1 1171 141 CONTRIBUTION OF MATURE HEPATOCYTES TO BILIARY REGENERATION IN RATS WITH ACUTE AND CHRONIC BILIARY INJURY. WHETHER HEPATOCYTES CAN CONVERT INTO BILIARY EPITHELIAL CELLS (BECS) DURING BILIARY INJURY IS MUCH DEBATED. TO TEST THIS CONCEPT, WE TRACED THE FATE OF GENETICALLY LABELED [DIPEPTIDYL PEPTIDASE IV (DPPIV)-POSITIVE] HEPATOCYTES IN HEPATOCYTE TRANSPLANTATION MODEL FOLLOWING ACUTE HEPATO-BILIARY INJURY INDUCED BY 4,4'-METHYLENE-DIANILINE (DAPM) AND D-GALACTOSAMINE (DAPM+D-GAL) AND IN DPPIV-CHIMERIC LIVER MODEL SUBJECTED TO ACUTE (DAPM+D-GAL) OR CHRONIC BILIARY INJURY CAUSED BY DAPM AND BILE DUCT LIGATION (DAPM+BDL). IN BOTH MODELS BEFORE BILIARY INJURY, BECS ARE UNIFORMLY DPPIV-DEFICIENT AND PROLIFERATION OF DPPIV-DEFICIENT HEPATOCYTES IS RESTRICTED BY RETRORSINE. WE FOUND THAT MATURE HEPATOCYTES UNDERWENT A STEPWISE CONVERSION INTO BECS AFTER BILIARY INJURY. IN THE HEPATOCYTE TRANSPLANTATION MODEL, DPPIV-POSITIVE HEPATOCYTES ENTRAPPED PERIPORTALLY PROLIFERATED, AND FORMED TWO-LAYERED PLATES ALONG PORTAL VEINS. WITHIN THE TWO-LAYERED PLATES, THE HEPATOCYTES GRADUALLY LOST THEIR HEPATOCYTIC IDENTITY, PROCEEDED THROUGH AN INTERMEDIATE STATE, ACQUIRED A BILIARY PHENOTYPE, AND SUBSEQUENTLY FORMED BILE DUCTS ALONG THE HILUM-TO-PERIPHERY AXIS. IN DPPIV-CHIMERIC LIVER MODEL, PERIPORTAL HEPATOCYTES EXPRESSING HEPATOCYTE NUCLEAR FACTOR-1BETA (HNF-1BETA) WERE EXCLUSIVELY DPPIV-POSITIVE AND WERE IN CONTINUITY TO DPPIV-POSITIVES BILE DUCTS. INHIBITION OF HEPATOCYTE PROLIFERATION BY ADDITIONAL DOSES OF RETRORSINE IN DPPIV-CHIMERIC LIVERS PREVENTED THE APPEARANCE OF DPPIV-POSITIVE BECS AFTER BILIARY INJURY. MOREOVER, ENRICHED DPPIV-POSITIVE BEC/HEPATIC OVAL CELL TRANSPLANTATION PRODUCED DPPIV-POSITIVE BECS OR BILE DUCTS IN UNEXPECTEDLY LOW FREQUENCY AND IN MID-LOBULAR REGIONS. THESE RESULTS TOGETHER SUGGEST THAT MATURE HEPATOCYTES BUT NOT CONTAMINATING BECS/HEPATIC OVAL CELLS ARE THE SOURCES OF PERIPORTAL DPPIV-POSITIVE BECS. WE CONCLUDE THAT MATURE HEPATOCYTES CONTRIBUTE TO BILIARY REGENERATION IN THE ENVIRONMENT OF ACUTE AND CHRONIC BILIARY INJURY THROUGH A DUCTAL PLATE CONFIGURATION WITHOUT THE NEED OF EXOGENOUSLY GENETIC OR EPIGENETIC MANIPULATION. 2015 2 5487 30 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF. 1990 3 2640 23 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS. 2021 4 2649 16 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME. 2021 5 3239 27 HEPATIC INACTIVATION OF THE TYPE 2 DEIODINASE CONFERS RESISTANCE TO ALCOHOLIC LIVER STEATOSIS. BACKGROUND: A MOUSE WITH HEPATOCYTE-SPECIFIC DEIODINASE TYPE II INACTIVATION (ALB-D2KO) IS RESISTANT TO DIET-INDUCED