1 2388 90 EPIGENETIC REMODELLING LICENCES ADULT CHOLANGIOCYTES FOR ORGANOID FORMATION AND LIVER REGENERATION. FOLLOWING SEVERE OR CHRONIC LIVER INJURY, ADULT DUCTAL CELLS (CHOLANGIOCYTES) CONTRIBUTE TO REGENERATION BY RESTORING BOTH HEPATOCYTES AND CHOLANGIOCYTES. WE RECENTLY SHOWED THAT DUCTAL CELLS CLONALLY EXPAND AS SELF-RENEWING LIVER ORGANOIDS THAT RETAIN THEIR DIFFERENTIATION CAPACITY INTO BOTH HEPATOCYTES AND DUCTAL CELLS. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH ADULT DUCTAL-COMMITTED CELLS ACQUIRE CELLULAR PLASTICITY, INITIATE ORGANOIDS AND REGENERATE THE DAMAGED TISSUE REMAIN LARGELY UNKNOWN. HERE, WE DESCRIBE THAT DUCTAL CELLS UNDERGO A TRANSIENT, GENOME-WIDE, REMODELLING OF THEIR TRANSCRIPTOME AND EPIGENOME DURING ORGANOID INITIATION AND IN VIVO FOLLOWING TISSUE DAMAGE. TET1-MEDIATED HYDROXYMETHYLATION LICENCES DIFFERENTIATED DUCTAL CELLS TO INITIATE ORGANOIDS AND ACTIVATE THE REGENERATIVE PROGRAMME THROUGH THE TRANSCRIPTIONAL REGULATION OF STEM-CELL GENES AND REGENERATIVE PATHWAYS INCLUDING THE YAP-HIPPO SIGNALLING. OUR RESULTS ARGUE IN FAVOUR OF THE REMODELLING OF GENOMIC METHYLOME/HYDROXYMETHYLOME LANDSCAPES AS A GENERAL MECHANISM BY WHICH DIFFERENTIATED CELLS EXIT A COMMITTED STATE IN RESPONSE TO TISSUE DAMAGE. 2019 2 5785 25 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 3 222 27 ACUTE LIVER STEATOSIS TRANSLATIONALLY CONTROLS THE EPIGENETIC REGULATOR MIER1 TO PROMOTE LIVER REGENERATION IN A STUDY WITH MALE MICE. THE EARLY PHASE LIPID ACCUMULATION IS ESSENTIAL FOR LIVER REGENERATION. HOWEVER, WHETHER THIS ACUTE LIPID ACCUMULATION CAN SERVE AS SIGNALS TO DIRECT LIVER REGENERATION RATHER THAN SIMPLY PROVIDING BUILDING BLOCKS FOR CELL PROLIFERATION REMAINS UNCLEAR. THROUGH IN VIVO CRISPR SCREENING, WE IDENTIFY MIER1 (MESODERM INDUCTION EARLY RESPONSE 1) AS A KEY EPIGENETIC REGULATOR THAT BRIDGES THE ACUTE LIPID ACCUMULATION AND CELL CYCLE GENE EXPRESSION DURING LIVER REGENERATION IN MALE ANIMALS. PHYSIOLOGICALLY, LIVER ACUTE LIPID ACCUMULATION INDUCES THE PHOSPHORYLATION OF EIF2S1(EUKARYOTIC TRANSLATION INITIATION FACTOR 2), WHICH CONSEQUENTLY ATTENUATED MIER1 TRANSLATION. MIER1 DOWNREGULATION IN TURN PROMOTES CELL CYCLE GENE EXPRESSION AND REGENERATION THROUGH CHROMATIN REMODELING. IMPORTANTLY, THE LIPIDS-EIF2S1-MIER1 PATHWAY IS IMPAIRED IN ANIMALS WITH CHRONIC LIVER STEATOSIS; WHEREAS MIER1 DEPLETION SIGNIFICANTLY IMPROVES REGENERATION IN THESE ANIMALS. TAKEN TOGETHER, OUR STUDIES IDENTIFY AN EPIGENETIC MECHANISM BY WHICH THE EARLY PHASE LIPID REDISTRIBUTION FROM ADIPOSE TISSUE TO LIVER DURING REGENERATION IMPACTS HEPATOCYTE PROLIFERATION, AND SUGGEST A POTENTIAL STRATEGY TO BOOST LIVER REGENERATION. 