIC MARKS AFFECT GENE EXPRESSION IN THE LUNG AND ARE ASSOCIATED WITH BENIGN LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND INTERSTITIAL LUNG DISEASE. TECHNOLOGICAL ADVANCES HAVE MADE IT FEASIBLE TO STUDY EPIGENETIC MARKS IN THE LUNG, AND IT IS ANTICIPATED THAT THIS KNOWLEDGE WILL ENHANCE OUR UNDERSTANDING OF THE DYNAMIC BIOLOGY IN THE LUNG AND LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES FOR OUR PATIENTS WITH LUNG DISEASE. 2011 20 4661 21 NEW ASPECTS OF THE EPIGENETIC REGULATION OF EMT RELATED TO PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE FIBROTIC DISEASE THAT RESULTS IN IMPAIRED GAS EXCHANGE, VENTILATION, AND EVENTUAL DEATH. THE PRO-FIBROTIC ENVIRONMENT IS INSTIGATED BY VARIOUS FACTORS, LEADING TO THE TRANSFORMATION OF EPITHELIAL CELLS INTO MYOFIBROBLASTS AND/OR FIBROBLASTS THAT TRIGGER FIBROSIS. EPITHELIAL MESENCHYMAL TRANSITION (EMT) IS A BIOLOGICAL PROCESS THAT PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PULMONARY FIBROSIS. EPIGENETIC REGULATION OF TISSUE-STROMAL CROSSTALK INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA, AND CHROMATIN REMODELING PLAYS A KEY ROLE IN THE CONTROL OF EMT. THE REVIEW INVESTIGATES THE EPIGENETIC REGULATION OF EMT AND ITS SIGNIFICANCE IN PULMONARY FIBROSIS. 2023