OBESITY, HEPATIC STEATOSIS, AND HYPERTRIGLYCERIDEMIA DUE TO PERINATAL EPIGENETIC MODIFICATIONS IN THE LIVER. THIS PHENOTYPE IS LINKED TO LOW LEVELS OF ZFP125, A HEPATIC TRANSCRIPTIONAL REPRESSOR THAT PROMOTES LIVER STEATOSIS BY INHIBITING GENES INVOLVED IN PACKAGING AND SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN. METHODS: HERE, WE USED CHRONIC AND BINGE ETHANOL (ETOH) IN MICE TO CAUSE LIVER STEATOSIS. RESULTS: THE ETOH TREATMENT CAUSES A 2.3-FOLD INCREASE IN HEPATIC TRIGLYCERIDE CONTENT; ZFP125 LEVELS WERE APPROXIMATELY 50% HIGHER IN THESE ANIMALS. IN CONTRAST, ALB-D2KO MICE DID NOT DEVELOP ETOH-INDUCED LIVER STEATOSIS. THEY ALSO FAILED TO ELEVATE ZFP125 TO THE SAME LEVELS, DESPITE BEING ON THE ETOH-CONTAINING DIET FOR THE SAME PERIOD OF TIME. THEIR PHENOTYPE WAS ASSOCIATED WITH 1.3- TO 2.9-FOLD UP-REGULATION OF HEPATIC GENES INVOLVED IN LIPID TRANSPORT AND EXPORT THAT ARE NORMALLY REPRESSED BY ZFP125, THAT IS, MTTP, ABCA1, LDLR, APOC1, APOC3, APOE, APOH, AND AZGP1. FURTHERMORE, GENES INVOLVED IN THE ETOH METABOLIC PATHWAY, THAT IS, ALDH2 AND ACSS2, WERE ALSO 1.6- TO 3.1-FOLD UP-REGULATED IN ALB-D2KO ETOH MICE COMPARED WITH CONTROL ANIMALS KEPT ON ETOH. CONCLUSIONS: ETOH CONSUMPTION ELEVATES EXPRESSION OF ZFP125. ALB-D2KO ANIMALS, WHICH HAVE LOWER LEVELS OF ZFP125, ARE MUCH LESS SUSCEPTIBLE TO ETOH-INDUCED LIVER STEATOSIS. 2019 6 1217 28 CREG PROTECTS FROM MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY REGULATING MYOCARDIAL AUTOPHAGY AND APOPTOSIS. AIMS: HUMAN CELLULAR REPRESSOR OF E1A-STIMULATED GENES (CREG) IS A SECRETED GLYCOPROTEIN THAT REGULATES TISSUE AND CELL HOMEOSTASIS AND HAS BEEN SHOWN TO ANTAGONIZE HEART FIBROSIS, WHICH INDICATES A POTENTIAL PROTECTIVE EFFECT OF CREG AGAINST CARDIOMYOCYTE CHRONIC DAMAGE. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF CREG IN MYOCARDIAL TISSUE ACUTE INJURY, IN THIS STUDY, WE AIMED TO INVESTIGATE THE ROLE OF CREG IN MYOCARDIAL ISCHEMIA/REPERFUSION (MI/R) INJURY AND CLARIFY THE MECHANISM OF ACTION. METHODS AND RESULTS: WILD-TYPE CREG (CREG(+/+)), HETEROZYGOUS CREG (CREG(+/-)) MICE AND MICE PRETREATED WITH INFUSION OF RECOMBINANT 0.3MG/KG.D CREG PROTEIN (RECREG(+/+)) WERE SUBJECTED TO 30MIN OF LEFT ASCENDING CORONARY ISCHEMIA AND 24H OF REPERFUSION. EVAN'S BLUE-TRIPHENYL- TETRAZOLIUM CHLORIDE (TTC) SOLUTION AND ECHOCARDIOGRAPHY ANALYSIS WERE USED TO EVALUATE THE EFFECTS OF CREG ON MI/R MICE. THE UNDERLYING MECHANISMS WERE FURTHER DETERMINED BY CULTURED MYOCARDIAL CELLS IN VITRO. OUR FINDINGS REVEALED THAT THE LEVEL OF CREG PROTEIN IN MOUSE HEARTS WAS SIGNIFICANTLY DECREASED AFTER MICE WERE SUBJECTED TO MI/R. MOREOVER, CREG(+/-) MICE