1 1649 154 DOG LEUKOCYTE ANTIGEN (DLA) CLASS II GENOTYPES ASSOCIATED WITH CHRONIC ENTEROPATHY IN FRENCH BULLDOGS AND MINIATURE DACHSHUNDS. CANINE CHRONIC ENTEROPATHY (CE) IS A GROUP OF IMMUNOGENETIC DISORDERS OF UNCLEAR ETIOLOGY CHARACTERIZED BY CHRONIC OR RECURRENT GASTROINTESTINAL SIGNS AND INFLAMMATION. DIAGNOSIS OF CE SUBTYPES BY TREATMENT RESPONSE IS A LENGTHY AND CHALLENGING PROCESS, PARTICULARLY IN REFRACTORY CASES OF THE DISEASE. GIVEN KNOWN ASSOCIATION OF DOG LEUKOCYTE ANTIGEN (DLA) CLASS II GENOTYPE AND VARIOUS IMMUNOGENETIC DISORDERS BETWEEN AND ACROSS BREEDS, THIS STUDY WAS DESIGNED TO EXAMINE THE POTENTIAL OF DETERMINING SUSCEPTIBILITY TO REFRACTORY CE THROUGH IDENTIFICATION OF RISK AND PROTECTIVE GENOTYPES IN FRENCH BULLDOGS AND MINIATURE DACHSHUNDS-TWO POPULAR DOG BREEDS IN JAPAN. SEQUENCE-BASED GENOTYPING OF THREE DLA CLASS II GENES IN 29 FRENCH BULLDOGS AND 30 MINIATURE DACHSHUNDS WITH REFRACTORY CE REVEALED A PROTECTIVE HAPLOTYPE DLA-DRB1*002:01-DQA1*009:01-DQB1*001:01 AGAINST CE IN FRENCH BULLDOGS (OR 0.09, 95 % CI 0.01-0.71, P = 0.0084). NO STATISTICAL DIFFERENCE WAS NOTED BETWEEN MINIATURE DACHSHUND CASES AND CONTROLS. THESE FINDINGS, LARGELY DISPARATE FROM A PREVIOUS STUDY ON GERMAN SHEPHERD DOGS IN THE UK, WERE TAKEN AS POSSIBLE INDICATION OF ETIOLOGICAL DIFFERENCES IN THE REFRACTORY CE NOTED BETWEEN AND WITHIN BREEDS, AND BY EXTENSION, THE POTENTIAL OF IDENTIFYING SUCH DISEASE HETEROGENEITY BY DLA TYPING. THE DLA-DQA1/DQB1 HAPLOTYPE, PROTECTIVE AGAINST CE IN OUR FRENCH BULLDOGS, HAS BEEN REPORTED AS PROTECTIVE IN VARIOUS IMMUNE-MEDIATED DISORDERS SUCH AS DOBERMAN HEPATITIS (DYGGVE ET AL., 2011). LIKEWISE, THE DLA-DRB1*006:01 RISK ALLELE FOR DOBERMAN HEPATITIS WAS NOTED IN MORE FRENCH BULLDOGS WITH CE COMPARED TO CONTROLS, IN LINE WITH REPORTS ON GENOTYPES ASSOCIATED WITH BOTH RISK AND PROTECTION BEING SHARED ACROSS VARIOUS AUTOIMMUNE DISEASES AND BREEDS. THESE FINDINGS SUPPORT AN IMMUNOGENETIC BASIS TO THE FRENCH BULLDOG-CE IN OUR ANALYSIS, CALLING FOR FURTHER DLA STUDIES WORKING WITH LARGER SAMPLES AND DIFFERENT BREEDS TOWARDS PHENOTYPIC CLARIFICATION THAT MAY AID IN EARLY DIAGNOSIS, TREATMENT, AND PROPHYLAXIS THROUGH EPIGENETIC APPROACHES AND BREEDING. 2021 2 1274 25 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 3 356 26 ALTERING A HISTONE H3K4 METHYLATION PATHWAY IN GLOMERULAR PODOCYTES PROMOTES A CHRONIC DISEASE PHENOTYPE. METHYLATION OF SPECIFIC LYSINE RESIDUES IN CORE HISTONE PROTEINS IS ESSENTIAL FOR EMBRYONIC DEVELOPMENT AND CAN IMPART ACTIVE AND INACTIVE EPIGENETIC MARKS ON CHROMATIN DOMAINS. THE UBIQUITOUS NUCLEAR PROTEIN PTIP IS ENCODED BY THE PAXIP1 GENE AND IS AN ESSENTIAL COMPONENT OF A HISTONE H3 LYSINE 4 (H3K4) METHYLTRANSFERASE COMPLEX CONSERVED IN METAZOANS. IN ORDER TO DETERMINE IF PTIP AND ITS ASSOCIATED COMPLEXES ARE NECESSARY FOR MAINTAINING STABLE GENE EXPRESSION PATTERNS IN A TERMINALLY DIFFERENTIATED, NON-DIVIDING CELL, WE CONDITIONALLY DELETED PTIP IN GLOMERULAR PODOCYTES IN MICE. RENAL DEVELOPMENT AND FUNCTION WERE NOT IMPAIRED IN YOUNG MICE. HOWEVER, OLDER ANIMALS PROGRESSIVELY EXHIBITED PROTEINURIA AND PODOCYTE ULTRA STRUCTURAL DEFECTS SIMILAR TO CHRONIC GLOMERULAR DISEASE. LOSS OF PTIP RESULTED IN SUBTLE CHANGES IN GENE EXPRESSION PATTERNS PRIOR TO THE ONSET OF A RENAL DISEASE PHENOTYPE. CHROMATIN IMMUNOPRECIPITATION SHOWED A LOSS OF PTIP BINDING AND LOWER H3K4 METHYLATION AT THE NTRK3 (NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 3) LOCUS, WHOSE EXPRESSION WAS SIGNIFICANTLY REDUCED AND WHOSE FUNCTION MAY BE ESSENTIAL FOR PODOCYTE FOOT PROCESS PATTERNING. THESE DATA DEMONSTRATE THAT ALTERATIONS OR MUTATIONS IN AN EPIGENETIC REGULATORY PATHWAY CAN ALTER THE PHENOTYPES OF DIFFERENTIATED CELLS AND LEAD TO A CHRONIC DISEASE STATE. 