1  3760 99 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW. CHRONIC HEAVY ALCOHOL DRINKING (CHD) REWIRES MONOCYTES AND MACROPHAGES TOWARD HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTIMICROBIAL DEFENSES THAT PERSIST AFTER 1-MONTH ABSTINENCE. TO DETERMINE WHETHER THESE CHANGES ARE MEDIATED THROUGH ALTERATIONS IN THE BONE MARROW NICHE, WE PROFILED MONOCYTES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCPS) FROM CHD RHESUS MACAQUES USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. CHD RESULTED IN TRANSCRIPTIONAL PROFILES CONSISTENT WITH INCREASED ACTIVATION AND INFLAMMATION WITHIN BONE MARROW RESIDENT MONOCYTES AND MACROPHAGES. FURTHERMORE, CHD RESULTED IN TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS IN HSCP. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARD MONOCYTES EXPRESSING "NEUTROPHIL-LIKE" MARKERS WITH GREATER INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. FURTHER ANALYSES OF HSCPS SHOWED BROAD EPIGENETIC CHANGES THAT WERE IN LINE WITH EXACERBATED INFLAMMATORY RESPONSES WITHIN MONOCYTES AND THEIR PROGENITORS. IN SUMMARY, CHD ALTERS HSCPS IN THE BONE MARROW LEADING TO THE PRODUCTION OF MONOCYTES POISED TO GENERATE DYSREGULATED HYPER-INFLAMMATORY RESPONSES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  1316 24 DELTA9-TETRAHYDROCANNABINOL (DELTA9-THC) PROMOTES NEUROIMMUNE-MODULATORY MICRORNA PROFILE IN STRIATUM OF SIMIAN IMMUNODEFICIENCY VIRUS (SIV)-INFECTED MACAQUES. CANNABINOID ADMINISTRATION BEFORE AND AFTER SIMIAN IMMUNODEFICIENCY VIRUS (SIV)-INOCULATION AMELIORATED DISEASE PROGRESSION AND DECREASED INFLAMMATION IN MALE RHESUS MACAQUES. DELTA9-TETRAHYDROCANNABINOL (DELTA9-THC) DID NOT INCREASE VIRAL LOAD IN BRAIN TISSUE OR PRODUCE ADDITIVE NEUROPSYCHOLOGICAL IMPAIRMENT IN SIV-INFECTED MACAQUES. TO DETERMINE IF THE NEUROIMMUNOMODULATION OF DELTA9-THC INVOLVED DIFFERENTIAL MICRORNA (MIR) EXPRESSION, MIR EXPRESSION IN THE STRIATUM OF UNINFECTED MACAQUES RECEIVING VEHICLE (VEH) OR DELTA9-THC (THC) AND SIV-INFECTED MACAQUES ADMINISTERED EITHER VEHICLE (VEH/SIV) OR DELTA9-THC (THC/SIV) WAS PROFILED USING NEXT GENERATION DEEP SEQUENCING. AMONG THE 24 MIRS THAT WERE DIFFERENTIALLY EXPRESSED AMONG THE FOUR GROUPS, 16 MIRS WERE MODULATED BY THC IN THE PRESENCE OF SIV. THESE 16 MIRS WERE CLASSIFIED INTO FOUR CATEGORIES AND THE BIOLOGICAL PROCESSES ENRICHED BY THE TARGET GENES DETERMINED. OUR RESULTS INDICATE THAT DELTA9-THC MODULATES MIRS THAT REGULATE MRNAS OF PROTEINS INVOLVED IN 1) NEUROTROPHIN SIGNALING, 2) MAPK SIGNALING, AND 3) CELL CYCLE AND IMMUNE RESPONSE THUS PROMOTING AN OVERALL NEUROPROTECTIVE ENVIRONMENT IN THE STRIATUM OF SIV-INFECTED MACAQUES. THIS IS ALSO REFLECTED BY INCREASED BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND DECREASED PROINFLAMMATORY CYTOKINE EXPRESSION COMPARED TO THE VEH/SIV GROUP. WHETHER DELTA9-THC-MEDIATED MODULATION OF EPIGENETIC MECHANISMS PROVIDES NEUROPROTECTION IN OTHER REGIONS OF THE BRAIN AND DURING CHRONIC SIV-INFECTION REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  3759 74 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW NICHE. CHRONIC ALCOHOL DRINKING REWIRES CIRCULATING MONOCYTES AND TISSUE-RESIDENT MACROPHAGES TOWARDS HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTI-MICROBIAL DEFENSES. AS THESE EFFECTS REMAIN CONSISTENT IN SHORT-LIVED MONOCYTES AFTER A 1-MONTH ABSTINENCE PERIOD IT IS UNCLEAR WHETHER THESE CHANGES ARE RESTRICTED TO THE PERIPHERY OR MEDIATED THROUGH ALTERATIONS IN THE PROGENITOR NICHE. TO TEST THIS HYPOTHESIS, WE PROFILED MONOCYTES/MACROPHAGES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCP) OF THE BONE MARROW COMPARTMENT FROM RHESUS MACAQUES AFTER 12 MONTHS OF ETHANOL CONSUMPTION USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. BONE MARROW-RESIDENT MONOCYTES/MACROPHAGES FROM ETHANOL-CONSUMING ANIMALS EXHIBITED HEIGHTENED INFLAMMATION. