1 3807 149 INTRACELLULAR PROTONS ACCELERATE AGING AND SWITCH ON AGING HALLMARKS IN MICE. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. THE SERUM BICARBONATE LEVEL IS AN INDEPENDENT PREDICTOR OF CHRONIC KIDNEY DISEASE PROGRESSION. WE INVESTIGATED WHETHER PROTON ACCELERATES AGING BY ANALYZING BOTH COUPLING FACTOR 6-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH DISPLAY SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1) F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+) -K(+) ATPASE INHIBITION. BOTH TYPES OF MICE DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN CHRONIC INTRACELLULAR ACIDOSIS MICE, AUTOPHAGY WAS IMPAIRED BY REGRESSION OF ATG7, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THE INCREASE IN HISTONE 3 TRIMETHYLATION AT LYSINE 4 (H3K4ME3) AND H4K20ME3 AND THE DECREASE IN H3K9ME3 AND H3K27ME3 WERE OBSERVED IN THE HEART AND KIDNEY OBTAINED FROM BOTH TG AND HIGH SALT-FED MICE. THE DECREASE IN LAMIN A/C, EMERIN, AND HETEROCHROMATIN PROTEIN 1ALPHA WITHOUT CHANGES IN BARRIER-TO-AUTOINTEGRATION FACTOR AND HIGH-MOBILITY GROUP BOX 1 WAS CONFIRMED IN TG AND HIGH SALT-FED MICE. SUPPRESSION OF NUCLEAR HISTONE DEACETYLASE 3-EMERIN SYSTEM IS ATTRIBUTABLE TO EPIGENETIC REGRESSION OF ATG7 AND H4K5 ACETYLATION. THESE FINDINGS WILL SHED LIGHT ON NOVEL AGING AND IMPAIRED AUTOPHAGY MECHANISM, AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTIAGING THERAPY. 2018 2 4731 103 NOVEL ANTI-AGING GENE NM_026333 CONTRIBUTES TO PROTON-INDUCED AGING VIA NCX1-PATHWAY. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. LOW SERUM BICARBONATE IS ASSOCIATED WITH HIGH MORTALITY IN HEALTHY OLDER INDIVIDUALS. RECENTLY, WE DEMONSTRATED THAT BOTH COUPLING FACTOR 6 (CF6)-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH HAD SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1)F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+)-K(+) ATPASE INHIBITION, DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN THIS STUDY, WE SEARCHED CAUSATIVE GENES OF PROTON-INDUCED AGING IN CF6-OVEREXPRESSING TG AND HIGH SALT-FED MICE. WE DISCOVERED NM_026333 AS A NOVEL ANTI-AGING GENE WHICH WAS DOWNREGULATED IN THE HEART AND KIDNEY IN BOTH TYPES OF MICE. NM_026333 PROTEIN CONSISTS OF 269 AMINO ACIDS WITH TRANSMEMBRANE REGION (90-193AA). INDUCTION OF NM_026333 OR RECOMBINANT PROTEIN RESCUED TG CELLS AND CF6-TREATED HUMAN CELLS FROM AGING HALLMARKS OF IMPAIRED AUTOPHAGY, GENOMIC INSTABILITY, AND EPIGENETIC ALTERATION. NM_026333 PROTEIN DIRECTLY BOUND PLASMA MEMBRANE NA(+)-CA(2+) EXCHANGER 1 (NCX1) TO SUPPRESS ITS REVERSE MODE, AND CANCELLED PROTON-INDUCED EPIGENETIC REGRESSION OF ATG7 THAT WAS CAUSED BY H3K4 AND H4K20 TRI-METHYLATION VIA SUPPRESSION OF DEMETHYLASE AND H4K5 ACETYLATION VIA SUPPRESSION OF NUCLEAR HDAC3-HDAC4-EMERIN SYSTEM. NM_026333 ALSO ATTENUATED PROTON-INDUCED IMPAIRED FORMATION OF AUTOLYSOSOME, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THESE EFFECTS REAPPEARED BY NCX1 INHIBITOR. FURTHERMORE, NCX1 INHIBITOR EXTENDED LIFESPAN COMPARED WITH VEHICLE-TREATMENT IN TG MICE. THIS STUDY WILL SHED LIGHT ON NOVEL AGING MECHANISM AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTI-AGING THERAPY. 