2010 4 4227 29 METHYLATION OF FREE-FLOATING DEOXYRIBONUCLEIC ACID FRAGMENTS IN THE BRONCHOALVEOLAR LAVAGE FLUID OF DOGS WITH CHRONIC BRONCHITIS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE. BACKGROUND: THE ETIOLOGY OF CANINE CHRONIC BRONCHITIS (CB) IS NOT COMPLETELY UNDERSTOOD, ALTHOUGH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE (ETS) AFFECTS THE AIRWAY INFLAMMATORY RESPONSES IN SOME DOGS WITH CB. THE MECHANISM BY WHICH THIS OCCURS IS UNKNOWN. FINDINGS: WE INVESTIGATED THE CONCENTRATIONS AND METHYLATION RATES OF FREE-FLOATING DNA FRAGMENTS IN BRONCHOALVEOLAR LAVAGE FLUID (BALF) FROM DOGS WITH CHRONIC BRONCHITIS. BASED ON SERUM COTININE LEVELS, DOGS WITH CB WERE DIVIDED INTO 2 GROUPS: DOGS THAT EITHER HAD OR HAD NOT BEEN EXPOSED TO ETS. OUR RESULTS DEMONSTRATED THAT THE TOTAL NUCLEATED CELL AND MACROPHAGE NUMBERS INCREASED IN BALF OF ETS-EXPOSED DOGS WITH CB. THERE WERE NO SIGNIFICANT DIFFERENCES IN DNA CONCENTRATIONS AND METHYLATION RATES IN BALF BETWEEN THE 2 GROUPS. HOWEVER, 3 OUT OF 8 DOGS EXPOSED TO ETS HAD HIGH DNA METHYLATION RATES IN THEIR BALF SAMPLES. CONCLUSION: OUR RESULTS SUGGEST THAT ETS EXPOSURE LEADS TO EPIGENETIC MODIFICATIONS OF CELLULAR COMPONENTS IN BALF IN DOGS DIAGNOSED WITH CB. 2015 5 1118 37 COMPARATIVE GENOTYPING AND PHENOTYPING OF ASPERGILLUS FUMIGATUS ISOLATES FROM HUMANS, DOGS AND THE ENVIRONMENT. BACKGROUND: ASPERGILLUS FUMIGATUS IS A UBIQUITOUS SAPROTROPHIC FUNGUS AND AN OPPORTUNISTIC PATHOGEN OF HUMANS AND ANIMALS. HUMANS AND ANIMALS CAN INHALE HUNDREDS OF A. FUMIGATUS SPORES DAILY. NORMALLY THIS IS HARMLESS FOR HUMANS, BUT IN CASE OF IMMUNODEFICIENCY, INVASIVE PULMONARY ASPERGILLOSIS (IPA) CAN DEVELOP WITH A HIGH MORTALITY RATE. A. FUMIGATUS ALSO CAUSES NON-INVASIVE MYCOSES LIKE SINO-NASAL ASPERGILLOSIS (SNA) IN DOGS. RESULTS: IN THIS STUDY WE COMPARED A. FUMIGATUS ISOLATES FROM HUMANS WITH SUSPECTED IPA, DOGS WITH SNA, AND A SET OF ENVIRONMENTAL ISOLATES. PHYLOGENETIC INFERENCE BASED ON CALMODULIN (CAM) AND BETA-TUBULIN (BENA) SEQUENCES DID NOT REVEAL A. FUMIGATUS SUB-GROUPS LINKED TO THE ORIGIN OF THE ISOLATES. GENOTYPING AND MICROSATELLITE ANALYSIS SHOWED THAT EACH DOG WAS INFECTED BY ONE A. FUMIGATUS GENOTYPE, WHEREAS HUMAN PATIENTS HAD MIXED INFECTIONS. AZOLE RESISTANCE WAS DETERMINED BY ANTIFUNGAL SUSCEPTIBILITY TESTING AND SEQUENCING OF THE CYP51A GENE. A TOTAL OF 12 OUT OF 29 HUMAN ISOLATES AND 1 OUT OF 27 ENVIRONMENTAL ISOLATES WERE AZOLE RESISTANT. OF THE AZOLE RESISTANT STRAINS, 11 HUMAN ISOLATES SHOWED TR(34)/L98H (N = 6) OR TR46/Y121F/T289A (N = 5). PHENOTYPICALLY, ISOLATES FROM DOGS WERE MORE VARIABLE IN GROWTH SPEED AND MORPHOLOGY WHEN COMPARED TO THOSE ISOLATED FROM HUMAN AND THE ENVIRONMENT. CONCLUSIONS: 1. A. FUMIGATUS FROM DOGS WITH SNA ARE PHENOTYPICALLY VERY DIVERSE IN CONTRAST TO THEIR ENVIRONMENTAL AND HUMAN COUNTERPARTS. 2. PHENOTYPIC VARIABILITY CAN BE INDUCED DURING THE CHRONIC INFECTION PROCESS IN THE SINUS OF THE DOGS. THE BASIS OF THIS HETEROGENEITY MIGHT BE DUE TO GENOMIC DIFFERENCES AND/OR EPIGENETIC VARIATIONS. 3. DIFFERENCES IN DOGS IS A COULD BE A RESULT OF WITHIN-HOST ADAPTION AND MIGHT BE TRIGGERED BY ENVIRONMENTAL FACTORS IN THE SINUS, HOWEVER THIS HYPOTHESIS STILL NEEDS TO BE TESTED. 2018 6 5403 27 REGENERATION AFTER ACUTE KIDNEY INJURY REQUIRES PTIP-MEDIATED EPIGENETIC MODIFICATIONS. A TERMINALLY DIFFERENTIATED CELLULAR PHENOTYPE IS THOUGHT TO BE MAINTAINED, AT LEAST IN PART, BY BOTH ACTIVE AND REPRESSIVE HISTONE MARKS. HOWEVER, IT IS UNCLEAR WHETHER REGENERATING CELLS AFTER INJURY NEED TO REPLICATE SUCH EPIGENETIC MARKS TO RECOVER. TO TEST WHETHER RENAL EPITHELIAL CELL REGENERATION IS DEPENDENT ON HISTONE H3K4 METHYLATION, WE GENERATED A MOUSE MODEL THAT DELETED THE PAXIP1 GENE IN MATURE RENAL PROXIMAL TUBULES. PAXIP1 ENCODES PTIP, AN ESSENTIAL PROTEIN IN THE MLL3/4 HISTONE H3K4 METHYLTRANSFERASE COMPLEX. MICE WITH PTIP DELETIONS IN THE ADULT KIDNEY PROXIMAL TUBULES WERE VIABLE AND FERTILE. UPON ACUTE KIDNEY INJURY, SUCH MICE FAILED TO REGENERATE DAMAGED TUBULES, LEADING TO SCARRING AND INTERSTITIAL FIBROSIS. THE INABILITY TO REPAIR DAMAGE WAS LIKELY DUE TO A FAILURE TO REENTER MITOSIS AND REACTIVATE REGULATORY GENES SUCH AS SOX9. PTIP DELETION REDUCED HISTONE H3K4 METHYLATION IN UNINJURED ADULT KIDNEYS BUT DID NOT SIGNIFICANTLY AFFECT FUNCTION OR THE EXPRESSION OF EPITHELIAL SPECIFIC MARKERS. STRIKINGLY, CELL LINEAGE TRACING REVEALED THAT SURVIVING PTIP MUTANT CELLS COULD ALTER THEIR PHENOTYPE AND LOSE EPITHELIAL MARKERS. THESE DATA DEMONSTRATE THAT PTIP AND ASSOCIATED MLL3/4-MEDIATED HISTONE METHYLATION ARE NEEDED FOR REGENERATING PROXIMAL TUBULES AND TO MAINTAIN OR REESTABLISH THE CELLULAR EPITHELIAL PHENOTYPE. 