HAD LARGER INFARCTION SIZE 2H AFTER REPERFUSION AND WORSE CARDIAC FUNCTION 28DAYS AFTER MI/R INJURY COMPARED TO THAT IN CREG(+/+) MICE. HOWEVER, RECREG(+/+) MICE COULD MAINTAIN CREG AT A HIGH LEVEL EVEN AFTER MI/R INJURY, AND MITIGATED INFARCTION SIZE AND IMPROVED CARDIAC FUNCTION SIGNIFICANTLY. IN CREG(+/-) MICE, MYOCARDIAL AUTOPHAGY WAS DYSFUNCTIONAL CHARACTERIZED BY ACCUMULATION OF LC3A AND P62, WHILE APOPTOTIC CELL NUMBER INCREASE WAS DETECTED BY CLEAVED CASPASE-3 BLOTTING AND TUNEL STAINING. CONVERSELY, DECREASED APOPTOSIS AND ACTIVATED AUTOPHAGY WERE DETECTED IN RECREG(+/+) MICE. FURTHERMORE, CHLOROQUINE, A KIND OF AUTOPHAGY BLOCKER, WAS USED TO DEMONSTRATE RECOMBINANT CREG PROTECTED CARDIOMYOCYTES AGAINST APOPTOSIS MEDIATED BY ACTIVATING AUTOPHAGY BOTH IN VIVO AND IN VITRO. FINALLY, WE FOUND CREG WAS INVOLVED INTO LYSOSOMAL PROTEIN TRANSFER AND IMPROVE CELLULAR AUTOPHAGY. CONCLUSION: CREG PROTECTS HEART AGAINST MI/R INJURY-INDUCED CARDIOMYOCYTES APOPTOSIS BY ACTIVATING LYSOSOMAL AUTOPHAGY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN AND MEGAN YINGMEI ZHANG. 2017 7 5017 31 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION. 1995 8 1791 18 EFFECT OF CHRONIC RADIATION ON THE FLAX (LINUM USITATISSIMUM L.) GENOME GROWN FOR SIX CONSECUTIVE GENERATIONS IN THE RADIOACTIVE CHERNOBYL AREA. THE GROWTH OF PLANTS UNDER CHRONIC RADIATION STRESS IN THE CHERNOBYL AREA MAY CAUSE CHANGES IN THE GENOME OF PLANTS. TO ASSESS THE EXTENT OF GENETIC AND EPIGENETIC CHANGES IN NUCLEAR DNA, SEEDS OF THE ANNUAL CROP FLAX (LINUM USITATISSIMUM L.) OF THE KYIVSKYI VARIETY, SOWN 21 YEARS AFTER THE ACCIDENT AND GROWN FOR SIX GENERATIONS IN RADIOACTIVE (RAD) AND REMEDIATED (REM) FIELDS WERE ANALYSED. FLAXSEED USED FOR SOWING FIRST GENERATION, WHICH SERVED AS A REFERENCE (REF), WAS ALSO ANALYSED. THE AFLP (AMPLIFIED FRAGMENT LENGTH POLYMORPHISM) REVEALED A HIGHER NUMBER OF SPECIFIC ECORI-MSEI LOCI (3.4-FOLD) IN POOLED FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH THE REM FIELD, INDICATING A LINK BETWEEN THE MUTATION PROCESS IN THE FLAX GENOME AND THE ONGOING ADAPTATION PROCESS. MSAP (METHYLATION-SENSITIVE AMPLIFIED POLYMORPHISM) DETECTING ECORI-MSPI AND ECORI-HPAII LOCI IN FLAX NUCLEAR DNA GENOME SHOWED NO SIGNIFICANT DIFFERENCES IN METHYLATION LEVEL, REACHING ABOUT 33% IN EACH OF THE GROUPS STUDIED. ON THE OTHER HAND, SIGNIFICANT CHANGES IN THE DNA METHYLATION PATTERN OF FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH CONTROLS WERE DETECTED. PAIRWISE F(ST) COMPARISON REVEALED WITHIN BOTH, ECORI-MSPI AND TRANSFORMED METHYLATION-SENSITIVE DATA SETS MORE THAN A 3-FOLD INCREASE OF GENETIC DIVERGENCE IN THE RAD FIELD COMPARED WITH BOTH CONTROLS. THESE RESULTS INDICATE THAT THE NUCLEAR GENOME OF FLAX EXPOSED TO CHRONIC RADIATION FOR SIX GENERATIONS HAS MORE MUTATIONS AND USES DNA METHYLATION AS ONE OF THE ADAPTATION MECHANISMS FOR SUSTAINABILITY UNDER ADVERSE CONDITIONS. 