2018 3 5590 22 ROLE OF THE BICARBONATE-RESPONSIVE SOLUBLE ADENYLYL CYCLASE IN CHOLANGIOCYTE APOPTOSIS IN PRIMARY BILIARY CHOLANGITIS; A NEW HYPOTHESIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC FIBROSING CHOLANGIOPATHY CHARACTERIZED BY AN AUTOIMMUNE STEREOTYPE AND DEFECTIVE BILIARY BICARBONATE SECRETION DUE TO DOWN-REGULATION OF ANION EXCHANGER 2 (AE2). DESPITE THE AUTOIMMUNE FEATURES, IMMUNOSUPPRESSANTS ARE INEFFECTIVE WHILE TWO BILE ACID-BASED THERAPIES (URSODEOXYCHOLIC ACID AND OBETICHOLIC ACID) HAVE BEEN SHOWN TO IMPROVE BIOCHEMICAL AND HISTOLOGICAL FEATURES OF CHOLESTASIS AND LONG-TERM PROGNOSIS. HOWEVER, THE ETIOLOGY AND PATHOGENESIS OF PBC IS LARGELY UNKNOWN. RECENTLY, IT HAS BEEN SHOWN THAT MICRORNA-506 (MIR-506) ON CHROMOSOME X IS UP-REGULATED IN PBC CHOLANGIOCYTES AND SUPPRESSES AE2 EXPRESSION, WHICH SENSITIZES CHOLANGIOCYTES TO BILE SALT-INDUCED APOPTOSIS BY ACTIVATING SOLUBLE ADENYLYL CYCLASE (SAC), AN EVOLUTIONARILY CONSERVED BICARBONATE SENSOR. IN THIS REVIEW, WE DISCUSS THE EXPERIMENTAL EVIDENCE FOR THE EMERGING ROLE OF THE MIR-506-AE2-SAC AXIS IN PBC PATHOGENESIS. WE FURTHER HYPOTHESIZE THAT THE INITIAL DISEASE TRIGGER INDUCES AN X-LINKED EPIGENETIC CHANGE, LEADING TO A FEMALE-BIASED ACTIVATION OF THE MIR-506-AE2-SAC AXIS. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: CHOLANGIOCYTES IN HEALTH AND DISEASEEDITED BY JESUS BANALES, MARCO MARZIONI AND PETER JANSEN. 2018 4 5272 32 PROMOTER HYPERMETHYLATION OF THE AE2/SLC4A2 GENE IN PBC. BACKGROUND & AIMS: PATIENTS WITH PRIMARY BILIARY CHOLANGITIS (PBC) EXHIBIT REDUCED AE2/SLC4A2 GENE EXPRESSION IN THE LIVER AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS). AE2 ENCODES A CL(-)/HCO(3) (-) EXCHANGER INVOLVED IN BILIARY BICARBONATE SECRETION AND INTRACELLULAR PH REGULATION. REDUCED AE2 EXPRESSION IN PBC MAY BE PATHOGENIC, AS AE2-KNOCKOUT MICE REPRODUCE CHARACTERISTIC PBC FEATURES. HEREIN, WE AIMED TO IDENTIFY CPG-METHYLATION ABNORMALITIES IN AE2 PROMOTER REGIONS THAT MIGHT CONTRIBUTE TO THE REDUCED GENE TRANSCRIPTION IN PBC LIVERS AND PBMCS. METHODS: CPG-CYTOSINE METHYLATION RATES WERE INTERROGATED AT 1-BASE PAIR RESOLUTION IN UPSTREAM AND ALTERNATE AE2 PROMOTER REGIONS THROUGH PYROSEQUENCING OF BISULPHITE-MODIFIED GENOMIC DNA FROM LIVER SPECIMENS AND PBMCS. AE2A AND ALTERNATIVE AE2B1 AND AE2B2 MRNA LEVELS WERE MEASURED BY REAL-TIME PCR. HUMAN LYMPHOBLASTOID-T2 CELLS WERE TREATED WITH 5-AZA-2 -DEOXYCYTIDINE FOR DEMETHYLATION ASSAYS. RESULTS: AE2 PROMOTERS WERE FOUND TO BE HYPERMETHYLATED IN PBC LIVERS COMPARED TO NORMAL AND DISEASED LIVER SPECIMENS. RECEIVER OPERATING CHARACTERISTIC (ROC) CURVE ANALYSIS SHOWED THAT MINIMAL CPG-HYPERMETHYLATION CLUSTERS OF 3 AE2A-CPG SITES AND 4 ALTERNATE-AE2B2-CPG SITES SPECIFICALLY DIFFERENTIATED PBC FROM NORMAL AND DISEASED CONTROLS, WITH MEAN METHYLATION RATES INVERSELY CORRELATING WITH RESPECTIVE TRANSCRIPT LEVELS. ADDITIONALLY, IN PBMCS A MINIMAL CLUSTER OF 3 HYPERMETHYLATED AE2A-CPG SITES DISTINGUISHED PBC FROM CONTROLS, AND MEAN METHYLATION RATES CORRELATED NEGATIVELY WITH AE2A MRNA LEVELS IN THESE IMMUNE CELLS. ALTERNATE AE2B2/AE2B1 PROMOTERS IN PBMCS WERE CONSTITUTIVELY HYPERMETHYLATED, IN LINE WITH ABSENT ALTERNATIVE MRNA EXPRESSION IN DISEASED AND HEALTHY PBMCS. DEMETHYLATION ASSAYS TREATING LYMPHOBLASTOID-T2 CELLS WITH 5-AZA-2 -DEOXYCYTIDINE TRIGGERED AE2B2/AE2B1 EXPRESSION AND UPREGULATED AE2A-PROMOTER