2020 7 5675 22 SHIFTS IN PODOCYTE HISTONE H3K27ME3 REGULATE MOUSE AND HUMAN GLOMERULAR DISEASE. HISTONE PROTEIN MODIFICATIONS CONTROL FATE DETERMINATION DURING NORMAL DEVELOPMENT AND DEDIFFERENTIATION DURING DISEASE. HERE, WE SET OUT TO DETERMINE THE EXTENT TO WHICH DYNAMIC CHANGES TO HISTONES AFFECT THE DIFFERENTIATED PHENOTYPE OF ORDINARILY QUIESCENT ADULT GLOMERULAR PODOCYTES. TO DO THIS, WE EXAMINED THE CONSEQUENCES OF SHIFTING THE BALANCE OF THE REPRESSIVE HISTONE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3) MARK IN PODOCYTES. ADRIAMYCIN NEPHROTOXICITY AND SUBTOTAL NEPHRECTOMY (SNX) STUDIES INDICATED THAT DELETION OF THE HISTONE METHYLATING ENZYME EZH2 FROM PODOCYTES DECREASED H3K27ME3 LEVELS AND SENSITIZED MICE TO GLOMERULAR DISEASE. H3K27ME3 WAS ENRICHED AT THE PROMOTER REGION OF THE NOTCH LIGAND JAG1 IN PODOCYTES, AND DEREPRESSION OF JAG1 BY EZH2 INHIBITION OR KNOCKDOWN FACILITATED PODOCYTE DEDIFFERENTIATION. CONVERSELY, INHIBITION OF THE JUMONJI C DOMAIN-CONTAINING DEMETHYLASES JMJD3 AND UTX INCREASED THE H3K27ME3 CONTENT OF PODOCYTES AND ATTENUATED GLOMERULAR DISEASE IN ADRIAMYCIN NEPHROTOXICITY, SNX, AND DIABETES. PODOCYTES IN GLOMERULI FROM HUMANS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS OR DIABETIC NEPHROPATHY EXHIBITED DIMINISHED H3K27ME3 AND HEIGHTENED UTX CONTENT. ANALOGOUS TO HUMAN DISEASE, INHIBITION OF JMJD3 AND UTX ABATED NEPHROPATHY PROGRESSION IN MICE WITH ESTABLISHED GLOMERULAR INJURY AND REDUCED H3K27ME3 LEVELS. TOGETHER, THESE FINDINGS INDICATE THAT OSTENSIBLY STABLE CHROMATIN MODIFICATIONS CAN BE DYNAMICALLY REGULATED IN QUIESCENT CELLS AND THAT EPIGENETIC REPROGRAMMING CAN IMPROVE OUTCOMES IN GLOMERULAR DISEASE BY REPRESSING THE REACTIVATION OF DEVELOPMENTAL PATHWAYS. 2018 8 868 20 CHRONIC ADVANCED-GLYCATION END PRODUCTS TREATMENT INDUCES TXNIP EXPRESSION AND EPIGENETIC CHANGES IN GLOMERULAR PODOCYTES IN VIVO AND IN VITRO. ADVANCED GLYCATION END PRODUCTS (AGES) PLAY AN IMPORTANT ROLE IN OXIDATIVE STRESS AND INFLAMMATION, PROCESSES IMPLICATED IN THE DEVELOPMENT AND PROGRESSION OF KIDNEY DYSFUNCTION. IN THE PRESENT STUDY, WE INVESTIGATED THE PARTICIPATION OF THE PRO-OXIDANT PROTEIN THIOREDOXIN-INTERACTING PROTEIN (TXNIP) AND OF EPIGENETIC MECHANISMS ON KIDNEY TISSUE (IN VIVO, IN NON-DIABETIC RATS) AND ON TERMINALLY DIFFERENTIATED GLOMERULAR PODOCYTES (IN VITRO) CHRONICALLY EXPOSED TO AGES. AGES INDUCED TOTAL KIDNEY AND GLOMERULAR TXNIP EXPRESSION AND DECREASED H3K27ME3 CONTENT. CONCOMITANT TREATMENT WITH THE ANTIOXIDANT N-ACETYL-CYSTEINE (NAC) REVERSED ONLY THE INCREASED TXNIP EXPRESSION. TXNIP EXPRESSION POSITIVELY CORRELATED WITH PROTEINURIA AND NEGATIVELY CORRELATED WITH H3K27ME3 CONTENT. IN VITRO STUDIES IN PODOCYTES SHOWED THAT 72 H EXPOSURE TO AGES DECREASED NEPHRIN EXPRESSION AND INCREASED TXNIP, NOX4, COL4A1, AND EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) MARKERS (ACTA2, SNAIL1, AND TGFB1). PODOCYTES TREATMENT WITH NAC REVERSED NOX4, COL4A1, ACTA2, AND TGFB1 INCREASED EXPRESSION BUT DID NOT ABROGATE THE REDUCED EXPRESSION OF NEPHRIN. MIR-29A EXPRESSION WAS DOWNREGULATED BY AGES IN VIVO, BUT NOT IN VITRO. IN CONCLUSION, TREATMENT OF NON-DIABETIC RATS WITH AGES INDUCED TXNIP EXPRESSION AND DECREASED THE CONTENTS OF THE REPRESSIVE EPIGENETIC MARK H3K27ME3 AND OF MIR-29A, POTENTIALLY DRIVING INJURY TO GLOMERULAR FILTRATION BARRIER AND PODOCYTES DYSFUNCTION. 