2022 9 1016 27 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM. 2022 10 2080 23 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS. 2021 11 1951 29 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE. 2023 12 5677 23 SHORT AIP1 (ASK1-INTERACTING PROTEIN-1) ISOFORM LOCALIZES TO THE MITOCHONDRIA AND PROMOTES VASCULAR DYSFUNCTION. OBJECTIVE: VASCULAR ENDOTHELIAL CELLS (ECS) NORMALLY MAINTAIN VASCULAR HOMEOSTASIS AND ARE REGULATED BY PROINFLAMMATORY CYTOKINES AND REACTIVE OXYGEN SPECIES. A HUMAN GENOME-WIDE ASSOCIATION STUDY IDENTIFIED THAT AIP1 (ASK1 [APOPTOSIS SIGNAL-REGULATING KINASE 1]-INTERACTING PROTEIN-1; ALSO IDENTIFIED AS DAB2IP) GENE VARIANTS CONFER SUSCEPTIBILITY TO CARDIOVASCULAR DISEASE, BUT THE UNDERLYING MECHANISM IS UNKNOWN. APPROACH AND RESULTS: WE DETECTED A NORMAL AIP1 FORM (NAMED AIP1A) IN THE HEALTHY AORTA, BUT A SHORTER FORM OF AIP1 (NAMED AIP1B) WAS FOUND IN DISEASED AORTAE THAT CONTAINED ATHEROSCLEROTIC PLAQUES AND GRAFT ARTERIOSCLEROSIS. AIP1B TRANSCRIPTION IN RESTING ECS WAS SUPPRESSED THROUGH EPIGENETIC INHIBITION BY RIF1 (RAP1 [RAS-RELATED PROTEIN 1]-INTERACTING FACTOR 1)/H3K9 (HISTONE H3 LYSINE 9) METHYLTRANSFERASE-MEDIATED H3K9 TRIMETHYLATION, AND THIS INHIBITION WAS RELEASED BY PROINFLAMMATORY CYTOKINES. AIP1A, BUT NOT AIP1B, WAS DOWNREGULATED BY PROTEOLYTIC DEGRADATION THROUGH A SMURF1 (SMAD [SUPPRESSOR OF MOTHERS AGAINST DECAPENTAPLEGIC MISCELLANEOUS] UBIQUITYLATION REGULATORY FACTOR 1)-DEPENDENT PATHWAY IN ECS UNDER INFLAMMATION. THEREFORE, AIP1B WAS THE MAJOR FORM PRESENT DURING INFLAMMATORY CONDITIONS. AIP1B, WHICH LACKS THE N-TERMINAL PLECKSTRIN HOMOLOGY DOMAIN OF AIP1A, LOCALIZED TO THE MITOCHONDRIA AND AUGMENTED TNFALPHA (TUMOR NECROSIS FACTOR ALPHA)-INDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES GENERATION AND EC ACTIVATION. AIP1B-ECTG (EC-SPECIFIC AIP1B TRANSGENIC) MICE EXHIBITED AUGMENTED REACTIVE OXYGEN SPECIES PRODUCTION, EC ACTIVATION, AND NEOINTIMA FORMATION IN VASCULAR REMODELING MODELS. CONCLUSIONS: OUR CURRENT STUDY SUGGESTS THAT A SHIFT FROM ANTI-INFLAMMATORY AIP1A TO PROINFLAMMATORY AIP1B DURING CHRONIC INFLAMMATION PLAYS A KEY ROLE IN INFLAMMATORY VASCULAR DISEASES. 