EXPRESSION. CONCLUSIONS: DISEASE-SPECIFIC HYPERMETHYLATION OF AE2 PROMOTER REGIONS AND SUBSEQUENT DOWNREGULATION OF AE2-GENE EXPRESSION IN THE LIVER AND PBMCS OF PATIENTS WITH PBC MIGHT BE CRITICALLY INVOLVED IN THE PATHOGENESIS OF THIS COMPLEX DISEASE. LAY SUMMARY: PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC IMMUNE-ASSOCIATED CHOLESTATIC LIVER DISEASE WITH UNCLEAR COMPLEX/MULTIFACTORIAL ETIOPATHOGENESIS AFFECTING MOSTLY MIDDLE-AGED WOMEN. PATIENTS WITH PBC EXHIBIT REDUCED EXPRESSION OF THE AE2/SLC4A2 GENE. HEREIN, WE FOUND THAT AE2 PROMOTER REGIONS ARE HYPERMETHYLATED IN THE LIVER AND PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH PBC. THIS INCREASED METHYLATION IS ASSOCIATED WITH DOWNREGULATED AE2-GENE EXPRESSION, WHICH MIGHT CONTRIBUTE TO THE PATHOGENESIS OF PBC. THEREFORE, NOVEL EPIGENETIC TARGETS MAY IMPROVE TREATMENT IN PATIENTS WITH PBC WHO RESPOND POORLY TO CURRENT PHARMACOLOGICAL THERAPIES. 2019 5 5716 38 SIRT6 PROTECTS VASCULAR SMOOTH MUSCLE CELLS FROM OSTEOGENIC TRANSDIFFERENTIATION VIA RUNX2 IN CHRONIC KIDNEY DISEASE. VASCULAR CALCIFICATION (VC) IS REGARDED AS AN IMPORTANT PATHOLOGICAL CHANGE LACKING EFFECTIVE TREATMENT AND ASSOCIATED WITH HIGH MORTALITY. SIRTUIN 6 (SIRT6) IS A MEMBER OF THE SIRTUIN FAMILY, A CLASS III HISTONE DEACETYLASE AND A KEY EPIGENETIC REGULATOR. SIRT6 HAS A PROTECTIVE ROLE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). HOWEVER, THE EXACT ROLE AND MOLECULAR MECHANISM OF SIRT6 IN VC IN PATIENTS WITH CKD REMAIN UNCLEAR. HERE, WE DEMONSTRATED THAT SIRT6 WAS MARKEDLY DOWNREGULATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND IN THE RADIAL ARTERY TISSUE OF PATIENTS WITH CKD WITH VC. SIRT6-TRANSGENIC (SIRT6-TG) MICE SHOWED ALLEVIATED VC, WHILE VASCULAR SMOOTH MUSCLE CELL-SPECIFIC (VSMC-SPECIFIC) SIRT6 KNOCKED-DOWN MICE SHOWED SEVERE VC IN CKD. SIRT6 SUPPRESSED THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS VIA REGULATION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2). COIMMUNOPRECIPITATION (CO-IP) AND IMMUNOPRECIPITATION (IP) ASSAYS CONFIRMED THAT SIRT6 BOUND TO RUNX2. MOREOVER, RUNX2 WAS DEACETYLATED BY SIRT6 AND FURTHER PROMOTED NUCLEAR EXPORT VIA EXPORTIN 1 (XPO1), WHICH IN TURN CAUSED DEGRADATION OF RUNX2 THROUGH THE UBIQUITIN-PROTEASOME SYSTEM. THESE RESULTS DEMONSTRATED THAT SIRT6 PREVENTED VC BY SUPPRESSING THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS, AND AS SUCH TARGETING SIRT6 MAY BE AN APPEALING THERAPEUTIC TARGET FOR VC IN CKD. 2022 6 1104 29 COMBINED EXPOSURE TO PROTONS AND (56)FE LEADS TO OVEREXPRESSION OF IL13 AND REACTIVATION OF REPETITIVE ELEMENTS IN THE MOUSE LUNG. INTEREST IN DEEP SPACE EXPLORATION UNDERLINES THE NEEDS TO INVESTIGATE THE EFFECTS OF EXPOSURE TO COMBINED SOURCES OF SPACE RADIATION. THE LUNG IS A TARGET ORGAN FOR RADIATION, AND EXPOSURE TO PROTONS AND HEAVY IONS AS RADIATION SOURCES MAY LEAD TO THE DEVELOPMENT OF DEGENERATIVE DISEASE AND CANCER. IN THIS STUDY, WE EVALUATED THE PRO-FIBROTIC AND EPIGENETIC EFFECTS OF EXPOSURE TO PROTONS (150 MEV/NUCLEON, 0.1 GY) AND HEAVY IRON IONS ((56)FE, 600 MEV/NUCLEON, 0.5 GY) ALONE OR IN COMBINATION (PROTONS ON DAY 1 AND (56)FE ON DAY 2) IN C57BL/6 MALE MICE 4 WEEKS AFTER IRRADIATION. EXPOSURE TO (56)FE, PROTON OR IN COMBINATION, DID NOT RESULT IN HISTOPATHOLOGICAL