1 4934 113 PATERNAL CHRONIC FOLATE SUPPLEMENTATION INDUCED THE TRANSGENERATIONAL INHERITANCE OF ACQUIRED DEVELOPMENTAL AND METABOLIC CHANGES IN CHICKENS. INCREASING EVIDENCE INDICATES THAT PATERNAL DIET CAN RESULT IN METABOLIC CHANGES IN OFFSPRING, BUT THE DEFINITE MECHANISM REMAINS UNCLEAR IN BIRDS. HERE, WE FED BREEDER COCKS FIVE DIFFERENT DIETS CONTAINING 0, 0.25, 1.25, 2.50 AND 5.00 MG KG(-1) FOLATE THROUGHOUT LIFE. PATERNAL FOLATE SUPPLEMENTATION (FS) WAS BENEFICIAL TO THE GROWTH AND ORGAN DEVELOPMENT OF BROILER OFFSPRING. MOST IMPORTANTLY, THE LIPID AND GLUCOSE METABOLISM OF BREEDER COCKS AND BROILER OFFSPRING WERE AFFECTED BY PATERNAL FS, ACCORDING TO BIOCHEMICAL AND METABOLOMIC ANALYSES. WE FURTHER EMPLOYED GLOBAL ANALYSES OF HEPATIC AND SPERMATOZOAL MESSENGER RNA (MRNA), LONG NON-CODING RNA (LNCRNA) AND MICRO RNA (MIRNA). SOME KEY GENES INVOLVED IN THE GLYCOLYSIS OR GLUCONEOGENESIS PATHWAY AND THE PPAR SIGNALLING PATHWAY, INCLUDING PEPCK, ANGPTL4 AND THRSP, WERE REGULATED BY DIFFERENTIALLY EXPRESSED HEPATIC AND SPERMATOZOAL MIRNAS AND LNCRNAS IN BREEDER COCKS AND BROILER OFFSPRING. MOREOVER, THE EXPRESSION OF ANGPTL4 COULD ALSO BE REGULATED BY DIFFERENTIALLY EXPRESSED MIRNAS AND LNCRNAS IN SPERMATOZOA VIA COMPETITIVE ENDOGENOUS RNA (CERNA) MECHANISMS. OVERALL, THIS MODEL SUGGESTS THAT PATERNAL FOLATE COULD TRANSGENERATIONALLY REGULATE LIPID AND GLUCOSE METABOLISM IN BROILER OFFSPRING AND THE EPIGENETIC TRANSMISSION MAY INVOLVE ALTERED SPERMATOZOAL MIRNAS AND LNCRNAS. 2019 2 4946 27 PATERNAL PSYCHOLOGICAL STRESS REPROGRAMS HEPATIC GLUCONEOGENESIS IN OFFSPRING. BOTH EPIDEMIOLOGIC AND EXPERIMENTAL ANIMAL STUDIES DEMONSTRATE THAT CHRONIC PSYCHOLOGICAL STRESS EXERTS ADVERSE EFFECTS ON THE INITIATION AND/OR PROGRESSION OF MANY DISEASES. HOWEVER, INTERGENERATIONAL EFFECTS OF THIS ENVIRONMENTAL INFORMATION REMAINS POORLY UNDERSTOOD. HERE, USING A C57BL/6 MOUSE MODEL OF RESTRAINT STRESS, WE SHOW THAT OFFSPRING OF STRESSED FATHERS EXHIBIT HYPERGLYCEMIA DUE TO ENHANCED HEPATIC GLUCONEOGENESIS AND ELEVATED EXPRESSION OF PEPCK. MECHANISTICALLY, WE IDENTIFY AN EPIGENETIC ALTERATION AT THE PROMOTER REGION OF THE SFMBT2 GENE, A MATERNALLY IMPRINTED POLYCOMB GENE, LEADING TO A DOWNREGULATION OF INTRONIC MICRORNA-466B-3P, WHICH POST-TRANSCRIPTIONALLY INHIBITS PEPCK EXPRESSION. IMPORTANTLY, HYPERGLYCEMIA IN F1 MICE IS REVERSED BY RU486 TREATMENT IN FATHERS, AND DEXAMETHASONE ADMINISTRATION IN F0 MICE PHENOCOPIES THE ROLES OF RESTRAINT STRESS. THUS, WE PROVIDE EVIDENCE SHOWING THE EFFECTS OF PATERNAL PSYCHOLOGICAL STRESS ON THE REGULATION OF GLUCOSE METABOLISM IN OFFSPRING, WHICH MAY HAVE PROFOUND IMPLICATIONS FOR OUR UNDERSTANDING OF HEALTH AND DISEASE RISK INHERITED FROM FATHERS. 2016 3 3301 17 HIGH-FAT OR ETHINYL-OESTRADIOL INTAKE DURING PREGNANCY INCREASES MAMMARY CANCER RISK IN SEVERAL GENERATIONS OF OFFSPRING. MATERNAL EXPOSURES TO ENVIRONMENTAL FACTORS DURING PREGNANCY INFLUENCE THE RISK OF MANY CHRONIC ADULT-ONSET DISEASES IN THE OFFSPRING. HERE WE INVESTIGATE WHETHER FEEDING PREGNANT RATS A HIGH-FAT (HF)- OR ETHINYL-OESTRADIOL (EE2)-SUPPLEMENTED DIET AFFECTS CARCINOGEN-INDUCED MAMMARY CANCER RISK IN DAUGHTERS, GRANDDAUGHTERS AND GREAT-GRANDDAUGHTERS. WE SHOW THAT MAMMARY TUMOURIGENESIS IS HIGHER IN DAUGHTERS AND GRANDDAUGHTERS OF HF RAT DAMS AND IN DAUGHTERS AND GREAT-GRANDDAUGHTERS OF EE2 RAT DAMS. OUTCROSS EXPERIMENTS SUGGEST THAT THE INCREASE IN MAMMARY CANCER RISK IS TRANSMITTED TO HF GRANDDAUGHTERS EQUALLY THROUGH THE FEMALE OR MALE GERM LINES, BUT IT IS ONLY TRANSMITTED TO EE2 GRANDDAUGHTERS THROUGH THE FEMALE GERM LINE. THE EFFECTS OF MATERNAL EE2 EXPOSURE ON OFFSPRING'S MAMMARY CANCER RISK ARE ASSOCIATED WITH CHANGES IN THE DNA METHYLATION MACHINERY AND METHYLATION PATTERNS IN MAMMARY TISSUE OF ALL THREE EE2 GENERATIONS. WE CONCLUDE THAT DIETARY AND OESTROGENIC EXPOSURES IN PREGNANCY INCREASE BREAST CANCER RISK IN MULTIPLE GENERATIONS OF OFFSPRING, POSSIBLY THROUGH EPIGENETIC MEANS. 