1  1154 149 CONSERVED DNA METHYLATION PATTERNS IN HEALTHY BLOOD CELLS AND EXTENSIVE CHANGES IN LEUKEMIA MEASURED BY A NEW QUANTITATIVE TECHNIQUE. GENOME WIDE ANALYSIS OF DNA METHYLATION PROVIDES IMPORTANT INFORMATION IN A VARIETY OF DISEASES, INCLUDING CANCER. HERE, WE DESCRIBE A SIMPLE METHOD, DIGITAL RESTRICTION ENZYME ANALYSIS OF METHYLATION (DREAM), BASED ON NEXT GENERATION SEQUENCING ANALYSIS OF METHYLATION-SPECIFIC SIGNATURES CREATED BY SEQUENTIAL DIGESTION OF GENOMIC DNA WITH SMAI AND XMAI ENZYMES. DREAM PROVIDES INFORMATION ON 150,000 UNIQUE CPG SITES, OF WHICH 39,000 ARE IN CPG ISLANDS AND 30,000 ARE AT TRANSCRIPTION START SITES OF 13,000 REFSEQ GENES. WE ANALYZED DNA METHYLATION IN HEALTHY WHITE BLOOD CELLS AND FOUND METHYLATION PATTERNS TO BE REMARKABLY UNIFORM. INTER INDIVIDUAL DIFFERENCES > 30% WERE OBSERVED ONLY AT 227 OF 28,331 (0.8%) OF AUTOSOMAL CPG SITES. SIMILARLY, > 30% DIFFERENCES WERE OBSERVED AT ONLY 59 SITES WHEN WE COMPARING THE CORD AND ADULT BLOOD. THESE CONSERVED METHYLATION PATTERNS CONTRASTED WITH EXTENSIVE CHANGES AFFECTING 18-40% OF CPG SITES IN A PATIENT WITH ACUTE MYELOID LEUKEMIA AND IN TWO LEUKEMIA CELL LINES. THE METHOD IS COST EFFECTIVE, QUANTITATIVE (R ( 2) = 0.93 WHEN COMPARED WITH BISULFITE PYROSEQUENCING) AND REPRODUCIBLE (R ( 2) = 0.997). USING 100-FOLD COVERAGE, DREAM CAN DETECT DIFFERENCES IN METHYLATION GREATER THAN 10% OR 30% WITH A FALSE POSITIVE RATE BELOW 0.05 OR 0.001, RESPECTIVELY. DREAM CAN BE USEFUL IN QUANTIFYING EPIGENETIC EFFECTS OF ENVIRONMENT AND NUTRITION, CORRELATING DEVELOPMENTAL EPIGENETIC VARIATION WITH PHENOTYPES, UNDERSTANDING EPIGENETICS OF CANCER AND CHRONIC DISEASES, MEASURING THE EFFECTS OF DRUGS ON DNA METHYLATION OR DERIVING NEW BIOLOGICAL INSIGHTS INTO MAMMALIAN GENOMES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  1159  26 CONTEXTUAL MODIFIERS OF HEALTHSPAN, LIFESPAN, AND EPIGENOME IN MICE UNDER CHRONIC SOCIAL STRESS. SUSTAINED LIFE STRESS AND LOW SOCIOECONOMIC STATUS ARE AMONG THE MAJOR CAUSES OF AGING-RELATED DISEASES AND DECREASED LIFE EXPECTANCY. EXPERIMENTAL RODENT MODELS CAN HELP TO IDENTIFY THE UNDERLYING MECHANISMS, YET VERY FEW STUDIES ADDRESS THE LONG-TERM CONSEQUENCES OF SOCIAL STRESS ON AGING. WE CONDUCTED A RANDOMIZED STUDY INVOLVING MORE THAN 300 MALE MICE OF COMMONLY USED LABORATORY STRAINS (C57BL/6J, CD1, AND SV129EV) CHOSEN FOR THE SPONTANEOUS AGGRESSION GRADIENT AND STRESS-VULNERABILITY. MICE WERE EXPOSED TO A LIFELONG CHRONIC PSYCHOSOCIAL STRESS PROTOCOL TO MODEL SOCIAL GRADIENTS IN AGING AND DISEASE VULNERABILITY. LOW SOCIAL RANK, INFERRED BASED ON A DISCRETIZED AGGRESSION INDEX, WAS FOUND TO NEGATIVELY IMPACT LIFESPAN IN OUR STUDY POPULATION. HOWEVER, SOCIAL RANK INTERACTED WITH GENETIC BACKGROUND IN THAT LOW-RANKING C57BL/6J, HIGH-RANKING SV129EV, AND MIDDLE-RANKING CD1 MICE HAD LOWER SURVIVAL, RESPECTIVELY, IMPLYING A COST OF MAINTAINING A GIVEN SOCIAL RANK THAT VARIES ACROSS STRAINS. MACHINE LEARNING LINEAR DISCRIMINANT ANALYSIS IDENTIFIED BASELINE FAT-FREE MASS AS THE MOST IMPORTANT PREDICTOR OF MOUSE GENETIC BACKGROUND AND SOCIAL RANK IN THE PRESENT DATASET. FINALLY, STRAIN AND SOCIAL RANK DIFFERENCES WERE SIGNIFICANTLY ASSOCIATED WITH EPIGENETIC CHANGES, MOST SIGNIFICANTLY IN SV129EV MICE AND IN HIGH-RANKING COMPARED TO LOWER RANKING SUBJECTS. OVERALL, WE IDENTIFIED GENETIC BACKGROUND AND SOCIAL RANK AS CRITICAL CONTEXTUAL MODIFIERS OF AGING AND LIFESPAN IN AN ETHOLOGICALLY RELEVANT RODENT MODEL OF SOCIAL STRESS, THEREBY PROVIDING A PRECLINICAL EXPERIMENTAL PARADIGM TO STUDY THE IMPACT OF SOCIAL DETERMINANTS OF HEALTH DISPARITIES AND ACCELERATED AGING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  5712  27 SIRT1 MEDIATES DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS. DEPRESSION IS A RECURRING