CHANGES IN THE MURINE LUNG. AT THE SAME TIME, COMBINED EXPOSURE TO PROTONS AND (56)FE RESULTED IN PRONOUNCED MOLECULAR ALTERATIONS IN COMPARISON WITH EITHER SOURCE OF RADIATION ALONE. SPECIFICALLY, WE OBSERVED A SUBSTANTIAL INCREASE IN THE EXPRESSION OF CYTOKINE IL13, LOSS OF EXPRESSION OF DNA METHYLTRANSFERASE DNMT1, AND REACTIVATION OF LINE-1, SINE B1 RETROTRANSPOSONS, AND MAJOR AND MINOR SATELLITES. GIVEN THE DELETERIOUS POTENTIAL OF THE OBSERVED EFFECTS THAT MAY LEAD TO DEVELOPMENT OF CHRONIC LUNG INJURY, PULMONARY FIBROSIS, AND CANCER, FUTURE STUDIES DEVOTED TO THE INVESTIGATION OF THE LONG-TERM EFFECTS OF COMBINED EXPOSURES TO PROTON AND HEAVY IONS ARE CLEARLY NEEDED. 2015 7 1125 37 COMPLEX INHIBITION OF AUTOPHAGY BY MITOCHONDRIAL ALDEHYDE DEHYDROGENASE SHORTENS LIFESPAN AND EXACERBATES CARDIAC AGING. AUTOPHAGY, A CONSERVATIVE DEGRADATION PROCESS FOR LONG-LIVED AND DAMAGED PROTEINS, PARTICIPATES IN A CASCADE OF BIOLOGICAL PROCESSES INCLUDING AGING. A NUMBER OF AUTOPHAGY REGULATORS HAVE BEEN IDENTIFIED. HERE WE DEMONSTRATED THAT MITOCHONDRIAL ALDEHYDE DEHYDROGENASE (ALDH2), AN ENZYME WITH THE MOST COMMON SINGLE POINT MUTATION IN HUMANS, GOVERNS CARDIAC AGING THROUGH REGULATION OF AUTOPHAGY. MYOCARDIAL MECHANICAL AND AUTOPHAGY PROPERTIES WERE EXAMINED IN YOUNG (4MONTHS) AND OLD (26-28MONTHS) WILD-TYPE (WT) AND GLOBAL ALDH2 TRANSGENIC MICE. ALDH2 OVEREXPRESSION SHORTENED LIFESPAN BY 7.7% WITHOUT AFFECTING AGING-ASSOCIATED CHANGES IN PLASMA METABOLIC PROFILES. MYOCARDIAL FUNCTION WAS COMPROMISED WITH AGING ASSOCIATED WITH CARDIAC HYPERTROPHY, THE EFFECTS WERE ACCENTUATED BY ALDH2. AGING OVERTLY SUPPRESSED AUTOPHAGY AND COMPROMISED AUTOPHAGY FLUX, THE EFFECTS WERE EXACERBATED BY ALDH2. AGING DAMPENED PHOSPHORYLATION OF JNK, BCL-2, IKKBETA, AMPK AND TSC2 WHILE PROMOTING PHOSPHORYLATION OF MTOR, THE EFFECTS OF WHICH WERE EXAGGERATED BY ALDH2. CO-IMMUNOPRECIPITATION REVEALED INCREASED DISSOCIATION BETWEEN BCL-2 AND BECLIN-1 (RESULT OF DECREASED BCL-2 PHOSPHORYLATION) IN AGING, THE EFFECT OF WHICH WAS EXACERBATED WITH ALDH2. CHRONIC TREATMENT OF THE AUTOPHAGY INDUCER RAPAMYCIN ALLEVIATED AGING-INDUCED CARDIAC DYSFUNCTION IN BOTH WT AND ALDH2 MICE. MOREOVER, ACTIVATION OF JNK AND INHIBITION OF EITHER BCL-2 OR IKKBETA OVERTLY ATTENUATED ALDH2 ACTIVATION-INDUCED ACCENTUATION OF CARDIOMYOCYTE AGING. EXAMINATION OF THE OTHERWISE ELDERLY INDIVIDUALS REVEALED A POSITIVE CORRELATION BETWEEN CARDIAC FUNCTION/GEOMETRY AND ALDH2 GENE MUTATION. TAKEN TOGETHER, OUR DATA REVEALED THAT ALDH2 ENZYME MAY SUPPRESS MYOCARDIAL AUTOPHAGY POSSIBLY THROUGH A COMPLEX JNK-BCL-2 AND IKKBETA-AMPK-DEPENDENT MECHANISM EN ROUTE TO ACCENTUATION OF MYOCARDIAL REMODELING AND CONTRACTILE DYSFUNCTION IN AGING. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN & MEGAN YINGMEI ZHANG. 