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARDS MONOCYTES EXPRESSING NEUTROPHIL-LIKE MARKERS WITH HEIGHTENED INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. SINGLE CELL TRANSCRIPTIONAL ANALYSIS OF HSCPS SHOWED REDUCED PROLIFERATION BUT INCREASED INFLAMMATORY MARKERS IN MATURE MYELOID PROGENITORS. WE OBSERVED TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS AS WELL AS OXIDATIVE PHOSPHORYLATION IN IMMATURE AND MATURE MYELOID PROGENITORS. SINGLE CELL ANALYSIS OF THE CHROMATIN LANDSCAPE SHOWED ALTERED DRIVERS OF DIFFERENTIATION IN MONOCYTES AND PROGENITORS. COLLECTIVELY, THESE DATA INDICATE THAT CHRONIC ETHANOL DRINKING RESULTS IN REMODELING OF THE TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPES OF THE BONE MARROW COMPARTMENT LEADING TO ALTERED FUNCTIONS IN THE PERIPHERY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  1788 20 EFFECT OF CHRONIC ETHANOL CONSUMPTION IN RHESUS MACAQUES ON THE NUCLEUS ACCUMBENS CORE TRANSCRIPTOME. THE NUCLEUS ACCUMBENS CORE (NACC) HAS BEEN REPEATEDLY DEMONSTRATED TO BE A KEY COMPONENT OF THE CIRCUITRY ASSOCIATED WITH EXCESSIVE ETHANOL CONSUMPTION. PREVIOUS STUDIES HAVE ILLUSTRATED THAT IN A NONHUMAN PRIMATE (NHP) MODEL OF CHRONIC ETHANOL CONSUMPTION, THERE IS SIGNIFICANT EPIGENETIC REMODELING OF THE NACC. IN THE CURRENT STUDY, RNA-SEQ WAS USED TO EXAMINE GENOME-WIDE GENE EXPRESSION IN EIGHT EACH OF CONTROL, LOW/BINGE (LD*), AND HIGH/VERY HIGH (HD*) RHESUS MACAQUE DRINKERS. USING AN FDR < 0.05, ZERO GENES WERE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED (DE) BETWEEN LD* AND CONTROLS, SIX GENES BETWEEN HD* AND LD*, AND 734 GENES BETWEEN HD* AND CONTROLS. FOCUSING ON HD* VERSUS CONTROL DE GENES, THE UPREGULATED GENES (N = 366) WERE ENRICHED IN GENES WITH ANNOTATIONS ASSOCIATED WITH SIGNAL RECOGNITION PARTICLE (SRP)-DEPENDENT CO-TRANSLATIONAL PROTEIN TARGETING TO MEMBRANE (FDR < 3 X 10(-59) ), STRUCTURAL CONSTITUENT OF RIBOSOME (FDR < 3 X 10(-47) ), AND RIBOSOMAL SUBUNIT (FDR < 5 X 10(-48) ). DOWNREGULATED GENES (N = 363) WERE ENRICHED IN ANNOTATIONS ASSOCIATED WITH BEHAVIOR (FDR < 2 X 10(-4) ), MEMBRANE ORGANIZATION (FDR < 1 X 10(-4) ), INORGANIC CATION TRANSMEMBRANE TRANSPORTER ACTIVITY (FDR < 2 X 10(-3) ), SYNAPSE PART (FDR < 4 X 10(-10) ), GLUTAMATERGIC SYNAPSE (FDR < 1 X 10(-6) ), AND GABAERGIC SYNAPSE (FDR < 6 X 10(-4) ). INGENUITY PATHWAY ANALYSIS (IPA) REVEALED THAT EIF2 SIGNALING AND MTOR PATHWAYS WERE SIGNIFICANTLY UPREGULATED IN HD* ANIMALS (FDR < 3 X 10(-33) AND <2 X 10(-16) , RESPECTIVELY). OVERALL, THE DATA SUPPORTED OUR WORKING HYPOTHESIS; EXCESSIVE CONSUMPTION WOULD BE ASSOCIATED WITH TRANSCRIPTIONAL DIFFERENCES IN GABA/GLUTAMATE-RELATED GENES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5  6540 39 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6   877 32 CHRONIC BINGE ALCOHOL ADMINISTRATION DYSREGULATES GLOBAL REGULATORY GENE NETWORKS ASSOCIATED WITH SKELETAL MUSCLE WASTING IN SIMIAN IMMUNODEFICIENCY VIRUS-INFECTED MACAQUES. BACKGROUND: THERE ARE MORE THAN 1 MILLION PERSONS LIVING WITH HIV/AIDS (PLWHA) IN THE UNITED STATES AND APPROXIMATELY 40 % OF THEM HAVE A HISTORY OF ALCOHOL USE DISORDERS (AUD). CHRONIC HEAVY ALCOHOL CONSUMPTION AND HIV/AIDS BOTH RESULT IN REDUCED LEAN BODY MASS AND MUSCLE DYSFUNCTION, INCREASING THE INCIDENCE OF COMORBID CONDITIONS. PREVIOUS STUDIES FROM OUR LABORATORY USING RHESUS MACAQUES INFECTED WITH SIMIAN IMMUNODEFICIENCY VIRUS (SIV) DEMONSTRATED THAT CHRONIC BINGE ALCOHOL (CBA) ADMINISTRATION IN THE ABSENCE OF ANTIRETROVIRAL THERAPY EXACERBATES SKELETAL MUSCLE (SKM) WASTING AT END-STAGE SIV