AND LIFE-THREATENING ILLNESS THAT AFFECTS UP TO 120 MILLION PEOPLE WORLDWIDE. IN THE PRESENT STUDY, WE SHOW THAT CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MODEL OF DEPRESSION IN MICE, INCREASES SIRT1 LEVELS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. INCREASES IN SIRT1, A WELL CHARACTERIZED CLASS III HISTONE DEACETYLASE, AFTER CHRONIC SOCIAL DEFEAT SUGGEST A ROLE FOR THIS ENZYME IN MEDIATING DEPRESSION-LIKE BEHAVIORS. WHEN RESVERATROL, A PHARMACOLOGICAL ACTIVATOR OF SIRT1, WAS DIRECTLY INFUSED BILATERALLY INTO THE NAC, WE OBSERVED AN INCREASE IN DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. CONVERSELY, INTRA-NAC INFUSIONS OF EX-527, A SIRT1 ANTAGONIST, REDUCED THESE BEHAVIORS; EX-527 ALSO REDUCED ACUTE STRESS RESPONSES IN STRESS-NAIVE MICE. NEXT, WE INCREASED SIRT1 LEVELS DIRECTLY IN NAC BY USE OF VIRAL-MEDIATED GENE TRANSFER AND OBSERVED AN INCREASE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS WHEN MICE WERE ASSESSED IN THE OPEN-FIELD, ELEVATED-PLUS-MAZE, AND FORCED SWIM TESTS. USING A CRE-INDUCIBLE VIRAL VECTOR SYSTEM TO OVEREXPRESS SIRT1 SELECTIVELY IN DOPAMINE D1 OR D2 SUBPOPULATIONS OF MEDIUM SPINY NEURONS (MSNS) IN THE NAC, WE FOUND THAT SIRT1 PROMOTES DEPRESSIVE-LIKE BEHAVIORS ONLY WHEN OVEREXPRESSED IN D1 MSNS, WITH NO EFFECT SEEN IN D2 MSNS. CONVERSELY, SELECTIVE ABLATION OF SIRT1 IN THE NAC USING VIRAL-CRE IN FLOXED SIRT1 MICE RESULTED IN DECREASED DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. TOGETHER, THESE RESULTS DEMONSTRATE THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN THE NAC IN REGULATING MOOD-RELATED BEHAVIORAL ABNORMALITIES AND IDENTIFIES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT MAJOR DEPRESSIVE DISORDERS. SIGNIFICANCE STATEMENT: IN THIS STUDY, WE DEMONSTRATE A PIVOTAL ROLE FOR SIRT1 IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW THAT STRESS STABLY INDUCES SIRT1 EXPRESSION IN THIS BRAIN REGION AND THAT ALTERING SIRT1 ACTIVITY USING A PHARMACOLOGICAL OR GENETIC APPROACH REGULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIORS. THESE RESULTS SUGGEST THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN REGULATING MOOD-RELATED BEHAVIORS AND INTRODUCES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT DEPRESSION AND OTHER STRESS-RELATED DISORDERS. A RECENT GROUNDBREAKING PUBLICATION BY THE CONVERGE CONSORTIUM (2015) IDENTIFIED A REPRODUCIBLE ASSOCIATION OF THE SIRT1 LOCUS WITH MAJOR DEPRESSION IN HUMANS. THEREFORE, OUR RESULTS ARE TIMELY AND HAVE SIGNIFICANT TRANSLATIONAL RELEVANCE.	2016	

4  2060  15 EPIGENETIC CONTROL OF HAEMATOPOIETIC STEM CELL AGING AND ITS CLINICAL IMPLICATIONS. AGING, CHRONIC INFLAMMATION, AND ENVIRONMENTAL INSULTS PLAY AN IMPORTANT ROLE IN A NUMBER OF DISEASE PROCESSES THROUGH ALTERATIONS OF THE EPIGENOME. IN THIS REVIEW WE EXPLORE HOW AGE-RELATED CHANGES IN THE EPIGENETIC LANDSCAPE CAN AFFECT HETEROGENEITY WITHIN THE HAEMATOPOIETIC STEM CELL (HSC) COMPARTMENT AND THE DERIVING CLINICAL IMPLICATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5   786  26 CELL-TYPE-SPECIFIC EPIGENETIC EDITING AT THE FOSB GENE CONTROLS SUSCEPTIBILITY TO SOCIAL DEFEAT STRESS. CHRONIC SOCIAL DEFEAT STRESS REGULATES THE EXPRESSION OF FOSB IN THE NUCLEUS ACCUMBENS (NAC) TO PROMOTE THE CELL-TYPE-SPECIFIC ACCUMULATION OF DELTAFOSB IN THE TWO MEDIUM SPINY NEURON (MSN) SUBTYPES IN THIS REGION. DELTAFOSB IS SELECTIVELY INDUCED IN D1-MSNS IN THE NAC OF RESILIENT MICE, AND IN D2-MSNS OF SUSCEPTIBLE MICE. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENCES OF SUCH SELECTIVE INDUCTION, PARTICULARLY IN D2-MSNS. THIS STUDY EXAMINED HOW CELL-TYPE-SPECIFIC CONTROL OF THE ENDOGENOUS FOSB GENE IN NAC REGULATES SUSCEPTIBILITY TO SOCIAL DEFEAT STRESS. HISTONE POST-TRANSLATIONAL MODIFICATIONS (HPTMS) WERE TARGETED SPECIFICALLY TO FOSB USING ENGINEERED ZINC-FINGER PROTEINS (ZFPS). FOSB-ZFPS WERE FUSED TO EITHER THE TRANSCRIPTIONAL REPRESSOR, G9A, WHICH PROMOTES HISTONE METHYLATION OR THE TRANSCRIPTIONAL ACTIVATOR, P65, WHICH PROMOTES HISTONE ACETYLATION. THESE ZFPS WERE EXPRESSED IN D1- VS D2-MSNS USING CRE-DEPENDENT VIRAL EXPRESSION IN THE NAC OF MICE TRANSGENIC FOR CRE RECOMBINASE IN THESE MSN SUBTYPES. WE FOUND THAT STRESS SUSCEPTIBILITY IS OPPOSITELY REGULATED BY THE SPECIFIC CELL TYPE AND HPTM TARGETED. WE REPORT THAT FOSB-TARGETED HISTONE ACETYLATION IN D2-MSNS OR HISTONE METHYLATION IN D1-MSNS PROMOTES A STRESS-SUSCEPTIBLE, DEPRESSIVE-LIKE PHENOTYPE, WHILE HISTONE METHYLATION IN D2-MSNS OR HISTONE ACETYLATION IN D1-MSNS INCREASES RESILIENCE TO SOCIAL STRESS AS QUANTIFIED BY SOCIAL INTERACTION BEHAVIOR AND SUCROSE PREFERENCE. THIS WORK PRESENTS THE FIRST DEMONSTRATION OF CELL- AND GENE-SPECIFIC TARGETING OF HISTONE MODIFICATIONS, WHICH MODEL NATURALLY OCCURRING TRANSCRIPTIONAL PHENOMENA THAT CONTROL SOCIAL DEFEAT STRESS BEHAVIOR. THIS EPIGENETIC-EDITING APPROACH, WHICH RECAPITULATES PHYSIOLOGICAL CHANGES IN GENE EXPRESSION, REVEALS CLEAR DIFFERENCES IN THE SOCIAL DEFEAT PHENOTYPE INDUCED BY FOSB GENE MANIPULATION IN MSN SUBTYPES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  1869  22 EMERGING ROLE OF DREAM IN HEALTHY BRAIN AND NEUROLOGICAL DISEASES. THE DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR (DREAM) IS A MULTIFUNCTIONAL CA(2+)-SENSITIVE PROTEIN EXERTING A DUAL MECHANISM OF ACTION TO REGULATE SEVERAL CA(2+)-DEPENDENT PROCESSES. UPON SUMOYLATION, DREAM ENTERS IN NUCLEUS WHERE IT DOWNREGULATES THE EXPRESSION OF SEVERAL GENES PROVIDED WITH A CONSENSUS SEQUENCE NAMED DREAM REGULATORY ELEMENT (DRE). ON THE OTHER HAND, DREAM COULD ALSO DIRECTLY MODULATE THE ACTIVITY OR THE LOCALIZATION OF SEVERAL CYTOSOLIC AND PLASMA MEMBRANE PROTEINS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE KNOWLEDGE OF DREAM DYSREGULATION AND DREAM-DEPENDENT EPIGENETIC REMODELING AS A CENTRAL MECHANISM IN THE PROGRESSION OF SEVERAL DISEASES AFFECTING CENTRAL NERVOUS SYSTEM, INCLUDING STROKE, ALZHEIMER'S AND HUNTINGTON'S DISEASES, AMYOTROPHIC LATERAL SCLEROSIS, AND NEUROPATHIC PAIN. INTERESTINGLY, DREAM SEEMS TO EXERT A COMMON DETRIMENTAL ROLE IN THESE DISEASES BY INHIBITING THE TRANSCRIPTION OF SEVERAL NEUROPROTECTIVE GENES, INCLUDING THE SODIUM/CALCIUM EXCHANGER ISOFORM 3 (NCX3), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), PRO-DYNORPHIN, AND C-FOS. THESE FINDINGS LEAD TO THE CONCEPT THAT DREAM MIGHT REPRESENT A PHARMACOLOGICAL TARGET TO AMELIORATE SYMPTOMS AND REDUCE NEURODEGENERATIVE PROCESSES IN SEVERAL PATHOLOGICAL CONDITIONS AFFECTING CENTRAL NERVOUS SYSTEM.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7   195  22 ACF CHROMATIN-REMODELING COMPLEX MEDIATES STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR. IMPROVED TREATMENT FOR MAJOR DEPRESSIVE DISORDER (MDD) REMAINS ELUSIVE BECAUSE OF THE LIMITED UNDERSTANDING OF ITS UNDERLYING BIOLOGICAL MECHANISMS. IT IS LIKELY THAT STRESS-INDUCED MALADAPTIVE TRANSCRIPTIONAL REGULATION IN LIMBIC NEURAL CIRCUITS CONTRIBUTES TO THE DEVELOPMENT OF MDD, POSSIBLY THROUGH EPIGENETIC FACTORS THAT REGULATE CHROMATIN STRUCTURE. WE ESTABLISH THAT PERSISTENT UPREGULATION OF THE ACF (ATP-UTILIZING CHROMATIN ASSEMBLY AND REMODELING FACTOR) ATP-DEPENDENT CHROMATIN-REMODELING COMPLEX, OCCURRING IN THE NUCLEUS ACCUMBENS OF STRESS-SUSCEPTIBLE MICE AND DEPRESSED HUMANS, IS NECESSARY FOR STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS. WE FOUND THAT ALTERED ACF BINDING AFTER CHRONIC STRESS WAS CORRELATED WITH ALTERED NUCLEOSOME POSITIONING, PARTICULARLY AROUND THE TRANSCRIPTION START SITES OF AFFECTED GENES. THESE ALTERATIONS IN ACF BINDING AND NUCLEOSOME POSITIONING