2017 8 3633 33 INCREASE IN HDAC9 SUPPRESSES MYOBLAST DIFFERENTIATION VIA EPIGENETIC REGULATION OF AUTOPHAGY IN HYPOXIA. EXTREMELY REDUCED OXYGEN (O(2)) LEVELS ARE DETRIMENTAL TO MYOGENIC DIFFERENTIATION AND MULTINUCLEATED MYOTUBE FORMATION, AND CHRONIC EXPOSURE TO HIGH-ALTITUDE HYPOXIA HAS BEEN REPORTED TO BE AN IMPORTANT FACTOR IN SKELETAL MUSCLE ATROPHY. HOWEVER, HOW CHRONIC HYPOXIA CAUSES MUSCLE DYSFUNCTION REMAINS UNKNOWN. IN THE PRESENT STUDY, WE FOUND THAT SEVERE HYPOXIA (1% O(2)) SIGNIFICANTLY INHIBITED THE FUNCTION OF C2C12 CELLS (FROM A MYOBLAST CELL LINE). IMPORTANTLY, THE IMPAIRMENT WAS CONTINUOUSLY MANIFESTED EVEN DURING CULTURE UNDER NORMOXIC CONDITIONS FOR SEVERAL PASSAGES. MECHANISTICALLY, WE REVEALED THAT HISTONE DEACETYLASES 9 (HDAC9), A MEMBER OF THE HISTONE DEACETYLASE FAMILY, WAS SIGNIFICANTLY INCREASED IN C2C12 CELLS UNDER HYPOXIC CONDITIONS, THEREBY INHIBITING INTRACELLULAR AUTOPHAGY LEVELS BY DIRECTLY BINDING TO THE PROMOTER REGIONS OF ATG7, BECLIN1, AND LC3. THIS PHENOMENON RESULTED IN THE SEQUENTIAL DEPHOSPHORYLATION OF GSK3BETA AND INACTIVATION OF THE CANONICAL WNT PATHWAY, IMPAIRING THE FUNCTION OF THE C2C12 CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT HYPOXIA-INDUCED MYOBLAST DYSFUNCTION IS DUE TO ABERRANT EPIGENETIC REGULATION OF AUTOPHAGY, AND OUR EXPERIMENTAL EVIDENCE REVEALS THE POSSIBLE MOLECULAR PATHOGENESIS RESPONSIBLE FOR SOME MUSCLE DISEASES CAUSED BY CHRONIC HYPOXIA AND SUGGESTS A POTENTIAL THERAPEUTIC OPTION. 2019 9 1906 36 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS. 2018 10 5764 31 SORAFENIB ATTENUATES FIBROTIC HEPATIC INJURY THROUGH MEDIATING LYSINE CROTONYLATION. BACKGROUND: LIVER FIBROSIS IS AN INDEPENDENT CONTRIBUTOR OF CHRONIC LIVER DISEASES, AND REGRESSING LIVER FIBROSIS IS CONSIDERED A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC LIVER DISEASES. WE AIMED TO EXPLORE THE EFFECTS AND MECHANISM OF SORAFENIB IN LIVER FIBROSIS. METHODS: MALE SPRAGUE DAWLEY (SD) RATS WERE SUBJECTED TO SUBCUTANEOUS INJECTION OF CARBON TETRACHLORIDE (CCL(4)) FOR 8 WEEKS TO INDUCE LIVER FIBROSIS AND THEN TREATED WITH SORAFENIB. THE DEGREE OF LIVER FIBROSIS WAS ANALYZED BY HEMATOXYLIN-EOSIN (H&E) STAINING, MASSON STAINING, AND PICROSIRIUS RED (PSR) STAINING. SERUM BIOCHEMICAL INDEXES WERE DETECTED BY FULLY AUTOMATIC BIOCHEMICAL ANALYZER OR ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS PERFORMED TO DETECT THE EXPRESSION OF PRO-FIBROTIC GENES. IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOTTING WERE CARRIED OUT TO EVALUATE THE LEVELS OF LYSINE CROTONYLATION. RESULTS: LIVER INDEX WAS REDUCED WITH ORAL SORAFENIB IN CCL(4)-INDUCED RATS. SERUM LIVER FUNCTION (ALANINE AMINOTRANSFERASE (ALT), ASPARTATE AMINOTRANSFERASE (AST), AND TOTAL BILIRUBIN (TBIL)) AND FIBROSIS INDICATORS (TYPE III PROCOLLAGEN (PC-III), HYALURONIC ACID (HA), AND LAMININ (LN)) WERE ATTENUATED WITH SORAFENIB TREATMENT. SORAFENIB IMPROVED THE HEPATIC STRUCTURE AND FIBROTIC PROGRESSION. THE EXPRESSION OF FIBROSIS-RELATED GENES WAS REMARKELY REDUCED WITH SORAFENIB TREATMENT. MEANWHILE, SORAFENIB INHIBITED ALPHA-SMA AND COLLAGEN I CUMULATION INDUCED BY CCL(4) INJECTION. BESIDES, PROTEIN LYSINE CROTONYLATION ESPECIALLY THE CROTONYLATED H2BK12 (H2BK12CR) AND CROTONYLATED H3K18 (H3K18CR) WERE REVERSED BY SORAFENIB, WHICH WERE DECREASED IN RESPONSE TO CCL(4) TREATMENT. SPEARMAN CORRELATION ANALYSIS SHOWN LYSINE CROTONYLATION EXPRESSION WAS NEGATIVELY CORRELATED WITH SERUM FIBROTIC INDICATORS. CONVERSELY, CROTONYLATION-REGULATED ENZYMES, WHICH NEGATIVELY REGULATE PROTEIN CROTONYLATION, WERE INCREASED IN RESPONSE TO CCL(4) TREATMENT, WHILE SORAFENIB REDUCED THEIR EXPRESSION. CONCLUSION: SORAFENIB EXERTS SIGNIFICANT ANTI-FIBROTIC EFFECTS THROUGH MEDIATING CROTONYLATION-REGULATED ENZYMES AND