2020 13 5763 14 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS. 1991 14 850 19 CHILDREN WITH CHRONIC IMMUNE THROMBOCYTOPENIA EXHIBIT HIGH EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUSES TRIM28 AND SETDB1. CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) IS AN AUTOIMMUNE DISEASE WHOSE UNDERLYING BIOLOGIC MECHANISMS REMAIN ELUSIVE. HUMAN ENDOGENOUS RETROVIRUSES (HERVS) DERIVE FROM ANCESTRAL INFECTIONS AND CONSTITUTE ABOUT 8% OF OUR GENOME. A WEALTH OF CLINICAL AND EXPERIMENTAL STUDIES HIGHLIGHTS THEIR PIVOTAL PATHOGENETIC ROLE IN AUTOIMMUNE DISEASES. EPIGENETIC MECHANISMS, SUCH AS THOSE MODULATED BY TRIM28 AND SETDB1, ARE INVOLVED IN HERV ACTIVATION AND REGULATION OF IMMUNE RESPONSE. WE ASSESSED, THROUGH A POLYMERASE CHAIN REACTION REAL-TIME TAQMAN AMPLIFICATION ASSAY, THE TRANSCRIPTION LEVELS OF POL GENES OF HERV-H, HERV-K, AND HERV-W; ENV GENES OF SYNCYTIN (SYN)1, SYN2, AND HERV-W; AS WELL AS TRIM28 AND SETDB1 IN WHOLE BLOOD FROM 34 CHILDREN WITH CITP AND AGE-MATCHED HEALTHY CONTROLS (HC). THE TRANSCRIPTIONAL LEVELS OF ALL HERV SEQUENCES, WITH THE EXCEPTION OF HERV-W-ENV, WERE SIGNIFICANTLY ENHANCED IN CHILDREN WITH CITP AS COMPARED TO HC. PATIENTS ON ELTROMBOPAG TREATMENT EXHIBITED LOWER EXPRESSION OF SYN1, SYN2, AND HERV-W-ENV AS COMPARED TO UNTREATED PATIENTS. THE MRNA CONCENTRATIONS OF TRIM28 AND SETDB1 WERE SIGNIFICANTLY HIGHER AND WERE POSITIVELY CORRELATED WITH THOSE OF HERVS IN CITP PATIENTS. THE OVER-EXPRESSIONS OF HERVS AND TRIM28/SETDB1 AND THEIR POSITIVE CORRELATIONS IN PATIENTS WITH CITP ARE SUGGESTIVE CLUES OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF THE DISEASE AND SUPPORT INNOVATIVE INTERVENTIONS TO INHIBIT HERV AND TRIM28/SETDB1 EXPRESSIONS IN PATIENTS UNRESPONSIVE TO STANDARD THERAPIES. 2023 15 1668 30 DOWNREGULATION OF SOCS1 INCREASES INTERFERON-INDUCED ISGYLATION DURING DIFFERENTIATION OF INDUCED-PLURIPOTENT STEM CELLS TO HEPATOCYTES. BACKGROUND & AIMS: INCREASED EXPRESSION OF IFN-STIMULATED GENE 15 (ISG15) AND SUBSEQUENTLY INCREASED ISGYLATION ARE KEY FACTORS IN THE HOST RESPONSE TO VIRAL INFECTION. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE EXPRESSION OF ISG15, ISGYLATION, AND ASSOCIATED ENZYMES AT EACH STAGE OF DIFFERENTIATION FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) TO HEPATOCYTES. METHODS: TO STUDY THE REGULATION OF ISGYLATION, WE UTILIZED PATIENT SAMPLES AND IN VITRO CELL CULTURE MODELS INCLUDING IPSCS, HEPATOCYTES-LIKE CELLS, IMMORTALIZED CELL LINES, AND PRIMARY HUMAN HEPATOCYTES. PROTEIN/MRNA EXPRESSION WERE MEASURED FOLLOWING TREATMENT WITH POLY(I:C), IFNALPHA AND HCV INFECTION. RESULTS: WHEN COMPARED TO HLCS, WE OBSERVED SEVERAL NOVEL ASPECTS OF THE ISGYLATION PATHWAY IN IPSCS. THESE INCLUDE A LOWER BASELINE EXPRESSION OF THE ISGYLATION-ACTIVATING