2021 9 6693 28 VARIABLE INDUCTION OF PRDM1 AND DIFFERENTIATION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH ANERGY. DESPITE ANTIGEN ENGAGEMENT AND INTACT B-CELL-RECEPTOR (BCR) SIGNALING, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS FAIL TO UNDERGO TERMINAL DIFFERENTIATION. WE HYPOTHESIZED THAT SUCH FAILURE MAY BE DUE TO ANERGY, AS CLL CELLS EXHIBIT VARIABLE LEVELS OF NONRESPONSIVENESS TO SURFACE IGM STIMULATION THAT IS REVERSIBLE IN VITRO. MOREOVER, ANERGY IS ASSOCIATED WITH REDUCED DIFFERENTIATION CAPACITY IN NORMAL B CELLS. WE INVESTIGATED RESPONSES OF CLL CELLS TO TWO POTENT DIFFERENTIATION-PROMOTING AGENTS, IL-21 AND CYTOSINE GUANINE DINUCLEOTIDE-ENRICHED OLIGO-DEOXYNUCLEOTIDES. THE INDUCTION OF PR DOMAIN-CONTAINING PROTEIN 1 (PRDM1; ALSO KNOWN AS BLIMP-1), A CRITICAL REGULATOR OF PLASMACYTIC DIFFERENTIATION, BY THESE AGENTS WAS CLOSELY CORRELATED BUT VARIED BETWEEN INDIVIDUAL CASES, DESPITE FUNCTIONALLY INTACT IL-21 RECEPTOR- AND TOLL-LIKE RECEPTOR 9-MEDIATED SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3, AND NUCLEAR FACTOR-KAPPAB PATHWAYS. PRDM1 INDUCTION WAS INVERSELY CORRELATED WITH THE EXTENT OF ANERGY AS MEASURED BY THE ABILITY TO MOBILIZE INTRACELLULAR CA(2+) FOLLOWING BCR CROSSLINKING. PRDM1 RESPONSIVENESS WAS ASSOCIATED WITH OTHER MARKERS OF DIFFERENTIATION AND PROLIFERATION BUT NOT WITH DIFFERENCES IN APOPTOSIS. THE ABILITY TO INDUCE PRDM1 DID CORRELATE WITH DIFFERENTIAL TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF THE PRDM1 GENE. THESE STUDIES EXTEND OUR UNDERSTANDING OF CLL PATHOBIOLOGY, DEMONSTRATING THAT REDUCED DIFFERENTIATION CAPACITY MAY BE A CONSEQUENCE OF ANERGY. EPIGENETIC DRUGS MAY OFFER POSSIBILITIES TO REACTIVATE PRDM1 EXPRESSION AS PART OF NOVEL DIFFERENTIATION THERAPY APPROACHES. 2014 10 6544 30 TRANSCRIPTOMIC AND EPIGENETIC ALTERATIONS IN DENDRITIC CELLS CORRESPOND WITH CHRONIC KIDNEY DISEASE IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A SERIOUS AUTOIMMUNE DISEASE WITH VARIETY OF ORGAN MANIFESTATIONS. THE MOST DREADFUL ONE, AFFECTING THE MAJORITY OF SLE PATIENTS, IS KIDNEY MANIFESTATION-LUPUS NEPHRITIS (LN). DENDRITIC CELLS (DC) ARE BELIEVED TO BE ONE OF THE CULPRITS OF IMMUNE DYSREGULATION IN LN. FLOW CYTOMETRY ANALYSIS WAS APPLIED TO IDENTIFY THE FREQUENCY AND ACTIVITY OF PERIPHERAL BLOOD DCS SUBPOPULATIONS: MYELOID AND PLASMACYTOID, IN LN PATIENTS. MAGNETICALLY ISOLATED MDCS AND PDCS WERE SUBJECTED TO MOLECULAR ANALYSIS OF GENES EXPRESSION, EVALUATION OF GLOBAL DNA METHYLATION AND HISTONE H3 METHYLATION. WE OBSERVED DISTINCTIVE FEATURES OF DCS ASSOCIATED WITH THE STAGES OF NEPHRITIS IN LN PATIENTS. LOWER NUMBERS OF PDCS WERE OBSERVED IN PATIENTS WITH SEVERE LN, WHILE INCREASED CO-STIMULATORY POTENTIAL OF MDCS WAS CONNECTED WITH THE EARLY, MILD STAGE OF THIS DISEASE. IRF1 TRANSCRIPT UPREGULATION WAS SPECIFIC FOR MDCS FROM TOTAL LN PATIENTS, WHILE EXCEPTIONAL AMOUNT OF IRF1 MRNA WAS DETECTED IN MDCS FROM SEVERE LN PATIENTS. DCS DNA HYPERMETHYLATION SEEMED CHARACTERISTIC FOR SEVERE LN, WHEREAS A DECREASE IN H3K4ME3 AND H3K27ME3 MARKS WAS SIGNIFICANT FOR THE EARLY STAGES OF LN. THESE FINDINGS PRESENT DENDRITIC CELL ALTERATIONS THAT MAY REFLECT RENAL INVOLVEMENT IN SLE, LAYING FOUNDATIONS FOR NEW STRATEGY OF DIAGNOSIS AND MONITORING OF LN PATIENTS, OMITTING INVASIVE KIDNEY BIOPSIES. 2019 11 1194 37 CORRELATION OF EPIGENETIC CHANGE AND IDENTIFICATION OF RISK FACTORS FOR ORAL SUBMUCOUS FIBROSIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES IS AN EPIGENETIC CHANGE THAT IS ESSENTIAL FOR TUMORIGENESIS. ORAL SUBMUCOUS FIBROSIS (OSF) IS A PRECANCEROUS CONDITION OF ORAL MUCOSA WITH INFLAMMATION AND PROGRESSIVE FIBROSIS OF THE LAMINA PROPRIA AND DEEPER CONNECTIVE TISSUE. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION MAY DEMONSTRATE A MILD LESION/MUTATION AT EPIGENETIC LEVELS. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES IN PATIENTS WITH ORAL CANCER AND PATIENTS WITH OSF AND ALSO AIMS TO IDENTIFY RISK FACTORS FOR THE DEVELOPMENT OF OSF. METHODS: DNA WAS EXTRACTED FROM BLOOD SAMPLES OF 50 HEALTHY SUBJECTS, 50 PATIENTS WITH OSF AND 60 PATIENTS WITH ORAL CANCER. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. SURVEYS ABOUT ORAL HEALTH HABITS AND CLINICAL PERIODONTAL EXAMINATIONS IN PATIENTS WITH OSF AND HEALTHY SUBJECTS WERE ALSO CONDUCTED BY WELL-TRAINED DENTISTS, AND LOGISTIC REGRESSION WAS PERFORMED TO IDENTIFY RISK FACTORS FOR OSF. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 36% AND 22% OF ORAL CANCER SAMPLES, RESPECTIVELY. IN PATIENTS WITH OSF, THE RATES WERE 52% AND 30%, AND IN HEALTHY CONTROLS THE RATES WERE 4% AND 6%. HYPERMETHYLATION WAS SHOWN TO BE CORRELATED BETWEEN THE 3 GROUPS WITH STATISTICAL SIGNIFICANCE (P<0.01). METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 OCCURRED MORE FREQUENTLY IN PATIENTS WITH OSF THAN IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN PATIENTS WITH ORAL CANCER. IN THE LOGISTIC REGRESSION ANALYSIS, SMOKING, BRUSHING MORE THAN TWICE DAILY, PERIODONTAL PROBING DEPTH AND PLAQUE INDEX WERE IDENTIFIED AS 4 MAJOR RISK FACTORS FOR OSF. CONCLUSIONS: THESE DATA CONFIRM THAT E-CADHERIN AND COX-2 EXPRESSIONS ARE RELATED TO OSF. THE EPIGENETIC CHANGES PRESENTED IN PATIENTS WITH CHRONIC INFLAMMATION MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC OSF WAS SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION, A CANCER RISK FACTOR. 2012 12 4485 32 MOLECULAR SIMILARITY BETWEEN MYELODYSPLASTIC FORM OF CHRONIC MYELOMONOCYTIC LEUKEMIA AND REFRACTORY ANEMIA WITH RING SIDEROBLASTS. CHRONIC MYELOMONOCYTIC LEUKEMIA IS SIMILAR TO BUT A SEPARATE ENTITY FROM BOTH MYELOPROLIFERATIVE NEOPLASMS AND MYELODYSPLASTIC SYNDROMES, AND SHOWS EITHER MYELOPROLIFERATIVE OR MYELODYSPLASTIC FEATURES. WE ASK WHETHER THIS DISTINCTION MAY HAVE A MOLECULAR BASIS. WE ESTABLISHED THE GENE EXPRESSION PROFILES OF 39 SAMPLES OF CHRONIC MYELOMONOCYTIC LEUKEMIA (INCLUDING 12 CD34-POSITIVE) AND 32 CD34-POSITIVE SAMPLES OF MYELODYSPLASTIC SYNDROMES BY USING AFFYMETRIX MICROARRAYS, AND STUDIED THE STATUS OF 18 GENES BY SANGER SEQUENCING AND ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION IN 53 SAMPLES. ANALYSIS OF 12 MRNAS FROM CHRONIC MYELOMONOCYTIC LEUKEMIA ESTABLISHED A GENE EXPRESSION SIGNATURE OF 122 PROBE SETS DIFFERENTIALLY EXPRESSED BETWEEN PROLIFERATIVE AND DYSPLASTIC CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA. AS COMPARED TO PROLIFERATIVE CASES, DYSPLASTIC CASES OVER-EXPRESSED GENES INVOLVED IN RED BLOOD CELL BIOLOGY. WHEN APPLIED TO 32 MYELODYSPLASTIC SYNDROMES, THIS GENE EXPRESSION SIGNATURE WAS ABLE TO DISCRIMINATE REFRACTORY ANEMIAS WITH RING SIDEROBLASTS FROM REFRACTORY ANEMIAS WITH EXCESS OF BLASTS. BY COMPARING MRNAS FROM THESE TWO FORMS OF MYELODYSPLASTIC SYNDROMES WE DERIVED A SECOND GENE EXPRESSION SIGNATURE. THIS SIGNATURE SEPARATED THE MYELODYSPLASTIC AND MYELOPROLIFERATIVE FORMS OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. THESE RESULTS WERE VALIDATED USING TWO INDEPENDENT GENE EXPRESSION DATA SETS. WE FOUND THAT MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS ARE CHARACTERIZED BY MUTATIONS IN TRANSCRIPTION/EPIGENETIC REGULATORS (ASXL1, RUNX1, TET2) AND SPLICING GENES (SRSF2) AND THE ABSENCE OF MUTATIONS IN SIGNALING GENES. MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS AND REFRACTORY ANEMIAS WITH RING SIDEROBLASTS SHARE A COMMON EXPRESSION PROGRAM SUGGESTING THEY ARE PART OF A CONTINUUM, WHICH IS NOT TOTALLY EXPLAINED BY THEIR SIMILAR BUT NOT, HOWEVER, IDENTICAL MUTATION SPECTRUM. 