2012 4 6556 21 TRANSGENERATIONAL EFFECTS OF POLYETHYLENE MICROPLASTIC FRAGMENTS CONTAINING BENZOPHENONE-3 ADDITIVE IN DAPHNIA MAGNA. MATERNAL EXPOSURE TO MICROPLASTICS (MPS) PLAYS AN IMPORTANT ROLE IN THE FITNESS OF UNEXPOSED PROGENY. IN THIS STUDY, THE TRANSGENERATIONAL EFFECTS OF POLYETHYLENE MP FRAGMENTS (17.35 +/- 5.50 MICROM) CONTAINING BENZOPHENONE-3 (BP-3; 2.85 +/- 0.16% W/W) ON CHRONIC TOXICITY (21 D) IN DAPHNIA MAGNA WERE INVESTIGATED ACROSS FOUR GENERATIONS. ONLY D. MAGNA IN THE F0 GENERATION WAS EXPOSED TO MP FRAGMENTS, MP/BP-3 FRAGMENTS, AND BP-3 LEACHATE TO IDENTIFY THE TRANSGENERATIONAL EFFECT IN THE F3 GENERATION. THE MORTALITY OF D. MAGNA INDUCED BY MP AND MP/BP-3 FRAGMENTS WAS RECOVERED IN THE F3 GENERATION, BUT SOMATIC GROWTH AND REPRODUCTION SIGNIFICANTLY DECREASED COMPARED TO THE CONTROL. ADDITIONALLY, REPRODUCTION OF D. MAGNA EXPOSED TO BP-3 LEACHATE SIGNIFICANTLY DECREASED IN THE F3 GENERATION. THESE FINDINGS CONFIRMED THE TRANSGENERATIONAL EFFECTS OF MP FRAGMENT AND BP-3 ADDITIVE ON D. MAGNA. PARTICULARLY, THE ADVERSE EFFECT ON D. MAGNA REPRODUCTION SEEMED TO BE CUMULATIVE ACROSS FOUR GENERATIONS FOR MP/BP-3 FRAGMENTS, WHILE IT WAS AN ACCLIMATION TREND FOR BP-3 LEACHATE. HOWEVER, THERE WAS NO SIGNIFICANT DIFFERENCE IN GLOBAL DNA METHYLATION IN D. MAGNA ACROSS FOUR GENERATIONS, THUS REQUIRING A GENE-SPECIFIC DNA METHYLATION STUDY TO IDENTIFY DIFFERENT EPIGENETIC TRANSGENERATIONAL INHERITANCE. 2022 5 3300 30 HIGH-FAT DIET REPROGRAMS THE EPIGENOME OF RAT SPERMATOZOA AND TRANSGENERATIONALLY AFFECTS METABOLISM OF THE OFFSPRING. OBJECTIVES: CHRONIC AND HIGH CONSUMPTION OF FAT CONSTITUTES AN ENVIRONMENTAL STRESS THAT LEADS TO METABOLIC DISEASES. WE HYPOTHESIZED THAT HIGH-FAT DIET (HFD) TRANSGENERATIONALLY REMODELS THE EPIGENOME OF SPERMATOZOA AND METABOLISM OF THE OFFSPRING. METHODS: F0-MALE RATS FED EITHER HFD OR CHOW DIET FOR 12 WEEKS WERE MATED WITH CHOW-FED DAMS TO GENERATE F1 AND F2 OFFSPRING. MOTILE SPERMATOZOA WERE ISOLATED FROM F0 AND F1 BREEDERS TO DETERMINE DNA METHYLATION AND SMALL NON-CODING RNA (SNCRNA) EXPRESSION PATTERN BY DEEP SEQUENCING. RESULTS: NEWBORN OFFSPRING OF HFD-FED FATHERS HAD REDUCED BODY WEIGHT AND PANCREATIC BETA-CELL MASS. ADULT FEMALE, BUT NOT MALE, OFFSPRING OF HFD-FED FATHERS WERE GLUCOSE INTOLERANT AND RESISTANT TO HFD-INDUCED WEIGHT GAIN. THIS PHENOTYPE WAS PERPETUATED IN THE F2 PROGENY, INDICATING TRANSGENERATIONAL EPIGENETIC INHERITANCE. THE EPIGENOME OF SPERMATOZOA FROM HFD-FED F0 AND THEIR F1 MALE OFFSPRING SHOWED COMMON DNA METHYLATION AND SMALL NON-CODING RNA EXPRESSION SIGNATURES. ALTERED EXPRESSION OF SPERM MIRNA LET-7C WAS PASSED DOWN TO METABOLIC TISSUES OF THE OFFSPRING, INDUCING A TRANSCRIPTOMIC SHIFT OF THE LET-7C PREDICTED TARGETS. CONCLUSION: OUR RESULTS PROVIDE INSIGHT INTO MECHANISMS BY WHICH HFD TRANSGENERATIONALLY REPROGRAMS THE EPIGENOME OF SPERM CELLS, THEREBY AFFECTING METABOLIC TISSUES OF OFFSPRING THROUGHOUT TWO GENERATIONS. 