ENZYME, UBE1L, A LACK OF IFN-INDUCED EXPRESSION OF THE ISGYLATION-CONJUGATION ENZYME UBE2L6, AN ATTENUATED ACTIVATION OF THE TRANSCRIPTION FACTOR STAT1 AND CONSTITUTIVE EXPRESSION OF SOCS1. ISGYLATION WAS OBSERVED IN IPSCS FOLLOWING DOWNREGULATION OF SOCS1, WHICH FACILITATED STAT1 ACTIVATION AND SUBSEQUENTLY INCREASED EXPRESSION OF UBE2L6. INTRIGUINGLY, HCV PERMISSIVE TRANSFORMED HEPATOMA CELL LINES DEMONSTRATED HIGHER INTRINSIC EXPRESSION OF SOCS1 AND WEAKER ISGYLATION FOLLOWING IFN TREATMENT. SOCS1 DOWNREGULATION IN HCV-INFECTED HUH 7.5.1 CELLS LED TO INCREASED ISGYLATION. CONCLUSIONS: HEREIN, WE SHOW THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. FURTHERMORE, AS IPSCS DIFFERENTIATE INTO HEPATOCYTES, EPIGENETIC MECHANISMS REGULATE ISGYLATION BY MODIFYING UBE1L AND SOCS1 EXPRESSION LEVELS. OVERALL, THIS STUDY DEMONSTRATES THAT THE DEVELOPMENT OF CELL-INTRINSIC INNATE IMMUNITY DURING THE DIFFERENTIATION OF IPSCS TO HEPATOCYTES PROVIDES INSIGHT INTO CELL TYPE-SPECIFIC REGULATION OF HOST DEFENSE RESPONSES AND RELATED ONCOGENIC PROCESSES. IMPACT AND IMPLICATIONS: TO ELUCIDATE THE MECHANISM UNDERLYING REGULATION OF ISGYLATION, A KEY PROCESS IN THE INNATE IMMUNE RESPONSE, WE STUDIED CHANGES IN ISGYLATION-ASSOCIATED GENES AT THE DIFFERENT STAGES OF DIFFERENTIATION FROM IPSCS TO HEPATOCYTES. WE FOUND THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. IMPORTANTLY, EPIGENETIC REGULATION OF SOCS1 AND SUBSEQUENTLY ISGYLATION MAY BE IMPORTANT FACTORS IN THE DEVELOPMENT OF CELL TYPE-SPECIFIC HOST DEFENSE RESPONSES IN HEPATOCYTES THAT SHOULD BE CONSIDERED WHEN STUDYING CHRONIC INFECTIONS AND ONCOGENIC PROCESSES IN THE LIVER. 2022 16 760 16 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS. 2023 17 2796 18 FBW7 MEDIATES SENESCENCE AND PULMONARY FIBROSIS THROUGH TELOMERE UNCAPPING. TISSUE STEM CELLS UNDERGO PREMATURE SENESCENCE UNDER STRESS, PROMOTING AGE-RELATED DISEASES; HOWEVER, THE ASSOCIATED MECHANISMS REMAIN UNCLEAR. HERE, WE REPORT THAT IN RESPONSE TO RADIATION, OXIDATIVE STRESS, OR BLEOMYCIN, THE E3 UBIQUITIN LIGASE FBW7 MEDIATES CELL SENESCENCE AND TISSUE FIBROSIS THROUGH TELOMERE UNCAPPING. FBW7 BINDING TO TELOMERE PROTECTION PROTEIN 1 (TPP1) FACILITATES TPP1 MULTISITE POLYUBIQUITINATION AND ACCELERATES DEGRADATION, TRIGGERING TELOMERE UNCAPPING AND DNA DAMAGE RESPONSE. OVEREXPRESSING TPP1 OR INHIBITING FBW7 BY GENETIC ABLATION, EPIGENETIC INTERFERENCE, OR PEPTIDOMIMETIC TELOMERE DYSFUNCTION INHIBITOR (TELODIN) REDUCES TELOMERE UNCAPPING AND SHORTENING, EXPANDING THE PULMONARY ALVEOLAR AEC2 STEM CELL POPULATION IN MICE. TELODIN, SYNTHESIZED FROM THE SEVENTH BETA STRAND BLADE OF FBW7 WD40 PROPELLER DOMAIN, INCREASES TPP1 STABILITY, LUNG RESPIRATORY FUNCTION, AND RESISTANCE TO SENESCENCE AND FIBROSIS IN ANIMALS CHRONICALLY EXPOSED TO ENVIRONMENTAL STRESS. OUR FINDINGS ELUCIDATE A PIVOTAL MECHANISM UNDERLYING STRESS-INDUCED PULMONARY EPITHELIAL STEM CELL SENESCENCE AND FIBROSIS, PROVIDING A FRAMEWORK FOR AGING-RELATED DISORDER INTERVENTIONS. 