1  370 151 AN APICOMPLEXAN BROMODOMAIN PROTEIN, TGBDP1, ASSOCIATES WITH DIVERSE EPIGENETIC FACTORS TO REGULATE ESSENTIAL TRANSCRIPTIONAL PROCESSES IN TOXOPLASMA GONDII. THE PROTOZOAN PATHOGEN TOXOPLASMA GONDII RELIES ON TIGHT REGULATION OF GENE EXPRESSION TO INVADE AND ESTABLISH INFECTION IN ITS HOST. THE DIVERGENT GENE REGULATORY MECHANISMS OF TOXOPLASMA AND RELATED APICOMPLEXAN PATHOGENS RELY HEAVILY ON REGULATORS OF CHROMATIN STRUCTURE AND HISTONE MODIFICATIONS. THE IMPORTANT CONTRIBUTION OF HISTONE ACETYLATION FOR TOXOPLASMA IN BOTH ACUTE AND CHRONIC INFECTION HAS BEEN DEMONSTRATED, WHERE HISTONE ACETYLATION INCREASES AT ACTIVE GENE LOCI. HOWEVER, THE DIRECT CONSEQUENCES OF SPECIFIC HISTONE ACETYLATION MARKS AND THE CHROMATIN PATHWAY THAT INFLUENCES TRANSCRIPTIONAL REGULATION IN RESPONSE TO THE MODIFICATION ARE UNCLEAR. AS A READER OF LYSINE ACETYLATION, THE BROMODOMAIN SERVES AS A MEDIATOR BETWEEN THE ACETYLATED HISTONE AND TRANSCRIPTIONAL REGULATORS. HERE WE SHOW THAT THE BROMODOMAIN PROTEIN, TGBDP1, WHICH IS CONSERVED AMONG APICOMPLEXA AND WITHIN THE ALVEOLATA SUPERPHYLUM, IS ESSENTIAL FOR TOXOPLASMA ASEXUAL PROLIFERATION. USING CLEAVAGE UNDER TARGETS AND TAGMENTATION, WE DEMONSTRATE THAT TGBDP1 IS RECRUITED TO TRANSCRIPTIONAL START SITES OF A LARGE PROPORTION OF PARASITE GENES. TRANSCRIPTIONAL PROFILING DURING TGBDP1 KNOCKDOWN REVEALED THAT LOSS OF TGBDP1 LEADS TO MAJOR DYSREGULATION OF GENE EXPRESSION, IMPLYING MULTIPLE ROLES FOR TGBDP1 IN BOTH GENE ACTIVATION AND REPRESSION. THIS IS SUPPORTED BY INTERACTOME ANALYSIS OF TGBDP1 DEMONSTRATING THAT TGBDP1 FORMS A CORE COMPLEX WITH TWO OTHER BROMODOMAIN PROTEINS AND AN APIAP2 FACTOR. THIS CORE COMPLEX APPEARS TO INTERACT WITH OTHER EPIGENETIC FACTORS SUCH AS NUCLEOSOME REMODELING COMPLEXES. WE CONCLUDE THAT TGBDP1 INTERACTS WITH DIVERSE EPIGENETIC REGULATORS TO EXERT OPPOSING INFLUENCES ON GENE EXPRESSION IN THE TOXOPLASMA TACHYZOITE. IMPORTANCE HISTONE ACETYLATION IS CRITICAL FOR PROPER REGULATION OF GENE EXPRESSION IN THE SINGLE-CELLED EUKARYOTIC PATHOGEN TOXOPLASMA GONDII. BROMODOMAIN PROTEINS ARE "READERS" OF HISTONE ACETYLATION AND MAY LINK THE MODIFIED CHROMATIN TO TRANSCRIPTION FACTORS. HERE, WE SHOW THAT THE BROMODOMAIN PROTEIN TGBDP1 IS ESSENTIAL FOR PARASITE SURVIVAL AND THAT LOSS OF TGBDP1 RESULTS IN GLOBAL DYSREGULATION OF GENE EXPRESSION. TGBDP1 IS RECRUITED TO THE PROMOTER REGION OF A LARGE PROPORTION OF PARASITE GENES, FORMS A CORE COMPLEX WITH TWO OTHER BROMODOMAIN PROTEINS, AND INTERACTS WITH DIFFERENT TRANSCRIPTIONAL REGULATORY COMPLEXES. WE CONCLUDE THAT TGBDP1 IS A KEY FACTOR FOR SENSING SPECIFIC HISTONE MODIFICATIONS TO INFLUENCE MULTIPLE FACETS OF TRANSCRIPTIONAL REGULATION IN TOXOPLASMA GONDII.	2023	