PROTEIN CROTONYLATION IN FIBROTIC RATS. 2022 11 3894 21 LAMIN B1 REGULATES SOMATIC MUTATIONS AND PROGRESSION OF B-CELL MALIGNANCIES. SOMATIC HYPERMUTATION (SHM) IS A PIVOTAL PROCESS IN ADAPTIVE IMMUNITY THAT OCCURS IN THE GERMINAL CENTRE AND ALLOWS B CELLS TO CHANGE THEIR PRIMARY DNA SEQUENCE AND DIVERSIFY THEIR ANTIGEN RECEPTORS. HERE, WE REPORT THAT GENOME BINDING OF LAMIN B1, A COMPONENT OF THE NUCLEAR ENVELOPE INVOLVED IN EPIGENETIC CHROMATIN REGULATION, IS REDUCED DURING B-CELL ACTIVATION AND FORMATION OF LYMPHOID GERMINAL CENTRES. CHROMATIN IMMUNOPRECIPITATION-SEQ ANALYSIS SHOWED THAT KAPPA AND HEAVY VARIABLE IMMUNOGLOBULIN DOMAINS WERE RELEASED FROM THE LAMIN B1 SUPPRESSIVE ENVIRONMENT WHEN SHM WAS INDUCED IN B CELLS. RNA INTERFERENCE-MEDIATED REDUCTION OF LAMIN B1 RESULTED IN SPONTANEOUS SHM AS WELL AS KAPPA-LIGHT CHAIN ABERRANT SURFACE EXPRESSION. FINALLY, LAMIN B1 EXPRESSION LEVEL CORRELATED WITH PROGRESSION-FREE AND OVERALL SURVIVAL IN CHRONIC LYMPHOCYTIC LEUKAEMIA, AND WAS STRONGLY INVOLVED IN THE TRANSFORMATION OF FOLLICULAR LYMPHOMA. IN SUMMARY, HERE WE REPORT THAT LAMIN B1 IS A NEGATIVE EPIGENETIC REGULATOR OF SHM IN NORMAL B-CELLS AND A 'MUTATIONAL GATEKEEPER', SUPPRESSING THE ABERRANT MUTATIONS THAT DRIVE LYMPHOID MALIGNANCY. 2018 12 5220 15 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION. 2018 13 3360 30 HISTONE H4K20 TRIMETHYLATION IS DECREASED IN MURINE MODELS OF HEART DISEASE. HEART DISEASE IS THE LEADING CAUSE OF DEATH IN THE DEVELOPED WORLD, AND ITS COMORBIDITIES SUCH AS HYPERTENSION, DIABETES, AND HEART FAILURE ARE ACCOMPANIED BY MAJOR TRANSCRIPTOMIC CHANGES IN THE HEART. DURING CARDIAC DYSFUNCTION, WHICH LEADS TO HEART FAILURE, THERE ARE GLOBAL EPIGENETIC ALTERATIONS TO CHROMATIN THAT OCCUR CONCOMITANTLY WITH MORPHOLOGICAL CHANGES IN THE HEART IN RESPONSE TO ACUTE AND CHRONIC STRESS. THESE EPIGENETIC ALTERATIONS INCLUDE THE REVERSIBLE METHYLATION OF LYSINE RESIDUES ON HISTONE PROTEINS. LYSINE METHYLATIONS ON HISTONES H3K4 AND H3K9 WERE AMONG THE FIRST METHYLATED LYSINE RESIDUES IDENTIFIED AND HAVE BEEN LINKED TO GENE ACTIVATION AND SILENCING, RESPECTIVELY. HOWEVER, MUCH LESS IS KNOWN REGARDING OTHER METHYLATED HISTONE RESIDUES, INCLUDING HISTONE H4K20. TRIMETHYLATION OF HISTONE H4K20 HAS BEEN SHOWN TO REPRESS GENE EXPRESSION; HOWEVER, THIS MODIFICATION HAS NEVER BEEN EXAMINED IN THE HEART. HERE, WE UTILIZED IMMUNOBLOTTING AND MASS SPECTROMETRY TO QUANTIFY HISTONE H4K20 TRIMETHYLATION IN THREE MODELS OF CARDIAC DYSFUNCTION. OUR RESULTS SHOW THAT LYSINE METHYLATION AT THIS SITE IS DIFFERENTIALLY REGULATED IN THE CARDIOMYOCYTE, LEADING TO INCREASED H4K20 TRIMETHYLATION DURING ACUTE HYPERTROPHIC STRESS IN CELL MODELS AND DECREASED H4K20 TRIMETHYLATION DURING SUSTAINED ISCHEMIC INJURY AND CARDIAC DYSFUNCTION IN ANIMAL MODELS. IN ADDITION, WE EXAMINED PUBLICLY AVAILABLE DATA SETS TO ANALYZE ENZYMES THAT REGULATE H4K20 METHYLATION AND IDENTIFIED TWO DEMETHYLASES (KDM7B AND KDM7C) AND TWO METHYLTRANSFERASES (KMT5A AND SMYD5) THAT WERE ALL DIFFERENTIALLY EXPRESSED IN HEART FAILURE PATIENTS. THIS IS THE FIRST STUDY TO EXAMINE HISTONE H4K20 TRIMETHYLATION IN THE HEART AND TO DETERMINE HOW THIS POST-TRANSLATIONAL MODIFICATION IS DIFFERENTIALLY REGULATED IN MULTIPLE MODELS OF CARDIAC DISEASE. 