2020 18 3279 21 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS. 2011 19 5340 29 QUORUM SENSING AND VIRULENCE OF PSEUDOMONAS AERUGINOSA DURING LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. PSEUDOMONAS AERUGINOSA IS THE PREDOMINANT MICROORGANISM IN CHRONIC LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. THE CHRONIC LUNG INFECTION IS PRECEDED BY INTERMITTENT COLONIZATION. WHEN THE CHRONIC INFECTION BECOMES ESTABLISHED, IT IS WELL ACCEPTED THAT THE ISOLATED STRAINS DIFFER PHENOTYPICALLY FROM THE INTERMITTENT STRAINS. DOMINATING CHANGES ARE THE SWITCH TO MUCOIDITY (ALGINATE OVERPRODUCTION) AND LOSS OF EPIGENETIC REGULATION OF VIRULENCE SUCH AS THE QUORUM SENSING (QS). TO ELUCIDATE THE DYNAMICS OF P. AERUGINOSA QS SYSTEMS DURING LONG TERM INFECTION OF THE CF LUNG, WE HAVE INVESTIGATED 238 ISOLATES OBTAINED FROM 152 CF PATIENTS AT DIFFERENT STAGES OF INFECTION RANGING FROM INTERMITTENT TO LATE CHRONIC. ISOLATES WERE CHARACTERIZED WITH REGARD TO QS SIGNAL MOLECULES, ALGINATE, RHAMNOLIPID AND ELASTASE PRODUCTION AND MUTANT FREQUENCY. THE GENETIC BASIS FOR CHANGE IN QS REGULATION WERE INVESTIGATED AND IDENTIFIED BY SEQUENCE ANALYSIS OF LASR, RHLR, LASI AND RHLI. THE FIRST QS SYSTEM TO BE LOST WAS THE ONE ENCODED BY LAS SYSTEM 12 YEARS (MEDIAN VALUE) AFTER THE ONSET OF THE LUNG INFECTION WITH SUBSEQUENT LOSS OF THE RHL ENCODED SYSTEM AFTER 17 YEARS (MEDIAN VALUE) SHOWN AS DEFICIENCIES IN PRODUCTION OF THE 3-OXO-C12-HSL AND C4-HSL QS SIGNAL MOLECULES RESPECTIVELY. THE CONCOMITANT DEVELOPMENT OF QS MALFUNCTION SIGNIFICANTLY CORRELATED WITH THE REDUCED PRODUCTION OF RHAMNOLIPIDS AND ELASTASE AND WITH THE OCCURRENCE OF MUTATIONS IN THE REGULATORY GENES LASR AND RHLR. ACCUMULATION OF MUTATIONS IN BOTH LASR AND RHLR CORRELATED WITH DEVELOPMENT OF HYPERMUTABILITY. INTERESTINGLY, A HIGHER NUMBER OF MUCOID ISOLATES WERE FOUND TO PRODUCE C4-HSL SIGNAL MOLECULES AND RHAMNOLIPIDS COMPARED TO THE NON-MUCOID ISOLATES. AS SEEN FROM THE PRESENT DATA, WE CAN CONCLUDE THAT P. AERUGINOSA AND PARTICULARLY THE MUCOID STRAINS DO NOT LOSE THE QS REGULATION OR THE ABILITY TO PRODUCE RHAMNOLIPIDS UNTIL THE LATE STAGE OF THE CHRONIC INFECTION. 2010 20 1843 23 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS. 2018