WERE ASSOCIATED WITH REPRESSED EXPRESSION OF GENES IMPLICATED IN SUSCEPTIBILITY TO STRESS. TOGETHER, OUR FINDINGS IDENTIFY THE ACF CHROMATIN-REMODELING COMPLEX AS A CRITICAL COMPONENT IN THE DEVELOPMENT OF SUSCEPTIBILITY TO DEPRESSION AND IN REGULATING STRESS-RELATED BEHAVIORS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  4593  36 NATURAL GENETIC VARIATION IN A MULTIGENERATIONAL PHENOTYPE IN C. ELEGANS. ALTHOUGH HEREDITY MOSTLY RELIES ON THE TRANSMISSION OF DNA SEQUENCE, ADDITIONAL MOLECULAR AND CELLULAR FEATURES ARE HERITABLE ACROSS SEVERAL GENERATIONS. IN THE NEMATODE CAENORHABDITIS ELEGANS, INSIGHTS INTO SUCH UNCONVENTIONAL INHERITANCE RESULT FROM TWO LINES OF WORK. FIRST, THE MORTAL GERMLINE (MRT) PHENOTYPE WAS DEFINED AS A MULTIGENERATIONAL PHENOTYPE WHEREBY A SELFING LINEAGE BECOMES STERILE AFTER SEVERAL GENERATIONS, IMPLYING MULTIGENERATIONAL MEMORY [1, 2]. SECOND, CERTAIN RNAI EFFECTS ARE HERITABLE OVER SEVERAL GENERATIONS IN THE ABSENCE OF THE INITIAL TRIGGER [3-5]. BOTH LINES OF WORK CONVERGED WHEN THE SUBSET OF MRT MUTANTS THAT ARE HEAT SENSITIVE WERE FOUND TO CLOSELY CORRESPOND TO MUTANTS DEFECTIVE IN THE RNAI-INHERITANCE MACHINERY, INCLUDING HISTONE MODIFIERS [6-9]. HERE, WE REPORT THE SURPRISING FINDING THAT SEVERAL C. ELEGANS WILD ISOLATES DISPLAY A HEAT-SENSITIVE MORTAL GERMLINE PHENOTYPE IN LABORATORY CONDITIONS: UPON CHRONIC EXPOSURE TO HIGHER TEMPERATURES, SUCH AS 25 DEGREES C, LINES REPRODUCIBLY BECOME STERILE AFTER SEVERAL GENERATIONS. THIS PHENOMENON IS REVERSIBLE, AS IT CAN BE SUPPRESSED BY TEMPERATURE ALTERNATIONS AT EACH GENERATION, SUGGESTING A NON-GENETIC BASIS FOR THE STERILITY. WE TESTED WHETHER NATURAL VARIATION IN THE TEMPERATURE-INDUCED MRT PHENOTYPE WAS OF GENETIC NATURE BY BUILDING RECOMBINANT INBRED LINES BETWEEN THE ISOLATES MY10 (MRT) AND JU1395 (NON-MRT). USING BULK SEGREGANT ANALYSIS, WE DETECTED TWO QUANTITATIVE TRAIT LOCI. AFTER FURTHER RECOMBINANT MAPPING AND GENOME EDITING, WE IDENTIFIED THE MAJOR CAUSAL LOCUS AS A POLYMORPHISM IN THE SET-24 GENE, ENCODING A SET- AND SPK-DOMAIN PROTEIN. WE CONCLUDE THAT C. ELEGANS NATURAL POPULATIONS MAY HARBOR NATURAL GENETIC VARIATION IN EPIGENETIC INHERITANCE PHENOMENA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  3316  25 HISTIOCYTIC SARCOMA AS A SECONDARY MALIGNANCY: PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT. HISTIOCYTIC SARCOMA (HS) IS AN EXTREMELY RARE NON-LANGERHANS CELL DISORDER WITH AN AGGRESSIVE COURSE AND LIMITED TREATMENT OPTIONS. RECENT ADVANCES IN MOLECULAR/GENETIC SEQUENCING HAVE SUGGESTED A COMMON CLONAL ORIGIN BETWEEN VARIOUS HEMATOLYMPHOID DISORDERS AND CASES OF SECONDARY HS. DERIVING CONCLUSIONS FROM PREVIOUSLY REPORTED CASES OF HS ARISING SECONDARILY TO CERTAIN HEMATOLYMPHOID DISORDERS, HERE WE HAVE TRIED TO PROVIDE INSIGHT INTO THE MECHANISMS INFLUENCING THIS EVOLUTION. WE ALSO DISCUSS A CLINICAL CASE OF A 72-YEAR-OLD MAN WITH A DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), PRESENTING SUBSEQUENTLY WITH A HETEROGENEOUS LIVER MASS POSITIVE WITH A DIAGNOSIS OF HS. THE LIVER MASS SHOWED A RETAINED BCR-ABL1 TRANSLOCATION SUGGESTING CLONALITY BETWEEN THE CML AND HS. AS SEEN IN OUR CASE AND OTHER REPORTED CASES OF HS DERIVED SECONDARILY, THE CONCURRENT EXPRESSION OF IMMUNOGLOBULIN HEAVY (IGH)-/LIGHT-CHAIN REARRANGEMENTS OR CYTOGENETIC MARKERS COMMON TO THE PRIMARY MALIGNANCY SUGGESTS AN EVOLUTIONARY MECHANISM INVOLVING LINEAGE SWITCHING THAT COULD POTENTIALLY BE INFLUENCED BY GENETIC OR EPIGENETIC CUES WHICH MAY OCCUR AT THE LEVEL OF A PROGENITOR OR THE MALIGNANT CELL ITSELF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  5974  31 TET1 IN NUCLEUS ACCUMBENS OPPOSES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. DEPRESSION IS A LEADING CAUSE OF DISEASE BURDEN, YET CURRENT THERAPIES FULLY TREAT <50% OF AFFECTED INDIVIDUALS. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS IN DEPRESSION AND ANTIDEPRESSANT ACTION. HERE WE EXAMINED A POSSIBLE ROLE FOR THE DNA DIOXYGENASE, TEN-ELEVEN TRANSLOCATION PROTEIN 1 (TET1), IN DEPRESSION-RELATED BEHAVIORAL ABNORMALITIES. WE APPLIED CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MOUSE MODEL OF DEPRESSION-LIKE BEHAVIORS, AND EXAMINED TET1 EXPRESSION CHANGES IN NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW DECREASED TET1 EXPRESSION IN NAC IN STRESS-SUSCEPTIBLE MICE ONLY. SURPRISINGLY, SELECTIVE KNOCKOUT OF TET1 IN NAC NEURONS OF ADULT MICE PRODUCED ANTIDEPRESSANT-LIKE EFFECTS IN SEVERAL BEHAVIORAL ASSAYS. TO IDENTIFY TET1 TARGETS THAT MEDIATE THESE ACTIONS, WE PERFORMED RNASEQ ON NAC AFTER CONDITIONAL DELETION OF TET1 AND FOUND THAT IMMUNE-RELATED GENES ARE THE MOST HIGHLY DYSREGULATED. MOREOVER, MANY OF THESE GENES ARE ALSO UPREGULATED IN THE NAC OF RESILIENT MICE AFTER CHRONIC SOCIAL DEFEAT STRESS. THESE FINDINGS REVEAL A NOVEL ROLE FOR TET1, AN ENZYME IMPORTANT FOR DNA HYDROXYMETHYLATION, IN THE BRAIN'S REWARD CIRCUITRY IN MODULATING STRESS RESPONSES IN MICE. WE ALSO IDENTIFY A SUBSET OF GENES THAT ARE REGULATED BY TET1 IN THIS CIRCUITRY. THESE FINDINGS PROVIDE NEW INSIGHT INTO THE PATHOPHYSIOLOGY OF DEPRESSION, WHICH CAN AID IN FUTURE ANTIDEPRESSANT DRUG DISCOVERY EFFORTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  6012  13 THE APKC-CBP PATHWAY REGULATES POST-STROKE NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY. EPIGENETIC MODIFICATIONS HAVE EMERGED AS ATTRACTIVE MOLECULAR SUBSTRATES THAT INTEGRATE EXTRINSIC CHANGES INTO THE DETERMINATION OF CELL IDENTITY. SINCE STROKE-RELATED BRAIN DAMAGE RELEASES MICRO-ENVIRONMENTAL CUES, WE EXAMINED THE ROLE OF A SIGNALING-INDUCED EPIGENETIC PATHWAY, AN ATYPICAL PROTEIN KINASE C (APKC)-MEDIATED PHOSPHORYLATION OF CREB-BINDING PROTEIN (CBP), IN POST-STROKE NEUROVASCULAR REMODELING. USING A KNOCKIN MOUSE STRAIN (CBPS436A) WHERE THE APKC-CBP PATHWAY WAS DEFECTIVE, WE SHOW THAT DISRUPTION OF THE APKC-CBP PATHWAY IN A MURINE FOCAL ISCHEMIC STROKE MODEL INCREASES THE REPROGRAMMING EFFICIENCY OF ISCHEMIA-ACTIVATED PERICYTES (I-PERICYTES) TO NEURAL PRECURSORS. AS A CONSEQUENCE OF ENHANCED CELLULAR REPROGRAMMING, CBPS436A MICE SHOW AN INCREASED TRANSIENT POPULATION OF LOCALLY DERIVED NEURAL PRECURSORS AFTER STROKE, WHILE DISPLAYING A REDUCED NUMBER OF I-PERICYTES, IMPAIRED VASCULAR REMODELING, AND PERTURBED MOTOR RECOVERY DURING THE CHRONIC PHASE OF STROKE. TOGETHER, THIS STUDY ELUCIDATES THE ROLE OF THE APKC-CBP PATHWAY IN MODULATING NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY FOLLOWING FOCAL ISCHEMIC STROKE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  3040  29 GENOME HYPERMETHYLATION IN PINUS SILVESTRIS OF CHERNOBYL--A MECHANISM FOR RADIATION ADAPTATION? ADAPTATION IS A COMPLEX PROCESS BY WHICH POPULATIONS OF ORGANISMS RESPOND TO LONG-TERM ENVIRONMENTAL STRESSES BY PERMANENT GENETIC CHANGE. HERE WE PRESENT DATA FROM THE NATURAL "OPEN-FIELD" RADIATION ADAPTATION EXPERIMENT AFTER THE CHERNOBYL ACCIDENT AND PROVIDE THE FIRST EVIDENCE OF THE INVOLVEMENT OF EPIGENETIC CHANGES IN ADAPTATION OF A EUKARYOTE-SCOTS PINE (PINUS SILVESTRIS), TO CHRONIC RADIATION EXPOSURE. WE HAVE EVALUATED GLOBAL GENOME METHYLATION OF CONTROL AND RADIATION-EXPOSED PINE TREES USING A METHOD BASED ON CLEAVAGE BY A METHYLATION-SENSITIVE HPAII RESTRICTION ENDONUCLEASE THAT LEAVES A 5' GUANINE OVERHANG AND SUBSEQUENT SINGLE NUCLEOTIDE EXTENSION WITH LABELED [3H] DCTP. WE HAVE FOUND THAT GENOMIC DNA OF EXPOSED PINE TREES WAS CONSIDERABLY HYPERMETHYLATED. MOREOVER, HYPERMETHYLATION APPEARED TO BE DEPENDENT UPON THE RADIATION DOSE ABSORBED BY THE TREES. SUCH HYPERMETHYLATION MAY BE VIEWED AS A DEFENSE