2023 4 5491 17 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 5 5292 28 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. 2014 6 4558 22 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 7 2002 24 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 8 1902 22 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 9 1326 18 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 10 6906 16 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 11 3418 21 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 12 2025 22 EPIGENETIC CHANGES DURING DISEASE PROGRESSION IN A MURINE MODEL OF HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC ALTERATIONS, INCLUDING GAIN OR LOSS OF DNA METHYLATION, ARE A HALLMARK OF NEARLY EVERY MALIGNANCY. CHANGES IN DNA METHYLATION CAN IMPACT EXPRESSION OF CANCER-RELATED GENES INCLUDING APOPTOSIS REGULATORS AND TUMOR SUPPRESSORS. BECAUSE SUCH EPIGENETIC CHANGES ARE REVERSIBLE, THEY ARE BEING AGGRESSIVELY INVESTIGATED AS POTENTIAL THERAPEUTIC TARGETS. HERE WE USE THE EMU-TCL1 TRANSGENIC MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TO DETERMINE THE TIMING AND PATTERNS OF ABERRANT DNA METHYLATION, AND TO INVESTIGATE THE MECHANISMS THAT LEAD TO ABERRANT DNA METHYLATION. WE SHOW THAT CLL CELLS FROM EMU-TCL1 MICE AT VARIOUS STAGES RECAPITULATE EPIGENETIC ALTERATIONS SEEN IN HUMAN CLL. ABERRANT METHYLATION OF PROMOTER SEQUENCES IS OBSERVED AS EARLY AS 3 MONTHS OF AGE IN THESE ANIMALS, WELL BEFORE DISEASE ONSET. ABNORMALLY METHYLATED PROMOTER REGIONS INCLUDE BINDING SITES FOR THE TRANSCRIPTION FACTOR FOXD3. WE SHOW THAT LOSS OF FOXD3 EXPRESSION DUE TO AN NF-KAPPAB P50/P50:HDAC1 REPRESSOR COMPLEX OCCURS IN TCL1-POSITIVE B CELLS BEFORE METHYLATION. THEREFORE, SPECIFIC TRANSCRIPTIONAL REPRESSION IS AN EARLY EVENT LEADING TO EPIGENETIC SILENCING OF TARGET GENES IN MURINE AND HUMAN CLL. THESE RESULTS PROVIDE STRONG RATIONALE FOR THE DEVELOPMENT OF STRATEGIES TO TARGET NF-KAPPAB COMPONENTS IN CLL AND POTENTIALLY OTHER B-CELL MALIGNANCIES. 2009 13 1615 22 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. 