DISEASE. THE AIM OF THIS STUDY WAS TO CHARACTERIZE HOW CBA ALTERS GLOBAL GENE REGULATORY NETWORKS THAT LEAD TO SKM WASTING AT END-STAGE DISEASE. ADMINISTRATION OF INTRAGASTRIC ALCOHOL OR SUCROSE TO MALE RHESUS MACAQUES BEGAN 3 MONTHS PRIOR TO SIV INFECTION AND CONTINUED THROUGHOUT THE DURATION OF STUDY. HIGH-OUTPUT ARRAY ANALYSIS WAS USED TO DETERMINE CBA-DEPENDENT CHANGES IN MRNA EXPRESSION, MIRNA EXPRESSION, AND PROMOTER METHYLATION STATUS OF SKM AT END-STAGE DISEASE (~10 MONTHS POST-SIV) FROM HEALTHY CONTROL (CONTROL), SUCROSE-ADMINISTERED, SIV-INFECTED (SUC/SIV), AND CBA-ADMINISTERED/SIV-INFECTED (CBA/SIV) MACAQUES. RESULTS: IN ADDITION TO PREVIOUSLY REPORTED EFFECTS ON THE EXTRACELLULAR MATRIX AND THE PROMOTION OF A PRO-INFLAMMATORY ENVIRONMENT, WE FOUND THAT CBA ADVERSELY AFFECTS GENE REGULATORY NETWORKS THAT INVOLVE "UNIVERSAL" CELLULAR FUNCTIONS, PROTEIN HOMEOSTASIS, CALCIUM AND ION HOMEOSTASIS, NEURONAL GROWTH AND SIGNALING, AND SATELLITE CELL GROWTH AND SURVIVAL. CONCLUSIONS: THE RESULTS FROM THIS STUDY PROVIDE AN OVERVIEW OF THE IMPACT OF CBA ON GENE REGULATORY NETWORKS INVOLVED IN BIOLOGICAL FUNCTIONS, INCLUDING TRANSCRIPTIONAL AND EPIGENETIC PROCESSES, ILLUSTRATING THE GENETIC AND MOLECULAR MECHANISMS ASSOCIATED WITH CBA-DEPENDENT SKM WASTING AT END-STAGE SIV INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  2671 39 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  1009 26 CHRONIC VOLUNTARY ETHANOL DRINKING IN CYNOMOLGUS MACAQUES ELICITS GENE EXPRESSION CHANGES IN PREFRONTAL CORTICAL AREA 46. BACKGROUND: GENOME-WIDE PROFILING TO EXAMINE BRAIN TRANSCRIPTIONAL FEATURES ASSOCIATED WITH EXCESSIVE ETHANOL (ETOH) CONSUMPTION HAS BEEN APPLIED TO A VARIETY OF SPECIES INCLUDING RODENTS, NONHUMAN PRIMATES (NHPS), AND HUMANS. HOWEVER, THESE DATA WERE OBTAINED FROM CROSS-SECTIONAL SAMPLES WHICH ARE PARTICULARLY VULNERABLE TO INDIVIDUAL VARIATION WHEN OBTAINED FROM SMALL OUTBRED POPULATIONS TYPICAL OF HUMAN AND NHP STUDIES. IN THE CURRENT STUDY, A NOVEL WITHIN-SUBJECT DESIGN WAS USED TO EXAMINE THE EFFECTS OF VOLUNTARY ETOH CONSUMPTION ON PREFRONTAL CORTEX (PFC) GENE EXPRESSION IN A NHP MODEL. METHODS: TWO COHORTS OF CYNOMOLGUS MACAQUES (N = 23) UNDERWENT A SCHEDULE-INDUCED POLYDIPSIA PROCEDURE TO ESTABLISH ETOH SELF-ADMINISTRATION FOLLOWED BY 6 MONTHS OF DAILY OPEN ACCESS TO ETOH (4% W/V) AND WATER. INDIVIDUAL DAILY ETOH INTAKES RANGED FROM AN AVERAGE OF 0.7 TO 3.7 G/KG/D. DORSAL LATERAL PFC AREA 46 (A46) BRAIN BIOPSIES WERE COLLECTED IN ETOH-NAIVE AND CONTROL MONKEYS; CONTRALATERAL A46 BIOPSIES WERE COLLECTED FROM THE SAME MONKEYS FOLLOWING THE 6 MONTHS OF FLUID CONSUMPTION. GENE EXPRESSION CHANGES WERE ASSESSED USING RNA-SEQ PAIRED ANALYSIS, WHICH ALLOWED FOR CORRECTION OF INDIVIDUAL BASELINE DIFFERENCES IN GENE EXPRESSION. RESULTS: A TOTAL OF 675 GENES WERE SIGNIFICANTLY DOWN-REGULATED FOLLOWING ETOH CONSUMPTION; THESE WERE FUNCTIONALLY ENRICHED FOR IMMUNE RESPONSE, CELL ADHESION, PLASMA MEMBRANE, AND EXTRACELLULAR MATRIX. A TOTAL OF 567 GENES THAT WERE UP-REGULATED FOLLOWING ETOH CONSUMPTION WERE ENRICHED IN MICRORNA TARGET SITES AND INCLUDED TARGET SITES ASSOCIATED WITH TOLL-LIKE RECEPTOR PATHWAYS. THE DIFFERENTIALLY EXPRESSED GENES WERE ALSO SIGNIFICANTLY ENRICHED IN TRANSCRIPTION FACTOR BINDING SITES. CONCLUSIONS: THE DATA PRESENTED HERE ARE THE FIRST TO USE A LONGITUDINAL BIOPSY STRATEGY TO EXAMINE HOW CHRONIC ETOH CONSUMPTION AFFECTS GENE EXPRESSION IN THE PRIMATE PFC. PROMINENT EFFECTS WERE SEEN IN BOTH CELL ADHESION AND NEUROIMMUNE PATHWAYS; THE LATTER CONTAINED BOTH PRO- AND ANTIINFLAMMATORY GENES. THE DATA ALSO INDICATE THAT CHANGES IN MIRNAS AND TRANSCRIPTION FACTORS MAY BE IMPORTANT EPIGENETIC REGULATORS OF ETOH CONSUMPTION.	2020	
                                                                                                                                                                                                                                                                       