2016 6 3943 29 LNCRNA ENST00000563492 PROMOTING THE OSTEOGENESIS-ANGIOGENESIS COUPLING PROCESS IN BONE MESENCHYMAL STEM CELLS (BMSCS) BY FUNCTIONS AS A CERNA FOR MIR-205-5P. PAIN, PHYSICAL DYSFUNCTION, AND MENTAL DISORDERS CAUSED BY BONE NONUNION BRING GREAT BURDEN TO PATIENTS. BONE MESENCHYMAL STEM CELLS (BMSCS) ISOLATED FROM BONE NONUNION PATIENTS WITH POOR PROLIFERATION AND OSTEOGENIC ABILITY ARE COMPARED WITH THAT FROM NORMAL BONE-HEALING PATIENTS. LONG NONCODING RNAS (LNCRNAS) ARE A CLASS OF RNAS THAT ARE MORE THAN 200 NUCLEOTIDES IN LENGTH, LACK AN OPEN-READING FRAME ENCODING A PROTEIN, AND HAVE LITTLE OR NO PROTEIN-CODING FUNCTION, AND COULD REGULATE GENE EXPRESSION, WHICH IS INVOLVED IN THE REGULATION OF IMPORTANT LIFE ACTIVITIES, SUCH AS GROWTH, DEVELOPMENT, AGING, AND DEATH AT EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSCRIPTIONAL LEVELS. IN THIS STUDY, WE INTENDED TO INVESTIGATE THE DIFFERENCE OF LNCRNA EXPRESSION BETWEEN PATIENTS WITH NONUNION AND NORMAL FRACTURE HEALING. OUR RESULT FOUND THAT LNCRNA ENST00000563492 WAS DOWNREGULATED IN BONE NONUNION TISSUES. LNCRNA ENST00000563492 PROMOTES OSTEOGENIC DIFFERENTIATION OF BMSCS THROUGH UPREGULATING THE EXPRESSION OF CDH11. ON THE OTHER HAND, LNCRNA ENST0000563492 COULD IMPROVE THE OSTEOGENESIS-ANGIOGENESIS COUPLING PROCESS THROUGH ENHANCING THE EXPRESSION OF VEGF DURING OSTEOGENIC DIFFERENTIATION OF BMSCS. LNCRNA ENST00000563492 FUNCTIONS AS A CERNA FOR MIR-205-5P THAT WAS TARGETING CDH11 AND VEGF. LNCRNA ENST00000563492 COULD PROMOTE THE OSTEOGENESIS OF BMSCS IN VIVO. OUR RESULT INDICATED THAT LNCRNA ENST00000563492 MAY BE A NEW TARGET FOR BONE NONUNION. 2020 7 6008 34 THE ANTI-INFLAMMATORY AGENT 5-ASA REDUCES THE LEVEL OF SPECIFIC TSRNAS IN SPERM CELLS OF HIGH-FAT FED C57BL/6J MOUSE SIRES AND IMPROVES GLUCOSE TOLERANCE IN FEMALE OFFSPRING. INTRODUCTION: THE PREVALENCE OF OBESITY AND ASSOCIATED COMORBIDITIES HAVE INCREASED TO EPIDEMIC PROPORTIONS GLOBALLY. PATERNAL OBESITY IS AN INDEPENDENT RISK FACTOR FOR DEVELOPING OBESITY AND TYPE 2 DIABETES IN THE FOLLOWING GENERATION, AND GROWING EVIDENCE SUGGESTS EPIGENETIC INHERITANCE AS A MECHANISM FOR THIS PREDISPOSITION. HOW AND WHY OBESITY INDUCES EPIGENETIC CHANGES IN SPERM CELLS REMAIN TO BE CLARIFIED IN DETAIL. YET, RECENT STUDIES SHOW THAT ALTERATIONS IN SPERM CONTENT OF TRANSFER RNA-DERIVED SMALL RNAS (TSRNAS) CAN TRANSMIT THE EFFECTS OF PATERNAL OBESITY TO OFFSPRING. OBESITY IS CLOSELY ASSOCIATED WITH LOW-GRADE CHRONIC INFLAMMATION. THUS, WE EVALUATED WHETHER THE ANTI-INFLAMMATORY AGENT 5-AMINOSALICYLIC ACID (5-ASA) COULD INTERVENE IN THE TRANSMISSION OF EPIGENETIC INHERITANCE OF PATERNAL OBESITY BY REDUCING THE INFLAMMATORY STATE IN OBESE FATHERS. METHODS: MALE C57BL/6JBOMTAC MICE WERE EITHER FED A HIGH-FAT DIET OR A HIGH-FAT DIET WITH 5-ASA FOR TEN WEEKS BEFORE MATING. THE OFFSPRING METABOLIC PHENOTYPE WAS EVALUATED, AND SPERMATOZOA FROM SIRES WERE ISOLATED FOR ASSESSMENT OF SPECIFIC TSRNAS LEVELS. RESULTS: 5-ASA INTERVENTION REDUCED THE LEVELS OF GLU-CTC TSRNAS IN SPERM CELLS AND IMPROVED GLUCOSE TOLERANCE IN FEMALE OFFSPRING FED A CHOW DIET. PATERNAL HIGH-FAT DIET-INDUCED OBESITY PER SE HAD ONLY A MODERATE IMPACT ON THE METABOLIC PHENOTYPE OF BOTH MALE AND FEMALE OFFSPRING IN OUR SETTING. CONCLUSION: THE RESULTS INDICATE THAT THE LOW-GRADE INFLAMMATORY RESPONSE ASSOCIATED WITH OBESITY MAY BE AN IMPORTANT FACTOR IN EPIGENETIC INHERITANCE OF PATERNAL OBESITY. 