2020 14 5688 23 SILENCING EFFECTS OF MUTANT RAS SIGNALLING ON TRANSCRIPTOMES. MUTATED GENES OF THE RAS FAMILY ENCODING SMALL GTP-BINDING PROTEINS DRIVE NUMEROUS CANCERS, INCLUDING PANCREATIC, COLON AND LUNG TUMORS. BESIDES THE NUMEROUS EFFECTS OF MUTANT RAS GENE EXPRESSION ON ABERRANT PROLIFERATION, TRANSFORMED PHENOTYPES, METABOLISM, AND THERAPY RESISTANCE, THE MOST STRIKING CONSEQUENCES OF CHRONIC RAS ACTIVATION ARE CHANGES OF THE GENETIC PROGRAM. BY PERFORMING SYSTEMATIC GENE EXPRESSION STUDIES IN CELLULAR MODELS THAT ALLOW COMPARISONS OF PRE-NEOPLASTIC WITH RAS-TRANSFORMED CELLS, WE AND OTHERS HAVE ESTIMATED THAT 7 PERCENT OR MORE OF ALL TRANSCRIPTS ARE ALTERED IN CONJUNCTION WITH THE EXPRESSION OF THE ONCOGENE. IN THIS CONTEXT, THE NUMBER OF UP-REGULATED TRANSCRIPTS APPROXIMATES THAT OF DOWN-REGULATED TRANSCRIPTS. WHILE UP-REGULATED TRANSCRIPTION FACTORS SUCH AS MYC, FOSL1, AND HMGA2 HAVE BEEN IDENTIFIED AND CHARACTERIZED AS RAS-RESPONSIVE DRIVERS OF THE ALTERED TRANSCRIPTOME, THE SUPPRESSED FACTORS HAVE BEEN LESS WELL STUDIED AS POTENTIAL REGULATORS OF THE GENETIC PROGRAM AND TRANSFORMED PHENOTYPE IN THE BREADTH OF THEIR OCCURRENCE. WE THEREFORE HAVE COLLECTED INFORMATION ON DOWNREGULATED RAS-RESPONSIVE FACTORS AND DISCUSS THEIR POTENTIAL ROLE AS TUMOR SUPPRESSORS THAT ARE LIKELY TO ANTAGONIZE ACTIVE CANCER DRIVERS. TO BETTER UNDERSTAND THE ACTIVE MECHANISMS THAT ENTAIL ANTI-RAS FUNCTION AND THOSE THAT LEAD TO LOSS OF TUMOR SUPPRESSOR ACTIVITY, WE FOCUS ON THE TUMOR SUPPRESSOR HREV107 (ALIAS PLAAT3 [PHOSPHOLIPASE A AND ACYLTRANSFERASE 3], PLA2G16 [PHOSPHOLIPASE A2, GROUP XVI] AND HRASLS3 [HRAS-LIKE SUPPRESSOR 3]). INACTIVATING HREV107 MUTATIONS IN TUMORS ARE EXTREMELY RARE, HENCE EPIGENETIC CAUSES MODULATED BY THE RAS PATHWAY ARE LIKELY TO LEAD TO DOWN-REGULATION AND LOSS OF FUNCTION. 2023 15 3950 17 LNFLAMMATION-INDUCED EPIGENETIC SWITCHES IN CANCER. THE LINK BETWEEN INFLAMMATION AND CANCER IS WELL ESTABLISHED. CHRONIC INFLAMMATION PROMOTES CANCER INITIATION AND PROGRESSION. VARIOUS STUDIES SHOWED THAT THE UNDERLYING MECHANISMS INVOLVE EPIGENETIC ALTERATIONS. THESE EPIGENETIC ALTERATIONS MIGHT CULMINATE INTO AN EPIGENETIC SWITCH THAT TRANSFORMS PREMALIGNANT CELLS INTO TUMOR CELLS OR NON-INVASIVE INTO INVASIVE TUMOR CELLS, THEREBY PROMOTING METASTASIS. EPIGENETIC SWITCHES REQUIRE AN INITIATING EVENT, WHICH CAN BE INFLAMMATION, WHEREAS THE RESULTING PHENOTYPE IS INHERITED WITHOUT THE INITIATING SIGNAL. EPIGENETIC SWITCHES ARE INDUCED AND MAINTAINED BY DNA METHYLATION, HISTONE MODIFICATIONS, POLYCOMB GROUP (PCG)/TRITHORAX GROUP (TRXG) PROTEINS, AND FEEDBACK LOOPS CONSISTING OF TRANSCRIPTION FACTORS AND MICRORNAS. SINCE EPIGENETIC SWITCHES ARE REVERSIBLE, THEY MIGHT REPRESENT AN IMPORTANT BASIS FOR THE DESIGN OF NOVEL ANTICANCER THERAPEUTICS. THIS REVIEW SUMMARIZES PUBLISHED EVIDENCE OF EPIGENETIC SWITCHES IN CANCER DEVELOPMENT THAT ARE INDUCED BY INFLAMMATION. 