9  4723 11 NONHUMAN PRIMATE MODELS OF POLYCYSTIC OVARY SYNDROME. WITH CLOSE GENOMIC AND PHENOTYPIC SIMILARITY TO HUMANS, NONHUMAN PRIMATE MODELS PROVIDE COMPREHENSIVE EPIGENETIC MIMICS OF POLYCYSTIC OVARY SYNDROME (PCOS), SUGGESTING EARLY LIFE TARGETING FOR PREVENTION. FETAL EXPOSURE TO TESTOSTERONE (T), OF ALL NONHUMAN PRIMATE EMULATIONS, PROVIDES THE CLOSEST PCOS-LIKE PHENOTYPES, WITH EARLY-TO-MID GESTATION T-EXPOSED FEMALE RHESUS MONKEYS EXHIBITING ADULT REPRODUCTIVE, ENDOCRINOLOGICAL AND METABOLIC DYSFUNCTIONAL TRAITS THAT ARE CO-PATHOLOGIES OF PCOS. LATE GESTATIONAL T EXPOSURE, WHILE INDUCING ADULT OVARIAN HYPERANDROGENISM AND MENSTRUAL ABNORMALITIES, HAS LESS DYSFUNCTIONAL METABOLIC ACCOMPANIMENT. FETAL EXPOSURES TO DIHYDROTESTOSTERONE (DHT) OR DIETHYLSTILBESTROL (DES) SUGGEST ANDROGENIC AND ESTROGENIC ASPECTS OF FETAL PROGRAMMING. NEONATAL EXPOSURE TO T PRODUCES NO PCOS-LIKE OUTCOME, WHILE CONTINUOUS T TREATMENT OF JUVENILE FEMALES CAUSES PRECOCIOUS WEIGHT GAIN AND EARLY MENARCHE (HIGH T), OR HIGH LH AND WEIGHT GAIN (MODERATE T). ACUTE T EXPOSURE OF ADULT FEMALES GENERATES POLYFOLLICULAR OVARIES, WHILE CHRONIC T EXPOSURE INDUCES SUBTLE MENSTRUAL IRREGULARITIES WITHOUT METABOLIC DYSFUNCTION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  4945 25 PATERNAL PRECONCEPTION EVERY-OTHER-DAY ETHANOL DRINKING ALTERS BEHAVIOR AND ETHANOL CONSUMPTION IN OFFSPRING. ALCOHOL USE DISORDER IS A DEVASTATING DISEASE WITH A COMPLEX ETIOLOGY. RECENT PRECLINICAL STUDIES HAVE REVEALED THAT PATERNAL PRECONCEPTION CHRONIC INTERMITTENT ETHANOL (ETOH) EXPOSURE VIA VAPORIZED ETOH ALTERED DRINKING BEHAVIORS AND SENSITIVITY TO ETOH SELECTIVELY IN MALE OFFSPRING. IN THE CURRENT STUDY, WE USED A VOLUNTARY ORAL ROUTE OF PATERNAL PRECONCEPTION ETOH EXPOSURE, I.E., INTERMITTENT EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING, AND TESTED OFFSPRING FOR BEHAVIORAL ALTERATIONS. FIFTEEN ETOH DRINKING SIRES AND 10 CONTROL SIRES WERE MATED TO ETOH NAIVE FEMALES TO PRODUCE ETOH-SIRED AND CONTROL-SIRED OFFSPRING. THESE OFFSPRING WERE TESTED USING THE ELEVATED PLUS MAZE, OPEN FIELD, DRINKING IN THE DARK, AND UNLIMITED ACCESS TWO-BOTTLE CHOICE ASSAYS. WE FOUND THAT PATERNAL PRECONCEPTION EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING RESULTED IN REDUCED ETOH CONSUMPTION SELECTIVELY IN MALE OFFSPRING IN THE DRINKING IN THE DARK ASSAY COMPARED TO CONTROL-SIRED OFFSPRING. NO DIFFERENCES WERE DETECTED IN EITHER SEX IN THE UNLIMITED ACCESS TWO-BOTTLE CHOICE AND ELEVATED PLUS MAZE ASSAYS. OPEN FIELD ANALYSIS REVEALED COMPLEX CHANGES IN BASAL BEHAVIOR AND ETOH-INDUCED BEHAVIORS THAT WERE SEX SPECIFIC. WE CONCLUDED THAT PATERNAL PRECONCEPTION VOLUNTARY ETOH CONSUMPTION HAS PERSISTENT EFFECTS THAT IMPACT THE NEXT GENERATION. THIS STUDY ADDS TO A GROWING APPRECIATION THAT ONE'S BEHAVIORAL RESPONSE TO ETOH AND ETOH DRINKING BEHAVIOR ARE IMPACTED BY ETOH EXPOSURE OF THE PRIOR GENERATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  5425 22 REGULATION OF MYELOPOIESIS BY THE TRANSCRIPTION FACTOR IRF8. INTERFERON REGULATORY FACTOR-8 (IRF8) IS A TRANSCRIPTION FACTOR EXPRESSED IN HEMATOPOIETIC CELLS, PARTICULARLY IN MONONUCLEAR PHAGOCYTES [MONOCYTES/MACROPHAGES AND DENDRITIC CELLS (DCS)] AND THEIR PROGENITORS. VARIOUS STUDIES HAVE DEMONSTRATED THAT IRF8 IS ESSENTIAL FOR THE DEVELOPMENT OF MONOCYTES, DCS, EOSINOPHILS, AND BASOPHILS. CONVERSELY, IRF8 SUPPRESSES THE GENERATION OF NEUTROPHILS. ACCORDINGLY, IRF8 (-/-) MICE DEVELOP