STRATEGY OF PLANTS THAT PREVENTS GENOME INSTABILITY AND RESHUFFLING OF THE HEREDITARY MATERIAL, ALLOWING SURVIVAL IN AN EXTREME ENVIRONMENT. FURTHER STUDIES ARE CLEARLY NEEDED TO ANALYZE IN DETAIL THE INVOLVEMENT OF DNA METHYLATION AND OTHER EPIGENETIC MECHANISMS IN THE COMPLEX PROCESS OF RADIATION STRESS AND ADAPTIVE RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  5516  26 RISE OF THE MUTANTS: REPORT FROM THE 19TH CONFERENCE OF THE EUROPEAN HAEMATOLOGY ASSOCIATION, MILAN, 12-15 JUNE 2014. AT THE 19TH CONFERENCE OF THE EUROPEAN HAEMATOLOGY ASSOCIATION IN MILAN, WE SAW THE TRUE AND DRAMATIC CHANGES BROUGHT ABOUT BY THE INTEGRATION OF EXTENSIVE GENOMIC INFORMATION IN CLINICAL PRACTICE, AND THE DILEMMAS THAT ACCOMPANY SUCH A RAPID INCREASE IN KNOWLEDGE. EACH DISEASE IS SLICED MORE AND MORE INTO SMALLER PIECES, EACH WITH ITS OWN BETTER-DETERMINED OUTCOME AND TREATMENT. WE ALSO OBSERVED THE RISE OF MUTANT-SPECIFIC EPIGENETIC AGENTS, WHICH BENEFIT FROM KNOWING THE UNDERLYING GENETIC ABNORMALITY TO SPECIFICALLY ASSIGN AN EPIGENETIC DRUG WHERE IT IS NEEDED. IN CONTRAST TO THE 'ONE MUTATION, ONE DRUG' APPROACH, OTHERS ARE PURSUING THE SEARCH FOR DRUGS TARGETING PATHWAYS FUNDAMENTAL FOR THE SURVIVAL OF ALL OR MOST CANCER CELLS, SOMETIMES LOOKING AT MORE 'EXOTIC' PATHWAYS LIKE NEDDYLATION OR NUCLEAR EXPORT.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  3120  24 GESTATIONAL HYPOXIA AND BLOOD-BRAIN BARRIER PERMEABILITY: EARLY ORIGINS OF CEREBROVASCULAR DYSFUNCTION INDUCED BY EPIGENETIC MECHANISMS. FETAL CHRONIC HYPOXIA LEADS TO INTRAUTERINE GROWTH RESTRICTION (IUGR), WHICH IS LIKELY TO REDUCE OXYGEN DELIVERY TO THE BRAIN AND INDUCE LONG-TERM NEUROLOGICAL IMPAIRMENTS. THESE INDICATE A MODULATORY ROLE FOR OXYGEN IN CEREBROVASCULAR DEVELOPMENT. DURING INTRAUTERINE HYPOXIA, THE FETAL CIRCULATION SUFFERS MARKED ADAPTATIONS IN THE FETAL CARDIAC OUTPUT TO MAINTAIN OXYGEN AND NUTRIENT DELIVERY TO VITAL ORGANS, KNOWN AS THE "BRAIN-SPARING PHENOTYPE." THIS IS A WELL-CHARACTERIZED RESPONSE; HOWEVER, LITTLE IS KNOWN ABOUT THE POSTNATAL COURSE AND OUTCOMES OF THIS FETAL CEREBROVASCULAR ADAPTATION. IN ADDITION, SEVERAL NEURODEVELOPMENTAL DISORDERS HAVE THEIR ORIGINS DURING GESTATION. STILL, FEW STUDIES HAVE FOCUSED ON HOW INTRAUTERINE FETAL HYPOXIA MODULATES THE NORMAL BRAIN DEVELOPMENT OF THE BLOOD-BRAIN BARRIER (BBB) IN THE IUGR NEONATE. THE BBB IS A CELLULAR STRUCTURE FORMED BY THE NEUROVASCULAR UNIT (NVU) AND IS ORGANIZED BY A MONOLAYER OF ENDOTHELIAL AND MURAL CELLS. THE BBB REGULATES THE ENTRY OF PLASMA CELLS AND MOLECULES FROM THE SYSTEMIC CIRCULATION TO THE BRAIN. A HIGHLY SELECTIVE PERMEABILITY SYSTEM ACHIEVES THIS THROUGH INTEGRAL MEMBRANE PROTEINS IN BRAIN ENDOTHELIAL CELLS. BBB BREAKDOWN AND DYSFUNCTION IN CEREBROVASCULAR DISEASES LEAD TO LEAKAGE OF BLOOD COMPONENTS INTO THE BRAIN PARENCHYMA, CONTRIBUTING TO NEUROLOGICAL DEFICITS. THE FETAL BRAIN CIRCULATION IS PARTICULARLY SUSCEPTIBLE IN IUGR AND IS PROPOSED TO BE ONE OF THE MAIN PATHOLOGICAL PROCESSES DERIVING BBB DISRUPTION. IN THE LAST DECADE, SEVERAL EPIGENETIC MECHANISMS ACTIVATED BY IU HYPOXIA HAVE BEEN PROPOSED TO REGULATE THE POSTNATAL BBB PERMEABILITY. HOWEVER, FEW MECHANISTIC STUDIES ABOUT THIS TOPIC ARE AVAILABLE, AND LITTLE EVIDENCE SHOWS CONTROVERSY. THEREFORE, IN THIS MINI-REVIEW, WE ANALYZE THE BBB PERMEABILITY-ASSOCIATED EPIGENETIC MECHANISMS IN THE BRAIN EXPOSED TO CHRONIC INTRAUTERINE HYPOXIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  2839  21 FOSB INDUCTION IN NUCLEUS ACCUMBENS BY COCAINE IS REGULATED BY E2F3A. THE TRANSCRIPTION FACTOR DELTAFOSB HAS BEEN PROPOSED AS A MOLECULAR SWITCH FOR THE TRANSITION FROM CASUAL, VOLITIONAL DRUG USE INTO A CHRONICALLY ADDICTED STATE, BUT THE UPSTREAM REGULATORY MECHANISMS GOVERNING DELTAFOSB