2022 14 3240 28 HEPATIC LIPID ACCUMULATION ALTERS GLOBAL HISTONE H3 LYSINE 9 AND 4 TRIMETHYLATION IN THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA NETWORK. RECENT DATA SUGGEST THAT THE ETIOLOGY OF SEVERAL METABOLIC DISEASES IS CLOSELY ASSOCIATED WITH TRANSCRIPTOME ALTERATION BY ABERRANT HISTONE METHYLATION. WE PERFORMED DNA MICROARRAY AND CHIP-ON-CHIP ANALYSES TO EXAMINE TRANSCRIPTOME PROFILING AND TRIMETHYLATION ALTERATIONS TO IDENTIFY THE GENOMIC SIGNATURE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST COMMON FORM OF CHRONIC LIVER DISEASE. TRANSCRIPTOME ANALYSIS SHOWED THAT STEATOTIC LIVERS IN HIGH-FAT DIET-FED APOLIPOPROTEIN E2 MICE SIGNIFICANTLY ALTERED THE EXPRESSION OF APPROXIMATELY 70% OF TOTAL GENES COMPARED WITH NORMAL DIET-FED CONTROL LIVERS, SUGGESTING THAT HEPATIC LIPID ACCUMULATION INDUCES DRAMATIC ALTERATIONS IN GENE EXPRESSION IN VIVO. ALSO, PATHWAY ANALYSIS SUGGESTED THAT GENES ENCODING CHROMATIN-REMODELING ENZYMES, SUCH AS JUMONJI C-DOMAIN-CONTAINING HISTONE DEMETHYLASES THAT REGULATE HISTONE H3K9 AND H3K4 TRIMETHYLATION (H3K9ME3, H3K4ME3), WERE SIGNIFICANTLY ALTERED IN STEATOTIC LIVERS. THUS, WE FURTHER INVESTIGATED THE GLOBAL H3K9ME3 AND H3K4ME3 STATUS IN LIPID-ACCUMULATED MOUSE PRIMARY HEPATOCYTES BY CHIP-ON-CHIP ANALYSIS. RESULTS SHOWED THAT HEPATIC LIPID ACCUMULATION INDUCED ABERRANT H3K9ME3 AND H3K4ME3 STATUS IN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA AND HEPATIC LIPID CATABOLISM NETWORK GENES, REDUCING THEIR MRNA EXPRESSION COMPARED WITH NON-TREATED CONTROL HEPATOCYTES. THIS STUDY PROVIDES THE FIRST EVIDENCE THAT EPIGENETIC REGULATION BY H3K9ME3 AND H3K4ME3 IN HEPATOCYTES MAY BE INVOLVED IN HEPATIC STEATOSIS AND THE PATHOGENESIS OF NAFLD. THUS, CONTROL OF H3K9ME3 AND H3K4ME3 REPRESENTS A POTENTIAL NOVEL NAFLD PREVENTION AND TREATMENT STRATEGY. 2012 15 4175 28 MELATONIN PROTECTS CHOLANGIOCYTES FROM OXIDATIVE STRESS-INDUCED PROAPOPTOTIC AND PROINFLAMMATORY STIMULI VIA MIR-132 AND MIR-34. BIOSYNTHESIS OF MELATONIN BY CHOLANGIOCYTES IS ESSENTIAL FOR MAINTAINING THE FUNCTION OF BILIARY EPITHELIUM. HOWEVER, THIS CYTOPROTECTIVE MECHANISM APPEARS TO BE IMPAIRED IN PRIMARY BILIARY CHOLANGITIS (PBC). MIR-132 HAS EMERGED AS A MEDIATOR OF INFLAMMATION IN CHRONIC LIVER DISEASES. THE EFFECT OF MELATONIN ON OXIDATIVE STRESS AND BILE ACID-INDUCED APOPTOSIS WAS ALSO EXAMINED IN CHOLANGIOCYES OVEREXPRESSING MIR506, AS A PBC-LIKE CELLULAR MODEL. IN PBC PATIENTS THE SERUM LEVELS OF MELATONIN WERE FOUND INCREASED IN COMPARISON TO HEALTHY CONTROLS. WHEREAS, IN CHOLANGIOCYTES WITHIN CIRRHOTIC PBC LIVERS THE MELATONIN BIOSYNTHETIC PATHWAY WAS SUBSTANTIALLY SUPPRESSED EVEN THOUGH THE EXPRESSIONS OF MELATONIN RATE-LIMITING ENZYME ARALKYLAMINE N-ACETYLTRANSFERASE (AANAT), AND CK-19 (MARKER OF CHOLANGIOCYTES) WERE ENHANCED. IN CHOLANGIOCYTES EXPOSED TO MITOCHONDRIAL OXIDATIVE STRESS MELATONIN DECREASED THE EXPRESSION OF PROAPOPTOTIC STIMULI (PTEN, BAX, MIR-34), WHICH WAS ACCOMPANIED BY THE INHIBITION OF A PIVOTAL MEDIATOR OF INFLAMMATORY RESPONSE NF-KAPPAB-P65 AND THE ACTIVATION OF ANTIAPOPTOTIC SIGNALING (MIR-132, BCL2). SIMILARLY, MELATONIN REDUCED BILE ACID-INDUCED PROAPOPTOTIC CASPASE 3 AND BIM LEVELS. IN SUMMARY, THE INSUFFICIENT HEPATIC EXPRESSION OF MELATONIN IN PBC PATIENTS MAY PREDISPOSE CHOLANGIOCYTES TO OXIDATIVE STRESS-RELATED DAMAGE. MELATONIN, VIA EPIGENETIC MODULATION, WAS ABLE TO SUPPRESS NF-KAPPAB SIGNALING ACTIVATION AND PROTECT AGAINST BILIARY CELLS APOPTOTIC SIGNALING. 