IMMUNODEFICIENCY AND A CHRONIC MYELOID LEUKEMIA (CML)-LIKE DISEASE. MUTATIONS AND LOSS OF EXPRESSION OF THE HUMAN IRF8 GENE ARE ALSO ASSOCIATED WITH IMMUNODEFICIENCY AND CML, RESPECTIVELY. RECENT FINDINGS HAVE BEGUN TO REVEAL THE TRANSCRIPTION FACTOR NETWORK AND EPIGENETIC CHANGES GOVERNED BY IRF8. FOR EXAMPLE, IN MONONUCLEAR PHAGOCYTE PROGENITORS, IRF8 COOPERATES WITH PU.1 TO PROMOTE THE FORMATION OF PROMOTER-DISTAL ENHANCERS TO INDUCE MONOCYTE-RELATED GENES INCLUDING THE CRITICAL DOWNSTREAM TRANSCRIPTION FACTOR GENE KLF4. ON THE OTHER HAND, IRF8 BLOCKS C/EBPALPHA ACTIVITY TO SUPPRESS THE NEUTROPHIL DIFFERENTIATION PROGRAM. INDEED, IRF8 (-/-) MONONUCLEAR PHAGOCYTE PROGENITORS FAIL TO EFFICIENTLY GENERATE MONOCYTES AND DCS AND, INSTEAD, ABERRANTLY GIVE RISE TO NEUTROPHILS. THIS ARTICLE PROVIDES AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF IRF8 IN MYELOPOIESIS AND RELATED DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12   914 35 CHRONIC HEAVY DRINKING DRIVES DISTINCT TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN SPLENIC MACROPHAGES. BACKGROUND: CHRONIC HEAVY ALCOHOL DRINKING (CHD) LEADS TO SIGNIFICANT ORGAN DAMAGE, INCREASED SUSCEPTIBILITY TO INFECTIONS, AND DELAYED WOUND HEALING. THESE ADVERSE OUTCOMES ARE BELIEVED TO BE MEDIATED BY ALTERATIONS IN THE FUNCTION OF MYELOID CELLS; HOWEVER, THE MECHANISMS UNDERLYING THESE CHANGES ARE POORLY UNDERSTOOD. METHODS: WE DETERMINED THE IMPACT OF CHD ON THE PHENOTYPE OF SPLENIC MACROPHAGES USING FLOW CYTOMETRY. CHANGES IN FUNCTIONAL RESPONSES TO LPS WERE MEASURED USING LUMINEX AND RNA-SEQ. FINALLY, ALTERATIONS IN CHROMATIN ACCESSIBILITY WERE UNCOVERED USING ATAC-SEQ. FINDINGS: A HISTORY OF CHD LED TO INCREASED FREQUENCY OF SPLENIC MACROPHAGES THAT EXHIBITED A HEIGHTENED ACTIVATION STATE AT RESTING. ADDITIONALLY, SPLENIC MACROPHAGES FROM CHD ANIMALS GENERATED A LARGER INFLAMMATORY RESPONSE TO LPS, BOTH AT PROTEIN AND GENE EXPRESSION LEVELS. FINALLY, CHD RESULTED IN INCREASED LEVELS OF H3K4ME3, A HISTONE MARK OF ACTIVE PROMOTERS, AS WELL AS CHROMATIN ACCESSIBILITY AT PROMOTERS AND INTERGENIC REGIONS THAT REGULATE INFLAMMATORY RESPONSES. INTERPRETATION: THESE FINDINGS SUGGEST THAT A HISTORY OF CHD ALTERS THE IMMUNE FITNESS OF TISSUE-RESIDENT MACROPHAGES VIA EPIGENETIC MECHANISMS. FUND: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM (NIAAA), NATIONAL INSTITUTES OF HEALTH (NIH) - R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, AND R21AA025839.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  6639 26 UNRAVELING THE EPIGENOMIC AND TRANSCRIPTOMIC INTERPLAY DURING ALCOHOL-INDUCED ANXIOLYSIS. POSITIVE EFFECTS OF ALCOHOL DRINKING SUCH AS ANXIOLYSIS AND EUPHORIA APPEAR TO BE A CRUCIAL FACTOR IN THE INITIATION AND MAINTENANCE OF ALCOHOL USE DISORDER (AUD). HOWEVER, THE MECHANISMS THAT LEAD FROM CHROMATIN REORGANIZATION TO TRANSCRIPTOMIC CHANGES AFTER ACUTE ETHANOL EXPOSURE REMAIN UNKNOWN. HERE, WE USED ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN FOLLOWED BY HIGH THROUGHPUT SEQUENCING (ATAC-SEQ) AND RNA-SEQ TO INVESTIGATE EPIGENOMIC AND TRANSCRIPTOMIC CHANGES THAT UNDERLIE ANXIOLYTIC EFFECTS OF ACUTE ETHANOL USING AN ANIMAL MODEL. ANALYSIS OF ATAC-SEQ DATA REVEALED AN OVERALL OPEN OR PERMISSIVE CHROMATIN STATE THAT WAS ASSOCIATED WITH TRANSCRIPTOMIC CHANGES IN THE AMYGDALA AFTER ACUTE ETHANOL EXPOSURE. WE IDENTIFIED A CANDIDATE GENE, HIF3A (HYPOXIA-INDUCIBLE FACTOR 3, ALPHA SUBUNIT), THAT HAD 'OPEN' CHROMATIN REGIONS (ATAC-SEQ PEAKS), ASSOCIATED WITH SIGNIFICANTLY INCREASED ACTIVE EPIGENETIC HISTONE ACETYLATION MARKS AND DECREASED DNA METHYLATION AT THESE REGIONS. THE MRNA LEVELS OF HIF3A WERE INCREASED BY ACUTE ETHANOL EXPOSURE, BUT DECREASED IN THE AMYGDALA DURING WITHDRAWAL AFTER