2023 8 4933 29 PATERNAL CHRONIC COLITIS CAUSES EPIGENETIC INHERITANCE OF SUSCEPTIBILITY TO COLITIS. INFLAMMATORY BOWEL DISEASE (IBD) ARISES BY UNKNOWN ENVIRONMENTAL TRIGGERS IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. EPIGENETIC REGULATION OF GENE EXPRESSION MAY INTEGRATE INTERNAL AND EXTERNAL INFLUENCES AND MAY THEREBY MODULATE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATION MAY ALSO AFFECT THE GERM-LINE AND IN CERTAIN CONTEXTS CAN BE INHERITED TO OFFSPRING. THIS STUDY INVESTIGATES EPIGENETIC ALTERATIONS CONSEQUENT TO EXPERIMENTAL MURINE COLITIS INDUCED BY DEXTRAN SODIUM SULPHATE (DSS), AND THEIR PATERNAL TRANSMISSION TO OFFSPRING. GENOME-WIDE METHYLOME- AND TRANSCRIPTOME-PROFILING OF INTESTINAL EPITHELIAL CELLS (IECS) AND SPERM CELLS OF MALES OF THE F0 GENERATION, WHICH RECEIVED EITHER DSS AND CONSEQUENTLY DEVELOPED COLITIS (F0(DSS)), OR NON-SUPPLEMENTED TAP WATER (F0(CTRL)) AND HENCE REMAINED HEALTHY, AND OF THEIR F1 OFFSPRING WAS PERFORMED USING REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) AND RNA-SEQUENCING (RNA-SEQ), RESPECTIVELY. OFFSPRING OF F0(DSS) MALES EXHIBITED ABERRANT METHYLATION AND EXPRESSION PATTERNS OF MULTIPLE GENES, INCLUDING IGF1R AND NR4A2, WHICH ARE INVOLVED IN ENERGY METABOLISM. IMPORTANTLY, DSS COLITIS IN F0(DSS) MICE WAS ASSOCIATED WITH DECREASED BODY WEIGHT AT BASELINE OF THEIR F1 OFFSPRING, AND THESE F1 MICE EXHIBITED INCREASED SUSCEPTIBILITY TO DSS-INDUCED COLITIS COMPARED TO OFFSPRING FROM F0(CTRL) MALES. THIS STUDY HENCE DEMONSTRATES EPIGENETIC TRANSMISSIBILITY OF METABOLIC AND INFLAMMATORY TRAITS RESULTING FROM EXPERIMENTAL COLITIS. 2016 9 3941 28 LNCRNA DRAIR IS DOWNREGULATED IN DIABETIC MONOCYTES AND MODULATES THE INFLAMMATORY PHENOTYPE VIA EPIGENETIC MECHANISMS. LONG NONCODING RNAS (LNCRNAS) ARE INCREASINGLY IMPLICATED IN THE PATHOLOGY OF DIABETIC COMPLICATIONS. HERE, WE EXAMINED THE ROLE OF LNCRNAS IN MONOCYTE DYSFUNCTION AND INFLAMMATION ASSOCIATED WITH HUMAN TYPE 2 DIABETES MELLITUS (T2D). RNA SEQUENCING ANALYSIS OF CD14+ MONOCYTES FROM PATIENTS WITH T2D VERSUS HEALTHY CONTROLS REVEALED DOWNREGULATION OF ANTIINFLAMMATORY AND ANTIPROLIFERATIVE GENES, ALONG WITH SEVERAL LNCRNAS, INCLUDING A POTENTIALLY NOVEL DIVERGENT LNCRNA DIABETES REGULATED ANTIINFLAMMATORY RNA (DRAIR) AND ITS NEARBY GENE CPEB2. HIGH GLUCOSE AND PALMITIC ACID DOWNREGULATED DRAIR IN CULTURED CD14+ MONOCYTES, WHEREAS ANTIINFLAMMATORY CYTOKINES AND MONOCYTE-TO-MACROPHAGE DIFFERENTIATION UPREGULATED DRAIR VIA KLF4 TRANSCRIPTION FACTOR. DRAIR OVEREXPRESSION INCREASED ANTIINFLAMMATORY AND MACROPHAGE DIFFERENTIATION GENES BUT INHIBITED PROINFLAMMATORY GENES. CONVERSELY, DRAIR KNOCKDOWN ATTENUATED ANTIINFLAMMATORY GENES, PROMOTED INFLAMMATORY RESPONSES, AND INHIBITED PHAGOCYTOSIS. DRAIR REGULATED TARGET GENE EXPRESSION THROUGH INTERACTION WITH CHROMATIN, AS WELL AS INHIBITION OF THE REPRESSIVE EPIGENETIC MARK H3K9ME2 AND ITS CORRESPONDING METHYLTRANSFERASE G9A. MOUSE ORTHOLOGOUS DRAIR AND CPEB2 WERE ALSO DOWNREGULATED IN PERITONEAL MACROPHAGES FROM T2D DB/DB MICE, AND DRAIR KNOCKDOWN IN NONDIABETIC MICE ENHANCED PROINFLAMMATORY GENES IN MACROPHAGES. THUS, DRAIR MODULATES THE INFLAMMATORY PHENOTYPE OF MONOCYTES/MACROPHAGES VIA EPIGENETIC MECHANISMS, AND ITS DOWNREGULATION IN T2D MAY PROMOTE CHRONIC INFLAMMATION. AUGMENTATION OF ENDOGENOUS LNCRNAS LIKE DRAIR COULD SERVE AS NOVEL ANTIINFLAMMATORY THERAPIES FOR DIABETIC COMPLICATIONS. 2021 10 2263 25 EPIGENETIC PROGRAMMING AT THE MOGAT1 LOCUS MAY LINK NEONATAL OVERNUTRITION WITH LONG-TERM HEPATIC STEATOSIS AND INSULIN RESISTANCE. POSTNATAL OVERFEEDING INCREASES THE RISK OF CHRONIC DISEASES LATER IN LIFE, INCLUDING OBESITY, INSULIN RESISTANCE, HEPATIC STEATOSIS, AND TYPE 2 DIABETES. EPIGENETIC MECHANISMS MIGHT UNDERLIE THE LONG-LASTING EFFECTS ASSOCIATED WITH EARLY NUTRITION. HERE WE AIMED TO EXPLORE THE MOLECULAR PATHWAYS INVOLVED IN EARLY DEVELOPMENT OF INSULIN RESISTANCE AND HEPATIC STEATOSIS, AND WE EXAMINED THE POTENTIAL CONTRIBUTION OF DNA METHYLATION AND HISTONE MODIFICATIONS TO LONG-TERM PROGRAMMING OF METABOLIC DISEASE. WE USED A WELL-CHARACTERIZED MOUSE MODEL OF NEONATAL OVERFEEDING AND EARLY