2020 16 364 30 AMELIORATION OF UREMIC TOXIN INDOXYL SULFATE-INDUCED OSTEOBLASTIC CALCIFICATION BY SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 PROTEIN. BACKGROUND: VASCULAR CALCIFICATION (VC) IS A VERY COMMON PHENOMENON IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). IT HAS BEEN REPORTED THAT SOME HISTONE METHYLATION PLAY A ROLE IN VC AS AN EPIGENETIC REGULATOR. INDOXYL SULFATE (IS) IS A PROTEIN-BOUND UREMIC TOXIN THAT HAS BEEN PROVEN AS ONE OF THE MAJOR RISK FACTORS OF CARDIOVASCULAR DISEASE IN CKD. SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 (SET7/9) IS ONE OF THE IMPORTANT HISTONE METHYLTRANSFERASES. OBJECTIVES: THIS STUDY AIMED TO DETERMINE THE EFFECT OF IS ON THE EXPRESSION OF SET7/9 AND THE ROLE OF SET7/9 IN IS-INDUCED OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS). METHODS: VSMCS WERE INCUBATED WITH VARIOUS CONCENTRATIONS OF IS FOR DIFFERENT DURATIONS TO ASSESS OSTEOBLASTIC DIFFERENTIATION AND EXPRESSION OF SET7/9. WESTERN BLOT ANALYSIS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION WERE PERFORMED TO ASSESS THE PROTEIN AND MRNA LEVELS OF SET7/9 RESPECTIVELY. THE CALCIUM CONTENT WAS MEASURED TO EVALUATE CALCIFICATION. RESULTS: OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VSMCS AND DOWNREGULATION OF THE EXPRESSION OF SET7/9 WERE OBSERVED AFTER IS TREATMENT. THE AUTOPHAGY WAS ACTIVATED AFTER TREATMENT WITH IS, WHEREAS THE INHIBITION OF THE AUTOPHAGY PARTIALLY ATTENUATED THE EFFECT OF IS ON BOTH THE STIMULATION OF THE EXPRESSION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 AND CALCIUM DEPOSITION. CONCLUSIONS: OUR DATA DEMONSTRATED THAT SET7/9 DOWNREGULATION AND AUTOPHAGY ACTIVATION MAY BE THE KEY MECHANISM OF IS-INDUCED VC IN CKD. 2019 17 5479 32 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT. 2022 18 5227 30 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL. 2020 19 3012 24 GENETICS AND EPIGENETICS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC, SLOWLY PROGRESSIVE CHOLESTATIC AUTOIMMUNE LIVER DISEASE PREDOMINANTLY AFFLICTING WOMEN. PBC IS CHARACTERIZED BY THE PRESENCE OF DISEASE-SPECIFIC ANTIMITOCHONDRIAL ANTIBODIES AND THE HISTOLOGICAL DESTRUCTION OF INTRAHEPATIC BILE DUCTS, WHICH EVENTUALLY LEAD TO CIRRHOSIS AND HEPATIC FAILURE. FORTUNATELY, URSODEOXYCHOLIC ACID THERAPY HAS IMPROVED THE OUTCOME OF THE VAST MAJORITY OF PBC CASES. ALTHOUGH THE ETIOLOGY OF PBC HAS NOT YET BEEN ELUCIDATED, HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II ALLELES HAVE BEEN CONSISTENTLY ASSOCIATED WITH DISEASE ONSET FOR DECADES. PBC PATIENTS MAY ALSO HAVE GENETICALLY DETERMINED RISK FACTORS IN NON-HLA REGIONS. MEANWHILE, EXPOSURE TO ENVIRONMENTAL FACTORS, SUCH AS INFECTIOUS DISEASES AND HARMFUL CHEMICALS, CAN PRODUCE EPIGENETIC ALTERATIONS IN SOME INDIVIDUALS AND SUBSEQUENT PBC ONSET. IN THIS REVIEW, WE DESCRIBE THE INFLUENCE OF HLA ALLELES AND OTHER GENE POLYMORPHISMS ON PBC ALONG WITH THE RESULTS OF GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE AND ITS FUTURE PROSPECTS IN TERMS OF EPIGENETICS. 2018 20 5222 19 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE. 2011