CHRONIC ETHANOL EXPOSURE. KNOCKDOWN OF HIF3A EXPRESSION IN THE CENTRAL NUCLEUS OF AMYGDALA ATTENUATED ACUTE ETHANOL-INDUCED INCREASES IN HIF3A MRNA LEVELS AND BLOCKED ANXIOLYSIS IN RATS. THESE DATA INDICATE THAT CHROMATIN ACCESSIBILITY AND TRANSCRIPTOMIC SIGNATURES IN THE AMYGDALA AFTER ACUTE ETHANOL EXPOSURE UNDERLIE ANXIOLYSIS AND POSSIBLY PRIME THE CHROMATIN FOR THE DEVELOPMENT OF AUD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  2120 14 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  2156 22 EPIGENETIC MECHANISMS ARE INVOLVED IN THE REGULATION OF ETHANOL CONSUMPTION IN MICE. BACKGROUND: REPEATED ALCOHOL EXPOSURE IS KNOWN TO INCREASE SUBSEQUENT ETHANOL CONSUMPTION IN MICE. HOWEVER, THE UNDERLYING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. ONE POSTULATED MECHANISM INVOLVES EPIGENETIC MODIFICATIONS, INCLUDING HISTONE MODIFICATIONS AND DNA METHYLATION OF RELEVANT GENES SUCH AS NR2B OR BDNF. METHODS: TO INVESTIGATE THE ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF ALCOHOL DRINKING BEHAVIOR, AN ESTABLISHED CHRONIC INTERMITTENT ETHANOL EXPOSURE REINFORCED ETHANOL DRINKING MOUSE MODEL WITH VAPOR INHALATION OVER TWO 9-DAY TREATMENT REGIMENS WAS USED. THE DNA METHYLTRANSFERASE INHIBITOR, 5-AZACYTIDINE OR THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A WAS ADMINISTERED (INTRAPERITONEALLY) TO C57BL/6 MICE 30 MIN BEFORE DAILY EXPOSURE TO CHRONIC INTERMITTENT ETHANOL. CHANGES IN ETHANOL CONSUMPTION WERE MEASURED USING THE 2-BOTTLE CHOICE TEST. RESULTS: THE RESULTS INDICATED THAT SYSTEMIC ADMINISTRATION OF TRICHOSTATIN A (2.5 MICROG/G) FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING, BUT SYSTEMIC ADMINISTRATION OF 5-AZACYTIDINE (2 MICROG/G) DID NOT CAUSE THE SAME EFFECT. HOWEVER, WHEN 5-AZACYTIDINE WAS ADMINISTERED BY INTRACEREBROVENTRICULAR INJECTION, IT FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING. FURTHERMORE, THE INCREASED DRINKING CAUSED BY CHRONIC INTERMITTENT ETHANOL WAS PREVENTED BY INJECTION OF A METHYL DONOR, S-ADENOSYL-L-METHIONINE. TO PROVIDE EVIDENCE THAT CHRONIC INTERMITTENT ETHANOL- OR TRICHOSTATIN A-INDUCED DNA DEMETHYLATION AND HISTONE MODIFICATIONS OF THE NR2B PROMOTER MAY UNDERLIE THE ALTERED ETHANOL CONSUMPTION, WE EXAMINED EPIGENETIC MODIFICATIONS AND NR2B EXPRESSION IN THE PREFRONTAL CORTEX OF THESE MICE. CHRONIC INTERMITTENT ETHANOL OR TRICHOSTATIN A DECREASED DNA METHYLATION AND INCREASED HISTONE ACETYLATION IN THE NR2B GENE PROMOTER, AS WELL AS MRNA LEVELS OF NR2B IN THESE MICE. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS INDICATE THAT EPIGENETIC MODIFICATIONS ARE INVOLVED IN REGULATING ETHANOL DRINKING BEHAVIOR, PARTIALLY THROUGH ALTERING NR2B EXPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                
16   894 22 CHRONIC ETHANOL FEEDING ALTERS HEPATOCYTE MEMORY WHICH IS NOT ALTERED BY ACUTE FEEDING. BACKGROUND: GENE EXPRESSION CHANGES IN THE LIVER AFTER ACUTE BINGE DRINKING MAY DIFFER FROM THE CHANGES SEEN IN CHRONIC ETHANOL FEEDING IN THE RAT. THE CHANGES IN GENE EXPRESSION AFTER CHRONIC ETHANOL FEEDING MAY SENSITIZE THE LIVER TO ALCOHOL-INDUCED LIVER DAMAGE, WHICH IS NOT SEEN AFTER ACUTE BINGE DRINKING. METHODS: TO TEST THIS HYPOTHESIS, GENE MICROARRAY ANALYSIS WAS PERFORMED ON THE LIVERS OF RATS (N = 3) FED AN ACUTE BINGE DOSE OF ETHANOL (6 G/KG BODY WT) AND KILLED AT 3 AND 12 HOURS AFTER ETHANOL BY GAVAGE. THE GENE MICROARRAYS WERE COMPARED WITH THOSE MADE ON THE LIVER OF RATS FROM A PREVIOUS STUDY, IN WHICH THE RATS WERE FED ETHANOL BY INTRAGASTRIC TUBE FOR 1 MONTH (36% OF CALORIES DERIVED FROM ETHANOL). RESULTS: MICROARRAY ANALYSIS DATA VARIED BETWEEN THE ACUTE AND CHRONIC MODELS IN SEVERAL IMPORTANT RESPECTS. GROWTH FACTORS INCREASED MAINLY IN THE