ADIPOSITY BY LITTER SIZE REDUCTION. NEONATAL OVERFEEDING LED TO HEPATIC INSULIN RESISTANCE VERY EARLY IN LIFE THAT PERSISTED THROUGHOUT ADULTHOOD DESPITE NORMALIZING FOOD INTAKE. UP-REGULATION OF MONOACYLGLYCEROL O-ACYLTRANSFERASE ( MOGAT) 1 CONCEIVABLY MEDIATES HEPATIC STEATOSIS AND INSULIN RESISTANCE THROUGH INCREASING INTRACELLULAR DIACYLGLYCEROL CONTENT. EARLY AND SUSTAINED DEREGULATION OF MOGAT1 WAS ASSOCIATED WITH A COMBINATION OF HISTONE MODIFICATIONS THAT MIGHT FAVOR MOGAT1 EXPRESSION. IN SUM, POSTNATAL OVERFEEDING CAUSES EXTREMELY RAPID DERANGEMENTS OF HEPATIC INSULIN SENSITIVITY THAT REMAIN RELATIVELY STABLE UNTIL ADULTHOOD. EPIGENETIC MECHANISMS, PARTICULARLY HISTONE MODIFICATIONS, COULD CONTRIBUTE TO SUCH LONG-LASTING EFFECTS. OUR DATA SUGGEST THAT TARGETING HEPATIC MONOACYLGLYCEROL ACYLTRANSFERASE ACTIVITY DURING EARLY LIFE MIGHT PROVIDE A NOVEL STRATEGY TO IMPROVE HEPATIC INSULIN SENSITIVITY AND PREVENT LATE-ONSET INSULIN RESISTANCE AND FATTY LIVER DISEASE.-RAMON-KRAUEL, M., PENTINAT, T., BLOKS, V. W., CEBRIA, J., RIBO, S., PEREZ-WIENESE, R., VILA, M., PALACIOS-MARIN, I., FERNANDEZ-PEREZ, A., VALLEJO, M., TELLEZ, N., RODRIGUEZ, M. A., YANES, O., LERIN, C., DIAZ, R., PLOSCH, T., TIETGE, U. J. F., JIMENEZ-CHILLARON, J. C. EPIGENETIC PROGRAMMING AT THE MOGAT1 LOCUS MAY LINK NEONATAL OVERNUTRITION WITH LONG-TERM HEPATIC STEATOSIS AND INSULIN RESISTANCE. 2018 11 2155 26 EPIGENETIC MECHANISMS AND METABOLIC REPROGRAMMING IN FIBROGENESIS: DUAL TARGETING OF G9A AND DNMT1 FOR THE INHIBITION OF LIVER FIBROSIS. OBJECTIVE: HEPATIC STELLATE CELLS (HSC) TRANSDIFFERENTIATION INTO MYOFIBROBLASTS IS CENTRAL TO FIBROGENESIS. EPIGENETIC MECHANISMS, INCLUDING HISTONE AND DNA METHYLATION, PLAY A KEY ROLE IN THIS PROCESS. CONCERTED ACTION BETWEEN HISTONE AND DNA-MEHYLTRANSFERASES LIKE G9A AND DNMT1 IS A COMMON THEME IN GENE EXPRESSION REGULATION. WE AIMED TO STUDY THE EFFICACY OF CM272, A FIRST-IN-CLASS DUAL AND REVERSIBLE G9A/DNMT1 INHIBITOR, IN HALTING FIBROGENESIS. DESIGN: G9A AND DNMT1 WERE ANALYSED IN CIRRHOTIC HUMAN LIVERS, MOUSE MODELS OF LIVER FIBROSIS AND CULTURED MOUSE HSC. G9A AND DNMT1 EXPRESSION WAS KNOCKED DOWN OR INHIBITED WITH CM272 IN HUMAN HSC (HHSC), AND TRANSCRIPTOMIC RESPONSES TO TRANSFORMING GROWTH FACTOR-BETA1 (TGFBETA1) WERE EXAMINED. GLYCOLYTIC METABOLISM AND MITOCHONDRIAL FUNCTION WERE ANALYSED WITH SEAHORSE-XF TECHNOLOGY. GENE EXPRESSION REGULATION WAS ANALYSED BY CHROMATIN IMMUNOPRECIPITATION AND METHYLATION-SPECIFIC PCR. ANTIFIBROGENIC ACTIVITY AND SAFETY OF CM272 WERE STUDIED IN MOUSE CHRONIC CCL(4) ADMINISTRATION AND BILE DUCT LIGATION (BDL), AND IN HUMAN PRECISION-CUT LIVER SLICES (PCLSS) IN A NEW BIOREACTOR TECHNOLOGY. RESULTS: G9A AND DNMT1 WERE DETECTED IN STROMAL CELLS IN AREAS OF ACTIVE FIBROSIS IN HUMAN AND MOUSE LIVERS. G9A AND DNMT1 EXPRESSION WAS INDUCED DURING MOUSE HSC ACTIVATION, AND TGFBETA1 TRIGGERED THEIR CHROMATIN RECRUITMENT IN HHSC. G9A/DNMT1 KNOCKDOWN AND CM272 INHIBITED TGFBETA1 FIBROGENIC RESPONSES IN HHSC. TGFBETA1-MEDIATED PROFIBROGENIC METABOLIC REPROGRAMMING WAS ABROGATED BY CM272, WHICH RESTORED GLUCONEOGENIC GENE EXPRESSION AND MITOCHONDRIAL FUNCTION THROUGH ON-TARGET EPIGENETIC EFFECTS. CM272 INHIBITED FIBROGENESIS IN MICE AND PCLSS WITHOUT TOXICITY. CONCLUSIONS: DUAL G9A/DNMT1 INHIBITION BY COMPOUNDS LIKE CM272 MAY BE A NOVEL THERAPEUTIC STRATEGY FOR TREATING LIVER FIBROSIS. 