2016 16 2926 18 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 17 5889 20 SYSTEMS APPROACHES TO MODELING CHRONIC MUCOSAL INFLAMMATION. THE RESPIRATORY MUCOSA IS A MAJOR COORDINATOR OF THE INFLAMMATORY RESPONSE IN CHRONIC AIRWAY DISEASES, INCLUDING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SIGNALS PRODUCED BY THE CHRONIC INFLAMMATORY PROCESS INDUCE EPITHELIAL MESENCHYMAL TRANSITION (EMT) THAT DRAMATICALLY ALTERS THE EPITHELIAL CELL PHENOTYPE. THE EFFECTS OF EMT ON EPIGENETIC REPROGRAMMING AND THE ACTIVATION OF TRANSCRIPTIONAL NETWORKS ARE KNOWN, ITS EFFECTS ON THE INNATE INFLAMMATORY RESPONSE ARE UNDEREXPLORED. WE USED A MULTIPLEX GENE EXPRESSION PROFILING PLATFORM TO INVESTIGATE THE PERTURBATIONS OF THE INNATE PATHWAYS INDUCED BY TGF BETA IN A PRIMARY AIRWAY EPITHELIAL CELL MODEL OF EMT. EMT HAD DRAMATIC EFFECTS ON THE INDUCTION OF THE INNATE PATHWAY AND THE COUPLING INTERVAL OF THE CANONICAL AND NONCANONICAL NF- KAPPA B PATHWAYS. SIMULATION EXPERIMENTS DEMONSTRATE THAT RAPID, COORDINATED CAP-INDEPENDENT TRANSLATION OF TRAF-1 AND NF- KAPPA B2 IS REQUIRED TO REDUCE THE NONCANONICAL PATHWAY COUPLING INTERVAL. EXPERIMENTS USING AMANTADINE CONFIRMED THE PREDICTION THAT TRAF-1 AND NF- KAPPA B2/P100 PRODUCTION IS MEDIATED BY AN IRES-DEPENDENT MECHANISM. THESE DATA INDICATE THAT THE EPIGENETIC CHANGES PRODUCED BY EMT INDUCE DYNAMIC STATE CHANGES OF THE INNATE SIGNALING PATHWAY. FURTHER APPLICATIONS OF SYSTEMS APPROACHES WILL PROVIDE UNDERSTANDING OF THIS COMPLEX PHENOTYPE THROUGH DETERMINISTIC MODELING AND MULTIDIMENSIONAL (GENOMIC AND PROTEOMIC) PROFILING. 2013 18 2446 15 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 19 194 18 ACETYLSHIKONIN SUPPRESSES INVASION OF PORPHYROMONAS GINGIVALIS?INFECTED YD10B ORAL CANCER CELLS BY MODULATING THE INTERLEUKIN-8/MATRIX METALLOPROTEINASE AXIS. THE DEVELOPMENT OF PHARMACEUTICAL AGENTS POSSESSING ANTI?INVASIVE AND ANTI?METASTATIC ABILITIES, AS WELL AS APOPTOTIC ACTIVITY, IS IMPORTANT IN DECREASING THE INCIDENCE AND RECURRENCE OF ORAL CANCER. CANCER CELLS ARE KNOWN TO ACQUIRE INVASIVENESS NOT ONLY THROUGH EPIGENETIC CHANGES, BUT ALSO FROM INFLAMMATORY STIMULI WITHIN THE TUMOR MICROENVIRONMENT. ACCORDINGLY, THE IDENTIFICATION OF AGENTS THAT CAN SUPPRESS THE INFLAMMATION?PROMOTED INVASIVENESS OF CANCER CELLS MAY BE IMPORTANT IN TREATING CANCER AND IMPROVING THE PROGNOSIS OF PATIENTS WITH CANCER. ACETYLSHIKONIN, A FLAVONOID WITH ANTI?INFLAMMATORY ACTIVITY, INHIBITS PROLIFERATION AND INDUCES APOPTOSIS OF ORAL CANCER CELLS. IN