CHRONIC ALCOHOL FED RAT. CHANGES IN ENZYMES INVOLVED IN OXIDATIVE STRESS WERE NOTED ONLY WITH CHRONIC ETHANOL FEEDING. GENE EXPRESSION OF FAT METABOLISM WAS INCREASED ONLY WITH CHRONIC ETHANOL FEEDING. MOST IMPORTANTLY, EPIGENETIC RELATED ENZYMES AND ACETYLATION AND METHYLATION OF HISTONES CHANGED ONLY AFTER CHRONIC ETHANOL FEEDING. CONCLUSIONS: THE RESULTS SUPPORT THE CONCEPT THAT CHRONIC ETHANOL INGESTION INDUCES ALTERED GENE EXPRESSION AS A RESULT OF CHANGES IN EPIGENETIC MECHANISMS, WHERE ACETYLATION AND METHYLATION OF HISTONES WERE ALTERED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  5445 20 REPEATED VAPOR ETHANOL EXPOSURE INDUCES TRANSIENT HISTONE MODIFICATIONS IN THE BRAIN THAT ARE MODIFIED BY GENOTYPE AND BRAIN REGION. BACKGROUND: EMERGING RESEARCH IMPLICATES ETHANOL (ETOH)-INDUCED EPIGENETIC MODIFICATIONS IN REGULATING GENE EXPRESSION AND ETOH CONSUMPTION. HOWEVER, CONSENSUS ON SPECIFIC EPIGENETIC MODIFICATIONS INDUCED BY ETOH HAS NOT YET EMERGED, MAKING IT CHALLENGING TO IDENTIFY MECHANISMS AND DEVELOP TARGETED TREATMENTS. WE HYPOTHESIZED THAT CHRONIC INTERMITTENT ETOH (CIE) INDUCES PERSISTENT CHANGES IN HISTONE MODIFICATIONS ACROSS THE CEREBRAL CORTEX (CCX), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC), AND THAT THESE HISTONE MODIFICATIONS ARE ALTERED IN A KNOCK-IN MOUSE STRAIN WITH ALTERED SENSITIVITY TO ETOH. METHODS: C57BL/6J (B6) MICE AND ALPHA1SHLA KNOCKIN MICE ON A B6 BACKGROUND WERE EXPOSED TO 16 H OF VAPOR ETOH OR ROOM AIR FOLLOWED BY 8 H OF ROOM AIR FOR 4 CONSECUTIVE DAYS AND SACRIFICED AT MULTIPLE TIME POINTS UP TO 72 H FOLLOWING EXPOSURE. HISTONE MODIFICATIONS WERE ASSESSED USING WESTERN BLOT AND DOT BLOT. RT-QPCR WAS USED TO STUDY EXPRESSION OF CHROMATIN MODIFYING ENZYMES IN NAC AND PFC. RESULTS: IN NAC, CIE SIGNIFICANTLY INCREASED ACETYLATION OF HISTONE SUBUNIT H3 AT LYSINE 9 (H3K9AC) BUT NOT LYSINE 14 (H3K14AC) OR LYSINE 27 (H3K27AC). IN PFC, CIE SIGNIFICANTLY INCREASED H3K9AC BUT NOT H3K14 OR H3K27AC. THERE WERE NO SIGNIFICANT CHANGES AT 8 OR 72 H AFTER ETOH EXPOSURE IN EITHER NAC OR PFC. CIE WAS ALSO ASSOCIATED WITH INCREASED EXPRESSION OF KAT2B, KAT5, AND TET1 IN NAC BUT NOT PFC. IN CCX, CIE HAD A SIGNIFICANT EFFECT ON LEVELS OF H3K18AC; THERE WAS ALSO A SIGNIFICANT EFFECT OF THE ALPHA1SHLA MUTATION ON LEVELS OF H3K27ME3, H3K14AC, AND H3K18AC AS WELL AS A TREND FOR H3S10PK14AC. CONCLUSIONS: THE ETOH-INDUCED HISTONE MODIFICATIONS OBSERVED WERE TRANSIENT AND VARIED SIGNIFICANTLY BETWEEN BRAIN REGIONS. A GENETIC MUTATION THAT ALTERED SENSITIVITY TO ETOH WAS ASSOCIATED WITH ALTERED INDUCTION OF HISTONE MODIFICATIONS DURING CIE. THESE RESULTS HAVE IMPLICATIONS FOR STUDYING ETOH-INDUCED HISTONE MODIFICATIONS AND ETOH SENSITIVITY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  4944 20 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19   893 26 CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL IMPAIR SYNAPTIC GABA(A) RECEPTOR-MEDIATED NEUROTRANSMISSION IN DEEP-LAYER PREFRONTAL CORTEX. BACKGROUND: THE PREFRONTAL CORTEX (PFC) ACTS AS AN INTEGRATIVE HUB FOR THE PROCESSING OF CORTICAL AND SUBCORTICAL INPUT INTO MEANINGFUL EFFERENT SIGNALING, PERMITTING COMPLEX ASSOCIATIVE BEHAVIORS. PFC DYSFUNCTION IS CONSISTENTLY OBSERVED WITH ETHANOL (ETOH) DEPENDENCE AND IS A CORE COMPONENT OF THE PATHOLOGY OF ALCOHOL USE DISORDERS IN CURRENT MODELS OF ADDICTION. WHILE INTRACORTICAL GAMMA-AMINOBUTRYRIC ACID (GABA)ERGIC NEUROTRANSMISSION IS UNDERSTOOD TO BE ESSENTIAL FOR MAINTAINING COORDINATED NETWORK ACTIVITY WITHIN THE CORTEX, RELATIVELY LITTLE IS KNOWN REGARDING FUNCTIONAL GABAERGIC ADAPTATIONS IN PFC DURING ETOH DEPENDENCE. METHODS: IN THE PRESENT STUDY, MALE AND FEMALE (> POSTNATAL DAY 60) SPRAGUE-DAWLEY RATS WERE ADMINISTERED