2013 13 1585 36 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN DIABETES PATIENTS WITH ESRD AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED POTENTIAL EPIGENETIC BIOMARKERS FOR CHRONIC KIDNEY DISEASE PROGRESSION BY COMPARING SITE-SPECIFIC DNA METHYLATION LEVELS IN MORE THAN 14,000 GENES BETWEEN AFRICAN AMERICAN AND HISPANIC DIABETES PATIENTS WITH END STAGE RENAL DISEASE (ESRD) AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED 187 GENES THAT ARE DIFFERENTIALLY METHYLATED BETWEEN THE TWO GROUPS ON AT LEAST TWO CPG SITES IN EACH GENE IN DNA EXTRACTED FROM SALIVA. OF THE 187 GENES WHOSE MEAN METHYLATION LEVELS DIFFERED BETWEEN THE TWO GROUPS, 39 GENES, OR CLOSELY RELATED GENE FAMILY MEMBERS, HAVE BEEN REPORTED TO BE INVOLVED IN KIDNEY DEVELOPMENT OR DIABETIC NEPHROPATHY, PER SE, OR HAVE BEEN ASSOCIATED WITH DIALYSIS-INDUCED CHANGES IN GENE EXPRESSION IN PERIPHERAL BLOOD CELLS. THE FACT THAT SUCH A SUBSTANTIAL FRACTION (21%) OF THE 187 CANDIDATE GENES HAVE BEEN IMPLICATED PREVIOUSLY THROUGH GENOME ASSOCIATION OR TRANSCRIPTION PROFILING STUDIES SUGGESTS STRONGLY THAT THE DNA METHYLATION DIFFERENCES WE OBSERVE ARE ASSOCIATED WITH DISEASE PREDISPOSITION AND/OR TREATMENT. THE FACT THAT THESE NEPHROPATHY AND/OR DIALYSIS-ASSOCIATED DIFFERENCES BETWEEN PATIENTS WERE IDENTIFIED IN DNA EXTRACTED FROM SALIVA OFFERS PROOF-OF-PRINCIPLE THAT INTER-INDIVIDUAL EPIGENETIC DIFFERENCES MAY PROVE USEFUL AS PREDICTIVE BIOMARKERS OF DISEASE SUSCEPTIBILITY. 2011 14 406 35 ANALYSIS OF FIVE CHRONIC INFLAMMATORY DISEASES IDENTIFIES 27 NEW ASSOCIATIONS AND HIGHLIGHTS DISEASE-SPECIFIC PATTERNS AT SHARED LOCI. WE SIMULTANEOUSLY INVESTIGATED THE GENETIC LANDSCAPE OF ANKYLOSING SPONDYLITIS, CROHN'S DISEASE, PSORIASIS, PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS TO INVESTIGATE PLEIOTROPY AND THE RELATIONSHIP BETWEEN THESE CLINICALLY RELATED DISEASES. USING HIGH-DENSITY GENOTYPE DATA FROM MORE THAN 86,000 INDIVIDUALS OF EUROPEAN ANCESTRY, WE IDENTIFIED 244 INDEPENDENT MULTIDISEASE SIGNALS, INCLUDING 27 NEW GENOME-WIDE SIGNIFICANT SUSCEPTIBILITY LOCI AND 3 UNREPORTED SHARED RISK LOCI. COMPLEX PLEIOTROPY WAS SUPPORTED WHEN CONTRASTING MULTIDISEASE SIGNALS WITH EXPRESSION DATA SETS FROM HUMAN, RAT AND MOUSE TOGETHER WITH EPIGENETIC AND EXPRESSED ENHANCER PROFILES. THE COMORBIDITIES AMONG THE FIVE IMMUNE DISEASES WERE BEST EXPLAINED BY BIOLOGICAL PLEIOTROPY RATHER THAN HETEROGENEITY (A SUBGROUP OF CASES GENETICALLY IDENTICAL TO THOSE WITH ANOTHER DISEASE, POSSIBLY OWING TO DIAGNOSTIC MISCLASSIFICATION, MOLECULAR SUBTYPES OR EXCESSIVE COMORBIDITY). IN PARTICULAR, THE STRONG COMORBIDITY BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL DISEASE IS LIKELY THE RESULT OF A UNIQUE DISEASE, WHICH IS GENETICALLY DISTINCT FROM CLASSICAL INFLAMMATORY BOWEL DISEASE PHENOTYPES. 2016 15 5994 30 TGFBETA-INCURRED EPIGENETIC ABERRATIONS OF MIRNA AND DNA METHYLTRANSFERASE SUPPRESS KLOTHO AND POTENTIATE RENAL FIBROSIS. RENAL FIBROSIS IS A COMMON PATHOLOGICAL FEATURE OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS SUCH AS ABERRANT MIRNA AND DNA METHYLATION. KLOTHO IS AN ANTI-AGING AND ANTI-FIBROTIC PROTEIN AND ITS EARLY DECLINE AFTER RENAL INJURY IS REPORTEDLY ASSOCIATED WITH ABERRANT DNA METHYLATION. HOWEVER, THE KEY UPSTREAM PATHOLOGICAL MEDIATORS AND THE MOLECULAR CASCADE LEADING TO EPIGENETIC KLOTHO SUPPRESSION ARE NOT EXCLUSIVELY ESTABLISHED. HERE WE INVESTIGATE THE EPIGENETIC MECHANISM OF KLOTHO DEFICIENCY AND ITS FUNCTIONAL RELEVANCE IN RENAL FIBROGENESIS. FIBROTIC KIDNEYS INDUCED BY UNILATERAL URETERAL OCCLUSION (UUO) DISPLAYED MARKED KLOTHO SUPPRESSION AND THE PROMOTER HYPERMETHYLATION. THESE ABNORMALITIES WERE LIKELY DUE TO DEREGULATED TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) SINCE TGFBETA ALONE CAUSED THE SIMILAR EPIGENETIC ABERRATIONS IN CULTURED RENAL CELLS AND TGFBETA BLOCKADE PREVENTED THE ALTERATIONS IN UUO KIDNEY. FURTHER INVESTIGATION REVEALED THAT TGFBETA ENHANCED DNA METHYLTRANSFERASE (DNMT) 1 AND DNMT3A VIA INHIBITING MIR-152 AND MIR-30A IN BOTH RENAL CELLS AND FIBROTIC KIDNEYS. ACCORDINGLY THE BLOCKADE OF EITHER TGFBETA SIGNALING OR DNMT1/3A ACTIVITIES SIGNIFICANTLY RECOVERED THE KLOTHO LOSS AND ATTENUATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS. MOREOVER, KLOTHO KNOCKDOWN BY RNA INTERFERENCES ABOLISHED THE ANTI-FIBROTIC EFFECTS OF DNMT INHIBITION IN BOTH TGFBETA-TREATED RENAL CELL AND UUO KIDNEY, INDICATING THAT TGFBETA-MEDIATED MIR-152/30A INHIBITIONS, DNMT1/3A ABERRATIONS AND SUBSEQUENT KLOTHO LOSS CONSTITUTE A CRITICAL REGULATORY LOOP THAT ELIMINATES KLOTHO'S ANTI-FIBROTIC ACTIVITIES AND POTENTIATES RENAL FIBROGENESIS. THUS, OUR STUDY ELABORATES A NOVEL EPIGENETIC CASCADE OF RENAL FIBROGENESIS AND REVEALS THE POTENTIAL THERAPEUTIC TARGETS FOR TREATING THE RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. 