2021 12 2640 19 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 13 4034 23 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021 14 2316 25 EPIGENETIC REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 BY HOST TRANSCRIPTION FACTOR SPECKLED 110 KDA DURING HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV) IS THE LEADING CAUSE OF LIVER DISEASE RANGING FROM ACUTE AND CHRONIC HEPATITIS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). STUDIES HAVE REVEALED THAT HBV INFECTION BROADLY REPROGRAMMES THE HOST CELLULAR METABOLIC PROCESSES FOR VIRAL PATHOGENESIS. PREVIOUS REPORTS HAVE SHOWN THAT GLYCOLYSIS AND GLUCONEOGENESIS ARE AMONG THE MOST DEREGULATED PATHWAYS DURING HBV INFECTION. WE NOTED THAT DESPITE BEING ONE OF THE RATE-LIMITING ENZYMES OF GLUCONEOGENESIS, THE ROLE AND REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 (FBP1) DURING HBV INFECTION IS NOT MUCH EXPLORED. IN THIS STUDY, WE REPORT FBP1 UPREGULATION UPON HBV INFECTION AND UNRAVEL A NOVEL MECHANISM OF EPIGENETIC REPROGRAMMING OF FBP1 BY HBV VIA UTILIZING HOST FACTOR SPECKLED 110 KDA (SP110). HERE, WE IDENTIFIED ACETYLATED LYSINE 18 OF HISTONE H3 (H3K18AC) AS A SELECTIVE INTERACTOR OF SP110 BROMODOMAIN. FURTHERMORE, WE FOUND THAT SP110 GETS RECRUITED ON H3K18AC-ENRICHED FBP1 PROMOTER, AND FACILITATES RECRUITMENT OF DEACETYLASE SIRTUIN 2 (SIRT2) ON THAT SITE IN THE PRESENCE OF HBV. SIRT2 IN TURN BRINGS ITS INTERACTOR AND TRANSCRIPTIONAL ACTIVATOR HEPATOCYTE NUCLEAR FACTOR 4-ALPHA TO THE PROMOTER, WHICH ULTIMATELY LEADS TO A LOSS OF DNA METHYLATION NEAR THE COGNATE SITE. INTERESTINGLY, THIS SP110 DRIVEN FBP1 REGULATION DURING INFECTION WAS FOUND TO PROMOTE VIRAL-BORNE HCC PROGRESSION. MOREOVER, SP110 CAN BE USED AS A PROGNOSTIC MARKER FOR THE HEPATITIS-MEDIATED HCC PATIENTS, WHERE HIGH SP110 EXPRESSION SIGNIFICANTLY LOWERED THEIR SURVIVAL. THUS, THE EPIGENETIC READER PROTEIN SP110 HAS POTENTIAL TO BE A THERAPEUTIC TARGET TO CHALLENGE HBV-INDUCED HCCS. 2022 15 1274 20 DACH1 PROTECTS PODOCYTES FROM EXPERIMENTAL DIABETIC INJURY AND MODULATES PTIP-H3K4ME3 ACTIVITY. DACHSHUND HOMOLOG 1 (DACH1), A KEY CELL-FATE DETERMINANT, REGULATES TRANSCRIPTION BY DNA SEQUENCE-SPECIFIC BINDING. WE IDENTIFIED DIMINISHED DACH1 EXPRESSION IN A LARGE-SCALE SCREEN FOR MUTATIONS THAT CONVERT INJURY-RESISTANT PODOCYTES INTO INJURY-SUSCEPTIBLE PODOCYTES. IN DIABETIC KIDNEY DISEASE (DKD) PATIENTS, PODOCYTE DACH1 EXPRESSION LEVELS ARE DIMINISHED, A CONDITION THAT STRONGLY CORRELATES WITH POOR CLINICAL OUTCOMES. GLOBAL DACH1 KO MICE MANIFEST RENAL HYPOPLASIA AND DIE PERINATALLY. PODOCYTE-SPECIFIC DACH1 KO MICE, HOWEVER, MAINTAIN NORMAL GLOMERULAR ARCHITECTURE AT BASELINE, BUT RAPIDLY EXHIBIT PODOCYTE INJURY AFTER DIABETES ONSET. FURTHERMORE, PODOCYTE-SPECIFIC AUGMENTATION OF DACH1 EXPRESSION IN MICE PROTECTS FROM DKD. COMBINED RNA SEQUENCING AND IN SILICO PROMOTER ANALYSIS REVEAL CONVERSELY OVERLAPPING GLOMERULAR TRANSCRIPTOMIC SIGNATURES BETWEEN PODOCYTE-SPECIFIC DACH1 AND PAX TRANSACTIVATION-DOMAIN INTERACTING PROTEIN (PTIP) KO MICE, WITH UPREGULATED GENES POSSESSING HIGHER-THAN-EXPECTED NUMBERS OF PROMOTER DACH1-BINDING SITES. PTIP, AN ESSENTIAL COMPONENT OF THE ACTIVATING HISTONE H3 LYSINE 4 TRIMETHYLATION (H3K4ME3) COMPLEX, INTERACTS WITH DACH1 AND IS RECRUITED BY DACH1 TO ITS PROMOTER-BINDING SITES. DACH1-PTIP RECRUITMENT REPRESSES TRANSCRIPTION AND REDUCES PROMOTER H3K4ME3 LEVELS. DACH1 KNOCKDOWN IN PODOCYTES COMBINED WITH HYPERGLYCEMIA TRIGGERS TARGET GENE UPREGULATION AND INCREASES PROMOTER H3K4ME3. THESE FINDINGS REVEAL THAT IN DKD, DIMINISHED DACH1 EXPRESSION ENHANCES PODOCYTE INJURY VULNERABILITY VIA EPIGENETIC DEREPRESSION OF ITS TARGET GENES. 2021 16 1461 25 DISRUPTION OF RCAN1.4 EXPRESSION MEDIATED BY YY1/HDAC2 MODULATES CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS. CHRONIC ALLOGRAFT DYSFUNCTION (CAD) IS A MAJOR FACTOR THAT HINDERS KIDNEY TRANSPLANT SURVIVAL IN THE LONG RUN. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) HAS BEEN CONFIRMED TO SIGNIFICANTLY CONTRIBUTE TO INTERSTITIAL FIBROSIS/TUBULAR ATROPHY (IF/TA), WHICH IS THE MAIN HISTOPATHOLOGICAL FEATURE OF CAD. ABERRANT EXPRESSION OF THE REGULATOR OF CALCINEURIN 1 (RCAN1), RECOGNIZED AS AN ENDOGENOUS INHIBITOR OF THE CALCINEURIN PHOSPHATASE, HAS BEEN SHOWN TO BE EXTENSIVELY INVOLVED IN VARIOUS KIDNEY DISEASES. HOWEVER, IT REMAINS UNCLEAR HOW RCAN1.4 REGULATES IF/TA FORMATION IN CAD PATIENTS. HEREIN, AN IN VIVO MOUSE RENAL TRANSPLANTATION MODEL AND AN IN VITRO MODEL OF HUMAN RENAL TUBULAR EPITHELIAL CELLS (HK-2) TREATED WITH TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE EMPLOYED. OUR RESULTS PROVED THAT RCAN1.4 EXPRESSION WAS DECREASED IN VIVO AND IN VITRO, IN ADDITION TO THE UP-REGULATION OF YIN YANG 1 (YY1), A TRANSCRIPTION FACTOR THAT HAS BEEN REPORTED TO CONVEY MULTIPLE FUNCTIONS IN CHRONIC KIDNEY DISEASE (CKD). KNOCKING IN OF RCAN1.4 EFFICIENTLY ATTENUATED CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS IN VIVO AND INHIBITED TNF-ALPHA-INDUCED EMT IN VITRO THROUGH REGULATING ANTI-OXIDATIVE STRESS AND THE CALCINEURIN/NUCLEAR FACTOR OF ACTIVATED T CELLS CYTOPLASMIC 1 (NFATC1) SIGNALING PATHWAY. IN ADDITION, SUPPRESSION OF YY1 MEDIATED BY SHRNA OR SIRNA ALLEVIATED TNF-ALPHA-INDUCED EMT THROUGH ABOLISHING REACTIVE SPECIES PARTLY IN AN RCAN1.4-DEPENDENT MANNER. NOTABLY, WE CONFIRMED THAT YY1 NEGATIVELY REGULATED RCAN1.4 TRANSCRIPTION BY DIRECTLY INTERACTING WITH THE RCAN1.4 PROMOTER. IN ADDITION, HISTONE DEACETYLASE 2 (HDAC2) INTERACTED WITH YY1 TO FORM A MULTI-MOLECULAR COMPLEX, WHICH WAS INVOLVED IN TNF-ALPHA-INDUCED RCAN1.4 TRANSCRIPTIONAL REPRESSION. THEREFORE, RCAN1.4 IS SUGGESTED TO BE MODULATED BY THE YY1/HDAC2 TRANSCRIPTION REPRESSOR COMPLEX IN AN EPIGENETIC MANNER, WHICH IS A MEDIATED NEPHROPROTECTIVE EFFECT PARTLY THROUGH MODULATING O2?- GENERATION AND THE CALCINEURIN/NFATC1 SIGNALING PATHWAY. THUS, THE YY1-RCAN1.4 AXIS CONSTITUTES AN INNOVATIVE TARGET FOR IF/TA TREATMENT IN CAD PATIENTS. 2023 17 5298 20 PROTEIN ARGININE METHYLTRANSFERASE 5 SUPPRESSES THE TRANSCRIPTION OF THE RB FAMILY OF TUMOR SUPPRESSORS IN LEUKEMIA AND LYMPHOMA CELLS. THE PROPER EPIGENETIC MODIFICATION OF CHROMATIN BY PROTEIN ARGININE METHYLTRANSFERASES (PRMTS) IS CRUCIAL FOR NORMAL CELL GROWTH AND HEALTH. THE HUMAN SWI/SNF-ASSOCIATED PRMT5 IS INVOLVED IN THE TRANSCRIPTIONAL REPRESSION OF TARGET GENES BY DIRECTLY METHYLATING H3R8 AND H4R3. TO FURTHER UNDERSTAND THE IMPACT OF PRMT5-MEDIATED HISTONE METHYLATION ON CANCER, WE ANALYZED ITS EXPRESSION IN NORMAL AND TRANSFORMED HUMAN B LYMPHOCYTES. OUR FINDINGS REVEAL THAT PRMT5 PROTEIN LEVELS ARE ENHANCED IN VARIOUS HUMAN LYMPHOID CANCER CELLS, INCLUDING TRANSFORMED CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) CELL LINES. PRMT5 OVEREXPRESSION IS CAUSED BY THE ALTERED EXPRESSION OF THE PRMT5-SPECIFIC MICRORNAS 19A, 25, 32, 92, 92B, AND 96 AND RESULTS IN THE INCREASED GLOBAL SYMMETRIC METHYLATION OF H3R8 AND H4R3. AN EVALUATION OF BOTH EPIGENETIC MARKS AT PRMT5 TARGET GENES SUCH AS RB1 (P105), RBL1 (P107), AND RBL2 (P130) SHOWED THAT PROMOTERS H3R8 AND H4R3 ARE HYPERMETHYLATED, WHICH IN TURN TRIGGERS POCKET PROTEIN TRANSCRIPTIONAL REPRESSION. FURTHERMORE, REDUCING PRMT5 EXPRESSION IN WAC3CD5 B-CLL CELLS ABOLISHES H3R8 AND H4R3 HYPERMETHYLATION, RESTORES RBL2 EXPRESSION, AND INHIBITS CANCER CELL PROLIFERATION. THESE RESULTS INDICATE THAT PRMT5 OVEREXPRESSION EPIGENETICALLY ALTERS THE TRANSCRIPTION OF KEY TUMOR SUPPRESSOR GENES AND SUGGEST A CAUSAL ROLE OF THE ELEVATED SYMMETRIC METHYLATION OF H3R8 AND H4R3 AT THE RBL2 PROMOTER IN TRANSFORMED B-LYMPHOCYTE PATHOLOGY. 