ETOH (5.0 G/KG; INTRAGASTRIC GAVAGE) FOR 14 TO 15 CONSECUTIVE DAYS. TWENTY-FOUR HOURS AFTER THE FINAL ADMINISTRATION, ANIMALS WERE SACRIFICED AND BRAINS EXTRACTED FOR ELECTROPHYSIOLOGICAL RECORDINGS OF ISOLATED GABA(A) RECEPTOR-MEDIATED CURRENTS OR ANALYSIS OF GABA(A) RECEPTOR SUBUNIT PROTEIN EXPRESSION IN DEEP-LAYER PFC NEURONS. RESULTS: CHRONIC ETOH EXPOSURE SIGNIFICANTLY ATTENUATED ACTIVITY-DEPENDENT SPONTANEOUS GABA(A) RECEPTOR-MEDIATED INHIBITORY POSTSYNAPTIC CURRENT (IPSC) FREQUENCY WITH NO EFFECT ON AMPLITUDE. FURTHERMORE, ANALYSIS OF IPSC DECAY KINETICS REVEALED A SIGNIFICANT ENHANCEMENT OF IPSC DECAY TIME THAT WAS ASSOCIATED WITH DECREMENTS IN EXPRESSION OF THE ALPHA1 GABA(A) RECEPTOR SUBUNIT, INDICATIVE OF FURTHER IMPAIRED PHASIC INHIBITION. THESE PHENOMENA OCCURRED IRRESPECTIVE OF NEURON PROJECTION DESTINATION AND SEX. BASED ON PREVIOUS OBSERVATIONS BY OUR LABORATORY OF AN EPIGENETIC MECHANISM FOR ETOH-INDUCED CHANGES IN CORTICAL GABA(A) RECEPTOR SUBUNIT EXPRESSION, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A WAS ADMINISTERED TO WATER- AND ETOH-EXPOSED ANIMALS, AND PREVENTED ETOH-INDUCED CHANGES IN SPONTANEOUS IPSC FREQUENCY, IPSC DECAY KINETICS, AND GABA(A) RECEPTOR SUBUNIT EXPRESSION. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS DEMONSTRATE THAT CHRONIC ETOH EXPOSURE IMPAIRS SYNAPTIC INHIBITORY NEUROTRANSMISSION IN DEEP-LAYER PYRAMIDAL NEURONS OF THE MEDIAL PFC IN BOTH MALE AND FEMALE RATS. THESE MALADAPTATIONS OCCUR IN NEURONS PROJECTING TO NUMEROUS REGIONS IMPLICATED IN THE SEQUELAE OF ETOH DEPENDENCE, OFFERING A MECHANISTIC LINK BETWEEN THE MANIFESTATION OF PFC DYSFUNCTION AND NEGATIVE AFFECTIVE STATES OBSERVED WITH EXTENDED CONSUMPTION.	2019	

20  1715 25 DYSLIPIDEMIC DIET-INDUCED MONOCYTE "PRIMING" AND DYSFUNCTION IN NON-HUMAN PRIMATES IS TRIGGERED BY ELEVATED PLASMA CHOLESTEROL AND ACCOMPANIED BY ALTERED HISTONE ACETYLATION. MONOCYTES AND THE RECRUITMENT OF MONOCYTE-DERIVED MACROPHAGES INTO SITES OF INFLAMMATION PLAY A KEY ROLE IN ATHEROGENESIS AND OTHER CHRONIC INFLAMMATORY DISEASES LINKED TO CARDIOMETABOLIC SYNDROME AND OBESITY. PREVIOUS STUDIES FROM OUR GROUP HAVE SHOWN THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING, I.E., ENHANCED ADHESION AND ACCELERATED CHEMOTAXIS OF MONOCYTES IN RESPONSE TO CHEMOKINES, BOTH IN VITRO AND IN DYSLIPIDEMIC LDLR(-/-) MICE. WE ALSO SHOWED THAT METABOLIC STRESS-INDUCED MONOCYTE DYSFUNCTION IS, AT LEAST TO A LARGE EXTENT CAUSED BY THE S-GLUTATHIONYLATION, INACTIVATION, AND SUBSEQUENT DEGRADATION OF MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHATASE 1. HERE, WE ANALYZED THE EFFECTS OF A WESTERN-STYLE, DYSLIPIDEMIC DIET (DD), WHICH WAS COMPOSED OF HIGH LEVELS OF SATURATED FAT, CHOLESTEROL, AND SIMPLE SUGARS, ON MONOCYTE (DYS)FUNCTION IN NON-HUMAN PRIMATES (NHPS). WE FOUND THAT SIMILAR TO MICE, A DD ENHANCES MONOCYTE CHEMOTAXIS IN NHP WITHIN 4 WEEKS, OCCURRING CONCORDANTLY WITH THE ONSET OF HYPERCHOLESTEROLEMIA BUT PRIOR TO CHANGES IN TRIGLYCERIDES, BLOOD GLUCOSE, MONOCYTOSIS, OR CHANGES IN MONOCYTE SUBSET COMPOSITION. IN ADDITION, WE IDENTIFIED TRANSITORY DECREASES IN THE ACETYLATION OF HISTONE H3 AT THE LYSINE RESIDUES 18 AND 23 IN METABOLICALLY PRIMED MONOCYTES, AND WE FOUND THAT MONOCYTE PRIMING WAS CORRELATED WITH THE ACETYLATION OF HISTONE H3 AT LYSINE 27 AFTER AN 8-WEEK DD REGIMEN. OUR DATA SHOW THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING AND HYPER-CHEMOTACTIC RESPONSES IN NHP. THE HISTONE MODIFICATIONS ACCOMPANYING MONOCYTE PRIMING IN PRIMATES SUGGEST A REPROGRAMMING OF THE EPIGENETIC LANDSCAPE, WHICH MAY LEAD TO DYSREGULATED RESPONSES AND FUNCTIONALITIES IN MACROPHAGES DERIVED FROM PRIMED MONOCYTES THAT ARE RECRUITED TO SITES OF INFLAMMATION.	2017