2017 16 118 31 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY. 2012 17 1114 29 COMMONALITIES AND DISPARITIES BETWEEN ENDOMETRIOSIS AND CHRONIC ENDOMETRITIS: THERAPEUTIC POTENTIAL OF NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ECTOPIC ENDOMETRIUM. CHRONIC ENDOMETRITIS (CE) IS A LOCAL MUCOSAL INFLAMMATORY DISORDER OF THE UTERINE LINING, WHICH IS HISTOPATHOLOGICALLY RECOGNIZED AS THE UNUSUAL INFILTRATION OF CD138(+) PLASMACYTES INTO THE ENDOMETRIAL STROMAL COMPARTMENT. ACCUMULATING BODY OF RESEARCH DOCUMENTED THAT CE IS ASSOCIATED WITH FEMALE INFERTILITY AND SEVERAL OBSTETRIC/NEONATAL COMPLICATIONS. THE MAJOR CAUSE OF CE IS THOUGHT TO BE INTRAUTERINE INFECTION REPRESENTED BY COMMON BACTERIA (ESCHERICHIA COLI, ENTEROCOCCUS FAECALIS, STREPTOCOCCUS, AND STAPHYLOCOCCUS), MYCOPLASMA/UREAPLASMA, AND MYCOBACTERIUM. ADDITIONALLY, LOCAL DYSBIOSIS IN THE FEMALE REPRODUCTIVE TRACT MAY BE INVOLVED IN THE ONSET AND DEVELOPMENT OF CE. ANTIBIOTIC TREATMENTS AGAINST THESE MICROORGANISMS ARE EFFECTIVE IN THE ELIMINATION OF ENDOMETRIAL STROMAL PLASMACYTES IN THE AFFECTED PATIENTS. MEANWHILE, ENDOMETRIOSIS IS A COMMON FEMALE REPRODUCTIVE TRACT DISEASE CHARACTERIZED BY ENDOMETRIOTIC TISSUES (ECTOPIC ENDOMETRIUM) GROWING OUTSIDE THE UTERUS AND POTENTIALLY CAUSES CHRONIC PELVIC SYMPTOMS (DYSMENORRHEA, DYSPAREUNIA, DYSCHEZIA, AND DYSURIA), INFERTILITY, AND OVARIAN CANCERS. ENDOMETRIOSIS INVOLVES ENDOCRINOLOGICAL, GENETIC, AND EPIGENETIC FACTORS IN ITS ETIOLOGY AND PATHOGENESIS. RECENT STUDIES FOCUS ON IMMUNOLOGICAL, INFLAMMATORY, AND INFECTIOUS ASPECTS OF ENDOMETRIOSIS AND DEMONSTRATE SEVERAL COMMON CHARACTERISTICS BETWEEN ENDOMETRIOSIS AND CE. THIS REVIEW AIMED TO BETTER UNDERSTAND THE IMMUNOLOGICAL AND MICROBIAL BACKGROUNDS UNDERLYING ENDOMETRIOSIS AND CE AND LOOK INTO THE THERAPEUTIC POTENTIAL OF THE NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ENDOMETRIOSIS IN LIGHT OF ENDOMETRIAL INFECTIOUS DISEASE. 2023 18 203 24 ACTIVATION OF EPIGENETIC REGULATOR KDM6B BY SALMONELLA TYPHIMURIUM ENABLES CHRONIC INFECTIONS. NON-TYPHOIDAL SALMONELLA (NTS) INFECTIONS RESULT IN SELF LIMITING GASTROENTERITIS EXCEPT IN RARE CASES WHEREIN MANIFESTATIONS OF CHRONIC INFECTIONS CAN OCCUR. STRATEGIES EMPLOYED BY SALMONELLA TO THRIVE IN HOSTILE ENVIRONMENTS OF HOST DURING CHRONIC INFECTIONS ARE COMPLEX AND MULTIFACETED. IN CHRONIC STATE, A COORDINATED ACTION OF BACTERIAL EFFECTORS ALLOWS REPROGRAMMING OF MACROPHAGES TO M2 SUBTYPE AND THEREBY CREATING A PERMISSIBLE REPLICATIVE NICHE. THE MECHANISTIC DETAILS OF THESE PROCESSES ARE NOT FULLY KNOWN. IN THE CURRENT STUDY WE IDENTIFIED, HISTONE H3-LYSINE 27 TRIMETHYLATION (H3K27ME3)-SPECIFIC DEMETHYLASE, KDM6B TO BE UPREGULATED IN BOTH CELL CULTURE AND IN MURINE MODEL OF SALMONELLA INFECTION. KDM6B RECRUITMENT UPON INFECTION EXHIBITED AN ASSOCIATED LOSS OF OVERALL H3K27ME3 IN HOST CELLS AND WAS SALMONELLA SPI1 EFFECTORS COORDINATED. CHIP-QRT-PCR ARRAY ANALYSIS REVEALED SEVERAL NEW GENE PROMOTER TARGETS OF KDM6B DEMETHYLASE ACTIVITY INCLUDING PPARDELTA, A CRUCIAL REGULATOR OF FATTY ACID OXIDATION PATHWAY AND SALMONELLA-PERSISTENT INFECTIONS. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF KDM6B DEMETHYLASE ACTIVITY WITH GSKJ4 IN CHRONIC SALMONELLA INFECTION MICE MODEL LED TO A SIGNIFICANT REDUCTION IN PATHOGEN LOAD AND M2 MACROPHAGE POLARIZATION IN PERIPHERAL LYMPHOID ORGANS. THE FOLLOWING WORK THUS REVEALS SALMONELLA EFFECTOR-MEDIATED EPIGENETIC REPROGRAMMING OF MACROPHAGES RESPONSIBLE FOR ITS LONG-TERM SURVIVAL AND CHRONIC CARRIAGE. 