2008 18 2758 25 EXPRESSION OF HORMONAL CARCINOGENESIS GENES AND RELATED REGULATORY MICRORNAS IN UTERUS AND OVARIES OF DDT-TREATED FEMALE RATS. THE INSECTICIDE DICHLORODIPHENYLTRICHLOROETHANE (DDT) IS A NONMUTAGENIC XENOBIOTIC COMPOUND ABLE TO EXERT ESTROGEN-LIKE EFFECTS RESULTING IN ACTIVATION OF ESTROGEN RECEPTOR-ALPHA (ERALPHA) FOLLOWED BY CHANGED EXPRESSION OF ITS DOWNSTREAM TARGET GENES. IN ADDITION, STUDIES PERFORMED OVER RECENT YEARS SUGGEST THAT DDT MAY ALSO INFLUENCE EXPRESSION OF MICRORNAS. HOWEVER, AN IMPACT OF DDT ON EXPRESSION OF ER, MICRORNAS, AND RELATED TARGET GENES HAS NOT BEEN FULLY ELUCIDATED. HERE, USING REAL-TIME PCR, WE ASSESSED CHANGES IN EXPRESSION OF KEY GENES INVOLVED IN HORMONAL CARCINOGENESIS AS WELL AS POTENTIALLY RELATED REGULATORY ONCOGENIC/TUMOR SUPPRESSOR MICRORNAS AND THEIR TARGET GENES IN THE UTERUS AND OVARIES OF FEMALE WISTAR RATS DURING SINGLE AND CHRONIC MULTIPLE-DOSE DDT EXPOSURE. WE FOUND THAT APPLYING DDT RESULTS IN ALTERED EXPRESSION OF MICRORNAS-221, -222, -205, -126A, AND -429, THEIR TARGET GENES (PTEN, DICER1), AS WELL AS GENES INVOLVED IN HORMONAL CARCINOGENESIS (ESR1, PGR, CCND1, CYP19A1). NOTABLY, CYP19A1 EXPRESSION SEEMS TO BE ALSO REGULATED BY MICRORNAS-221, -222, AND -205. THE DATA SUGGEST THAT EPIGENETIC EFFECTS INDUCED BY DDT AS A POTENTIAL CARCINOGEN MAY BE BASED ON AT LEAST TWO MECHANISMS: (I) ACTIVATION OF ERALPHA FOLLOWED BY ALTERED EXPRESSION OF THE TARGET GENES ENCODING RECEPTOR PGR AND CCND1 AS WELL AS IMPAIRED EXPRESSION OF CYP19A1, AFFECTING, THEREBY, CELL HORMONE BALANCE; AND (II) CHANGED EXPRESSION OF MICRORNAS RESULTING IN IMPAIRED EXPRESSION OF RELATED TARGET GENES INCLUDING REDUCED LEVEL OF CYP19A1 MRNA. 2017 19 5228 19 PRMT7 TARGETS OF FOXM1 CONTROLS ALVEOLAR MYOFIBROBLAST PROLIFERATION AND DIFFERENTIATION DURING ALVEOLOGENESIS. ALTHOUGH ABERRANT ALVEOLAR MYOFIBROBLASTS (AMYFS) PROLIFERATION AND DIFFERENTIATION ARE OFTEN ASSOCIATED WITH ABNORMAL LUNG DEVELOPMENT AND DISEASES, SUCH AS BRONCHOPULMONARY DYSPLASIA (BPD), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND IDIOPATHIC PULMONARY FIBROSIS (IPF), EPIGENETIC MECHANISMS REGULATING PROLIFERATION AND DIFFERENTIATION OF AMYFS REMAIN POORLY UNDERSTOOD. PROTEIN ARGININE METHYLTRANSFERASE 7 (PRMT7) IS THE ONLY REPORTED TYPE III ENZYME RESPONSIBLE FOR MONOMETHYLATION OF ARGININE RESIDUE ON BOTH HISTONE AND NONHISTONE SUBSTRATES. HERE WE PROVIDE EVIDENCE FOR PRMT7'S FUNCTION IN REGULATING AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS. IN PRMT7-DEFICIENT MICE, WE FOUND REDUCED AMYFS PROLIFERATION AND DIFFERENTIATION, ABNORMAL ELASTIN DEPOSITION, AND FAILURE OF ALVEOLAR SEPTUM FORMATION. WE FURTHER SHOWN THAT ONCOGENE FORKHEAD BOX M1 (FOXM1) IS A DIRECT TARGET OF PRMT7 AND THAT PRMT7-CATALYZED MONOMETHYLATION AT HISTONE H4 ARGININE 3 (H4R3ME1) DIRECTLY ASSOCIATE WITH CHROMATIN OF FOXM1 TO ACTIVATE ITS TRANSCRIPTION, AND THEREBY REGULATE OF CELL CYCLE-RELATED GENES TO INHIBIT AMYFS PROLIFERATION AND DIFFERENTIATION. OVEREXPRESSION OF FOXM1 IN ISOLATED MYOFIBROBLASTS (MYFS) SIGNIFICANTLY RESCUED PRMT7-DEFICIENCY-INDUCED CELL PROLIFERATION AND DIFFERENTIATION DEFECTS. THUS, OUR RESULTS REVEAL A NOVEL EPIGENETIC MECHANISM THROUGH WHICH PRMT7-MEDIATED HISTONE ARGININE MONOMETHYLATION ACTIVATES FOXM1 TRANSCRIPTIONAL EXPRESSION TO REGULATE AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS AND MAY REPRESENT A POTENTIAL TARGET FOR INTERVENTION IN PULMONARY DISEASES. 2021 20 5601 21 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD). 2019