THE PRESENT STUDY, THE ANTI?INVASIVE EFFECT OF ACETYLSHIKONIN ON YD10B ORAL CANCER CELLS INFECTED WITH PORPHYROMONAS GINGIVALIS, A MAJOR PATHOGEN OF CHRONIC PERIODONTITIS, AND THE MECHANISMS INVOLVED WERE INVESTIGATED. FIRSTLY, WE EXAMINED WHETHER P. GINGIVALIS INFECTION INCREASED THE INVASIVENESS OF YD10B CELLS. RESULTS SUGGESTED THAT YD10B ORAL CANCER CELLS BECOME MORE AGGRESSIVE WHEN THEY ARE INFECTED WITH P. GINGIVALIS. SECONDLY, ACETYLSHIKONIN SIGNIFICANTLY INHIBITED THE INVASION OF P. GINGIVALIS?INFECTED YD10B CELLS BY SUPPRESSING IL?8 RELEASE AND IL?8?DEPENDENT MMP RELEASE. THESE DATA SUGGEST THAT ACETYLSHIKONIN MAY BE A USEFUL PREVENTIVE AND THERAPEUTIC CANDIDATE FOR ORAL CANCER THAT IS CHRONICALLY INFECTED WITH PERIODONTAL PATHOGENS. 2018 20 4 27 "MIX OF MICS"- PHENOTYPIC AND BIOLOGICAL HETEROGENEITY OF "MULTIPOTENT" MUSCLE INTERSTITIAL CELLS (MICS). THE CAPACITY OF ADULT SKELETAL MUSCLE FOR REGENERATION APPEARS TO BE LIMITED, WITH PROGRESSIVE IMPAIRMENT IN REPAIR EFFICIENCY OF INJURED MUSCLES OBSERVED IN CHRONIC MUSCULAR DISORDERS AND DURING AGING. WHILE SATELLITE CELLS, THE COMMITTED ADULT MUSCLE STEM CELLS, ARE THE MAIN DIRECT CELL SOURCE SUPPORTING THE REGENERATIVE POTENTIAL OF ADULT SKELETAL MUSCLES, THE CHARACTERIZATION OF THE CELL TYPES AND SIGNALS THAT CONSTITUTE THE FUNCTIONAL "NICHE" OF SATELLITE CELLS IS CURRENTLY THE OBJECT OF INTENSE INVESTIGATION. RECENT STUDIES HAVE IDENTIFIED A FUNCTIONAL RELATIONSHIP BETWEEN SATELLITE CELLS AND VARIOUS CELL TYPES LOCATED IN KEY ANATOMICAL POSITION, SUCH AS THE INTERSTITIUM OF SKELETAL MUSCLES. THIS HETEROGENEOUS POPULATION OF MUSCLE INTERSTITIAL CELLS (MICS) APPEARS TO RETAIN AN INTRINSIC MULTIPOTENCY WITHIN THE MESODERMAL LINEAGE, AND THEIR DIRECT OR INDIRECT CONTRIBUTION TO MYOFIBER TURNOVER, REPAIR AND DEGENERATION HAS BEEN SUGGESTED BY MANY STUDIES THAT WILL BE REVIEWED HERE. GIVEN THE EXISTING GAP OF KNOWLEDGE ON LINEAGE IDENTITY AND FUNCTIONAL PROPERTIES OF MICS, THEIR DETAILED CHARACTERIZATION AT THE SINGLE CELL LEVEL HOLDS THE PROMISE TO PROVIDE KEY INSIGHT INTO THE COMPOSITION OF THIS HETEROGENEOUS POPULATION AND THE DYNAMIC TRANSITION THROUGH DISTINCT SUB-POPULATIONS IN HEALTHY, DISEASED AND AGING MUSCLES. THIS REVIEW PROVIDES AN OVERVIEW OF THE RESULTS OF VARIOUS STUDIES DESCRIBING THE PHENOTYPE AND THE FUNCTION OF CELLS ISOLATED FROM SKELETAL MUSCLE INTERSTITIUM, AND DISCUSSES THE IMPORTANCE OF SINGLE CELL TRANSCRIPTION PROFILING IN ORDER TO DECIPHER THE FUNCTIONAL AND PHENOTYPICAL HETEROGENEITY OF MUSCLE INTERSTITIAL CELLS (MICS). 2012