2021 19 273 27 AGE-INDUCED SUPPRESSION OF EZH2 MEDIATES INJURY OF PODOCYTES BY REDUCING H3K27ME3. BACKGROUND: CHRONIC HYPERGLYCEMIA, A PIVOTAL FEATURE OF DIABETES MELLITUS (DM), INITIATES THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) AND THE DYSREGULATION OF EPIGENETIC MECHANISMS, WHICH MAY CAUSE INJURY TO RENAL PODOCYTES, A CENTRAL FEATURE OF DIABETIC KIDNEY DISEASE (DKD). PREVIOUS DATA OF OUR GROUP SHOWED THAT AGES SIGNIFICANTLY REDUCE THE EXPRESSION OF NIPP1 (NUCLEAR INHIBITOR OF PROTEIN PHOSPHATASE 1) IN PODOCYTES IN VITRO AS WELL AS IN HUMAN AND MURINE DKD. NIPP1 WAS SHOWN BY OTHERS TO INTERACT WITH ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE REPRESSIVE METHYLATION OF H3K27ME3 ON HISTONE 3. THEREFORE, WE HYPOTHESIZED THAT AGES CAN DIRECTLY INDUCE EPIGENETIC CHANGES IN PODOCYTES. METHODS: WE ANALYZED THE RELEVANCE OF AGES ON EZH2 EXPRESSION AND ACTIVITY IN A MURINE PODOCYTE CELL LINE. CELLS WERE TREATED WITH 5 MG/ML GLYCATED BSA FOR 24 H. TO DETERMINE THE MEANING OF EZH2 SUPPRESSION, EZH2 ACTIVITY WAS INHIBITED BY INCUBATING THE CELLS WITH THE PHARMACOLOGICAL METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A; EZH2 EXPRESSION WAS REPRESSED WITH SIRNA. MRNA EXPRESSION WAS ANALYZED WITH REAL-TIME PCR, AND PROTEIN EXPRESSION WITH WESTERN BLOT. EZH2 EXPRESSION AND LEVEL OF H3K27 TRIMETHYLATION IN PODOCYTES OF DIABETIC DB/DB MICE, A MOUSE MODEL FOR TYPE 2 DM, WERE ANALYZED USING IMMUNOFLUORESCENCE. RESULTS: OUR DATA DEMONSTRATED THAT AGES DECREASE EZH2 EXPRESSION IN PODOCYTES AND CONSEQUENTLY REDUCE H3K27ME3. THIS SUPPRESSION OF EZH2 MIMICKED THE AGE EFFECTS AND CAUSED AN UPREGULATED EXPRESSION OF PATHOLOGICAL FACTORS THAT CONTRIBUTE TO PODOCYTE INJURY IN DKD. IN ADDITION, ANALYSES OF DB/DB MICE SHOWED SIGNIFICANTLY REDUCED H3K27ME3 AND EZH2 EXPRESSION IN PODOCYTES. MOREOVER, THE SUPPRESSION OF NIPP1 AND EZH2 SHOWED SIMILAR EFFECTS REGARDING PODOCYTE INJURY. CONCLUSIONS: OUR STUDIES PROVIDE A NOVEL PATHWAY HOW AGES CONTRIBUTE TO PODOCYTE INJURY AND THE FORMATION OF THE SO-CALLED METABOLIC MEMORY IN DKD. 2020 20 1107 33 COMBINING CYTOGENETIC AND EPIGENETIC APPROACHES IN CHRONIC LYMPHOCYTIC LEUKEMIA IMPROVES PROGNOSIS PREDICTION FOR PATIENTS WITH ISOLATED 13Q DELETION. BACKGROUND: BOTH DEFECTIVE DNA METHYLATION AND ACTIVE DNA DEMETHYLATION PROCESSES ARE EMERGING AS IMPORTANT RISK FACTORS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, ASSOCIATIONS BETWEEN 5-CYTOSINE EPIGENETIC MARKERS AND THE MOST FREQUENT CHROMOSOMAL ABNORMALITIES DETECTED IN CLL REMAIN TO BE ESTABLISHED. METHODS: CLL PATIENTS WERE RETROSPECTIVELY CLASSIFIED INTO A CYTOGENETIC LOW-RISK GROUP (ISOLATED 13Q DELETION), AN INTERMEDIATE-RISK GROUP (NORMAL KARYOTYPE OR TRISOMY 12), AND A HIGH-RISK GROUP (11Q DELETION, 17P DELETION, OR COMPLEX KARYOTYPE [>/= 3 BREAKPOINTS]). THE TWO 5-CYTOSINE DERIVATIVES, 5-METHYLCYTOSINE (5-MCYT) AND 5-HYDROXYMETHYLCYTOSINE (5-HMCYT), WERE TESTED BY ELISA (N = 60), WHILE REAL-TIME QUANTITATIVE PCR WAS USED FOR DETERMINING TRANSCRIPTIONAL EXPRESSION LEVELS OF DNMT AND TET (N = 24). RESULTS: BY USING GLOBAL DNA METHYLATION/DEMETHYLATION LEVELS, IN THE LOW-RISK DISEASE GROUP, TWO SUBGROUPS WITH SIGNIFICANTLY DIFFERENT CLINICAL OUTCOMES HAVE BEEN IDENTIFIED (MEDIAN TREATMENT-FREE SURVIVAL [TFS] 45 VERSUS > 120 MONTHS FOR 5-MCYT, P = 0.0008, AND 63 VERSUS > 120 MONTHS FOR 5-HMCYT, P = 0.04). A DEFECTIVE 5-MCYT STATUS WAS FURTHER ASSOCIATED WITH A HIGHER PERCENTAGE OF 13Q DELETED NUCLEI (> 80%), THUS SUGGESTING AN ACQUIRED PROCESS. WHEN CONSIDERING THE CYTOGENETIC INTERMEDIATE/HIGH-RISK DISEASE GROUPS, AN ASSOCIATION OF 5-MCYT STATUS WITH LYMPHOCYTOSIS (P = 0.0008) AND THE LYMPHOCYTE DOUBLING TIME (P = 0.04) BUT NOT WITH TFS WAS OBSERVED, AS WELL AS A REDUCTION OF DNMT3A, TET1, AND TET2 TRANSCRIPTS. CONCLUSIONS: COMBINING CYTOGENETIC STUDIES WITH 5-MCYT ASSESSMENT ADDS ACCURACY TO CLL PATIENTS' PROGNOSES AND PARTICULARLY FOR THOSE WITH 13Q DELETION AS A SOLE CYTOGENETIC ABNORMALITY. 2017