EXPRESSION ARE INCOMPLETELY UNDERSTOOD. IN THIS STUDY, WE FIND A NOVEL REGULATORY ROLE FOR THE TRANSCRIPTION FACTOR E2F3, RECENTLY IMPLICATED IN TRANSCRIPTIONAL REGULATION BY COCAINE, IN CONTROLLING DELTAFOSB INDUCTION IN THE MOUSE NUCLEUS ACCUMBENS (NAC) FOLLOWING COCAINE ADMINISTRATION. WE FIND THAT AN E2F CONSENSUS SEQUENCE 500 BP UPSTREAM OF THE FOSB TRANSCRIPTION START SITE IS ENRICHED FOR E2F3 SPECIFICALLY OVER OTHER E2F ISOFORMS. WE FURTHER CONCLUDE THAT DELTAFOSB EXPRESSION IS REGULATED SPECIFICALLY BY E2F3A, NOT E2F3B, THAT E2F3A EXPRESSION IS SPECIFIC TO D1 RECEPTOR-EXPRESSING MEDIUM SPINY NEURONS, AND THAT E2F3A OVEREXPRESSION IN NAC RECAPITULATES THE INDUCTION OF FOSB AND DELTAFOSB MRNA EXPRESSION OBSERVED AFTER CHRONIC COCAINE EXPOSURE. E2F3A KNOCKDOWN IN NAC DOES NOT ABOLISH DELTAFOSB INDUCTION BY COCAINE, A RESULT CONSISTENT WITH PREVIOUSLY PUBLISHED DATA SHOWING THAT SINGULAR KNOCKDOWN OF UPSTREAM REGULATORS OF DELTAFOSB IS INSUFFICIENT TO BLOCK COCAINE-INDUCED EXPRESSION. FINALLY, TO ELUCIDATE POTENTIAL COMBINATORIAL EPIGENETIC MECHANISMS INVOLVED IN E2F3A'S REGULATION OF FOSB, WE EXPLORE H3K4ME3 ENRICHMENT AT THE FOSB PROMOTER AND FIND THAT IT IS NOT ENHANCED BY E2F3A OVEREXPRESSION, SUGGESTING THAT IT MAY INSTEAD BE A PRE-EXISTING PERMISSIVE MARK ALLOWING FOR E2F3A TO INTERACT WITH FOSB. TOGETHER, THESE FINDINGS SUPPORT A ROLE FOR E2F3A AS A NOVEL, UPSTREAM REGULATOR OF THE ADDICTION-MEDIATING TRANSCRIPTION FACTOR DELTAFOSB IN NAC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  4405  20 MOLECULAR ADAPTATIONS OF THE BLOOD-BRAIN BARRIER PROMOTE STRESS RESILIENCE VS. DEPRESSION. PRECLINICAL AND CLINICAL STUDIES SUGGEST THAT INFLAMMATION AND VASCULAR DYSFUNCTION CONTRIBUTE TO THE PATHOGENESIS OF MAJOR DEPRESSIVE DISORDER (MDD). CHRONIC SOCIAL STRESS ALTERS BLOOD-BRAIN BARRIER (BBB) INTEGRITY THROUGH LOSS OF TIGHT JUNCTION PROTEIN CLAUDIN-5 (CLDN5) IN MALE MICE, PROMOTING PASSAGE OF CIRCULATING PROINFLAMMATORY CYTOKINES AND DEPRESSION-LIKE BEHAVIORS. THIS EFFECT IS PROMINENT WITHIN THE NUCLEUS ACCUMBENS, A BRAIN REGION ASSOCIATED WITH MOOD REGULATION; HOWEVER, THE MECHANISMS INVOLVED ARE UNCLEAR. MOREOVER, COMPENSATORY RESPONSES LEADING TO PROPER BEHAVIORAL STRATEGIES AND ACTIVE RESILIENCE ARE UNKNOWN. HERE WE IDENTIFY ACTIVE MOLECULAR CHANGES WITHIN THE BBB ASSOCIATED WITH STRESS RESILIENCE THAT MIGHT SERVE A PROTECTIVE ROLE FOR THE NEUROVASCULATURE. WE ALSO CONFIRM THE RELEVANCE OF SUCH CHANGES TO HUMAN DEPRESSION AND ANTIDEPRESSANT TREATMENT. WE SHOW THAT PERMISSIVE EPIGENETIC REGULATION OF CLDN5 EXPRESSION AND LOW ENDOTHELIUM EXPRESSION OF REPRESSIVE CLDN5-RELATED TRANSCRIPTION FACTOR FOXO1 ARE ASSOCIATED WITH STRESS RESILIENCE. REGION- AND ENDOTHELIAL CELL-SPECIFIC WHOLE TRANSCRIPTOMIC ANALYSES REVEALED MOLECULAR SIGNATURES ASSOCIATED WITH STRESS VULNERABILITY VS. RESILIENCE. WE IDENTIFIED PROINFLAMMATORY TNFALPHA/NFKAPPAB SIGNALING AND HDAC1 AS MEDIATORS OF STRESS SUSCEPTIBILITY. PHARMACOLOGICAL INHIBITION OF STRESS-INDUCED INCREASE IN HDAC1 ACTIVITY RESCUED CLDN5 EXPRESSION IN THE NAC AND PROMOTED RESILIENCE. IMPORTANTLY, WE CONFIRMED CHANGES IN HDAC1 EXPRESSION IN THE NAC OF DEPRESSED PATIENTS WITHOUT ANTIDEPRESSANT TREATMENT IN LINE WITH CLDN5 LOSS. CONVERSELY, MANY OF THESE DELETERIOUS CLDN5-RELATED MOLECULAR CHANGES WERE REDUCED IN POSTMORTEM NAC FROM ANTIDEPRESSANT-TREATED SUBJECTS. THESE FINDINGS REINFORCE THE IMPORTANCE OF CONSIDERING STRESS-INDUCED NEUROVASCULAR PATHOLOGY IN DEPRESSION AND PROVIDE THERAPEUTIC TARGETS TO TREAT THIS MOOD DISORDER AND PROMOTE RESILIENCE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  6031  23 THE CANCER EPIGENOME: ITS ORIGINS, CONTRIBUTIONS TO TUMORIGENESIS, AND TRANSLATIONAL IMPLICATIONS. EPIGENETIC ABNORMALITIES IN LUNG AND OTHER CANCERS CONTINUE TO BE DEFINED AT A RAPID PACE. WE ARE COMING TO APPRECIATE THAT CANCERS HAVE AN "EPIGENETIC LANDSCAPE" WHEREIN GENES VULNERABLE TO ABNORMALITIES, SUCH AS PROMOTER DNA HYPERMETHYLATION AND ASSOCIATED GENE SILENCING, TEND TO RESIDE IN DEFINED NUCLEAR POSITIONS AND CHROMOSOME DOMAINS AND RELATIONSHIPS TO CHROMATIN REGULATION, WHICH FACILITATES STATES OF STEM CELL RENEWAL. THESE SAME GENES AND DOMAINS ARE ALSO VULNERABLE TO EPIGENETIC ABNORMALITIES INDUCED BY FACTORS TO WHICH CELLS ARE EXPOSED DURING CANCER RISK STATES, SUCH AS CHRONIC INFLAMMATION. WE CAN USE ALL OF THIS BASIC INFORMATION FOR TRANSLATIONAL PURPOSES IN TERMS OF DERIVING BIOMARKERS FOR CANCER RISK STATES AND DETECTION AND THERAPEUTIC STRATEGIES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  5814  18 STRESS AND FELINE HEALTH. IN THE HEALTH SCIENCES, STRESS OFTEN IS DEFINED IN TERMS OF STRESSORS; EVENTS THAT ARE PERCEIVED AS THREATS TO ONE'S PERCEPTION OF CONTROL. FROM THIS PERSPECTIVE, A STRESSOR IS ANYTHING THAT ACTIVATES THE CENTRAL THREAT RESPONSE SYSTEM (CTRS). RECENT RESEARCH SHOWS THAT THE CTRS CAN BE SENSITIZED TO ENVIRONMENTAL EVENTS THROUGH EPIGENETIC MODULATION OF GENE EXPRESSION. WHEN CTRS ACTIVATION IS CHRONIC, HEALTH AND WELFARE MAY BE HARMED. ENVIRONMENTAL MODIFICATION CAN MITIGATE THE HARMFUL EFFECTS OF CHRONIC CTRS ACTIVATION BY REDUCING THE INDIVIDUAL'S PERCEPTION OF THREAT AND INCREASING ITS PERCEPTION OF CONTROL, WHICH IMPROVES HEALTH AND WELFARE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19   568  24 BATF REGULATES PROGENITOR TO CYTOLYTIC EFFECTOR CD8(+) T CELL TRANSITION DURING CHRONIC VIRAL INFECTION. DURING CHRONIC VIRAL INFECTION, CD8(+) T CELLS DEVELOP INTO THREE MAJOR PHENOTYPICALLY AND FUNCTIONALLY DISTINCT SUBSETS: LY108(+)TCF-1(+) PROGENITORS, LY108(-)CX(3)CR1(-) TERMINALLY EXHAUSTED CELLS AND THE RECENTLY IDENTIFIED CX(3)CR1(+) CYTOTOXIC EFFECTOR CELLS. NEVERTHELESS, HOW CX(3)CR1(+) EFFECTOR CELL DIFFERENTIATION IS TRANSCRIPTIONALLY AND EPIGENETICALLY REGULATED REMAINS ELUSIVE. HERE, WE IDENTIFY DISTINCT GENE REGULATORY NETWORKS AND EPIGENETIC LANDSCAPES UNDERPINNING THE FORMATION OF THESE SUBSETS. NOTABLY, OUR DATA DEMONSTRATE THAT CX(3)CR1(+) EFFECTOR CELLS BEAR A STRIKING SIMILARITY TO SHORT-LIVED EFFECTOR CELLS DURING ACUTE INFECTION. GENETIC DELETION OF TBX21 SIGNIFICANTLY DIMINISHED FORMATION OF THE CX(3)CR1(+) SUBSET. IMPORTANTLY, WE FURTHER IDENTIFY A PREVIOUSLY UNAPPRECIATED ROLE FOR THE TRANSCRIPTION FACTOR BATF IN MAINTAINING A PERMISSIVE CHROMATIN STRUCTURE THAT ALLOWS THE TRANSITION FROM TCF-1(+) PROGENITORS TO CX(3)CR1(+) EFFECTOR CELLS. BATF DIRECTLY BOUND TO REGULATORY REGIONS NEAR TBX21 AND KLF2, MODULATING THEIR ENHANCER ACCESSIBILITY TO FACILITATE THE TRANSITION. THESE MECHANISTIC INSIGHTS CAN POTENTIALLY BE HARNESSED TO OVERCOME T CELL EXHAUSTION DURING CHRONIC INFECTION AND CANCER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  6777  22 [ASSOCIATION OF P-MOBILE ELEMENT ACTIVITY AND DNA METHYLATION PATTERN CHANGES IN THE CONDITIONS OF DROSOPHILA MELANOGASTER PROLONGED IRRADIATION]. ASSOCIATION OF THE RADIOSENSITIVITY AND EPIGENETIC PATTERN DNA CHANGES AT THE CONDITIONS OF PROLONGED IRRADIATION WAS INVESTIGATED. TWO LABORATORY DROSOPHILA MELANOGASTER STRAINS (CANTON-S AND RI) IRRADIATED FOR 20 GENERATIONS TO LOW DOSES RATE (1.2 X 10(-1), 0.8 X 10(-8) AND 0.12 X 10(-8) GY/S) WERE USED AS EXPERIMENTAL OBJECTS. DNA FOR THE ANALYSIS WAS EXTRACTED SEPARATELY FOR THE FLIES OF MALES AND FEMALES. RESTRICTION ENDONUCLEASES GLUL, GLAL WERE USED. RESTRICTION ANALYSIS HAS SHOWN THAT THERE ARE DIFFERENT DNA METHYLATED PATTERNS FOR MALES AND FEMALES AS FOR CONTROL AND EXPOSED VARIANTS. AT THE CHRONIC IRRADIATION THERE WAS THE DECLINE OF METHYLATION LEVEL AT THE ENZYMES GLUL, GLAL SITES RECOGNITION.	2010