2  984  37 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 5153  30 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4 3049  36 GENOME-WIDE ANALYSIS REVEALS ZINC TRANSPORTER ZIP9 REGULATED BY DNA METHYLATION PROMOTES RADIATION-INDUCED SKIN FIBROSIS VIA THE TGF-BETA SIGNALING PATHWAY. RADIATION-INDUCED SKIN FIBROSIS IS A DETRIMENTAL AND CHRONIC DISORDER THAT OCCURS AFTER RADIATION EXPOSURE. DNA METHYLATION HAS BEEN CHARACTERIZED AS AN IMPORTANT REGULATORY MECHANISM OF MULTIPLE PATHOLOGICAL PROCESSES. IN THIS STUDY, WE COMPARED THE GENOME-WIDE DNA METHYLATION STATUS IN RADIATION-INDUCED FIBROTIC SKIN AND ADJACENT NORMAL TISSUES OF RATS BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. RADIATION-INDUCED FIBROTIC SKIN SHOWED DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH 3,650 PROTEIN-CODING GENES, 72 MICRORNAS, 5,836 LONG NONCODING RNAS AND 3 PIWI-INTERACTING RNAS. BY INTEGRATING THE MRNA AND METHYLATION PROFILES, THE ZINC TRANSPORTER SLC39A9/ZIP9 WAS INVESTIGATED IN GREATER DETAIL. THE PROTEIN LEVEL OF ZIP9 WAS INCREASED IN IRRADIATED SKIN TISSUES OF HUMANS, MONKEYS, AND RATS, ESPECIALLY IN RADIOGENIC FIBROTIC SKIN TISSUES. RADIATION INDUCED THE DEMETHYLATION OF A CPG DINUCLEOTIDE IN EXON 1 OF ZIP9 THAT RESULTED IN RECRUITMENT OF THE TRANSCRIPTIONAL FACTOR SP1 AND INCREASED ZIP9 EXPRESSION. OVEREXPRESSION OF ZIP9 RESULTED IN ACTIVATION OF THE PROFIBROTIC TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY THROUGH PROTEIN KINASE B IN HUMAN FIBROBLASTS. IN ADDITION, RADIATION-INDUCED SKIN FIBROSIS WAS ASSOCIATED WITH INCREASED ZINC ACCUMULATION. THE ZINC CHELATOR N,N,N',N'-TETRAKIS(2-PYRIDYLMETHYL)-1,2-ETHYLENEDIAMINE ABROGATED ZIP9-INDUCED ACTIVATION OF THE TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY AND ATTENUATED RADIATION-INDUCED SKIN FIBROSIS IN A RAT MODEL. IN SUMMARY, OUR FINDINGS ILLUSTRATE EPIGENETIC REGULATION OF ZIP9 AND ITS CRITICAL ROLE IN PROMOTING RADIATION-INDUCED SKIN FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5 3327  41 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  662  39 BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME ANALYSES REVEAL LOCI ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. LITTLE IS KNOWN REGARDING THE EPIGENETIC BASIS OF ATHEROSCLEROSIS. HERE WE PRESENT THE CD14+ BLOOD MONOCYTE TRANSCRIPTOME AND EPIGENOME SIGNATURES ASSOCIATED WITH HUMAN ATHEROSCLEROSIS. THE TRANSCRIPTOME SIGNATURE INCLUDES TRANSCRIPTION COACTIVATOR, ARID5B, WHICH IS KNOWN TO FORM A CHROMATIN DEREPRESSOR COMPLEX WITH A HISTONE H3K9ME2-SPECIFIC DEMETHYLASE AND PROMOTE ADIPOGENESIS AND SMOOTH MUSCLE DEVELOPMENT. ARID5B CPG (CG25953130) METHYLATION IS INVERSELY ASSOCIATED WITH BOTH ARID5B EXPRESSION AND ATHEROSCLEROSIS, CONSISTENT WITH THIS CPG RESIDING IN AN ARID5B ENHANCER REGION, BASED ON CHROMATIN CAPTURE AND HISTONE MARKS DATA. MEDIATION ANALYSIS SUPPORTS ASSUMPTIONS THAT ARID5B EXPRESSION MEDIATES EFFECTS OF CG25953130 METHYLATION AND SEVERAL CARDIOVASCULAR DISEASE RISK FACTORS ON ATHEROSCLEROTIC BURDEN. IN LIPOPOLYSACCHARIDE-STIMULATED HUMAN THP1 MONOCYTES, ARID5B KNOCKDOWN REDUCED EXPRESSION OF GENES INVOLVED IN ATHEROSCLEROSIS-RELATED INFLAMMATORY AND LIPID METABOLISM PATHWAYS, AND INHIBITED CELL MIGRATION AND PHAGOCYTOSIS. THESE DATA SUGGEST THAT ARID5B EXPRESSION, POSSIBLY REGULATED BY AN EPIGENETICALLY CONTROLLED ENHANCER, PROMOTES ATHEROSCLEROSIS BY DYSREGULATING IMMUNOMETABOLISM TOWARDS A CHRONIC INFLAMMATORY PHENOTYPE.THE MOLECULAR MECHANISMS MEDIATING THE IMPACT OF ENVIRONMENTAL FACTORS IN ATHEROSCLEROSIS ARE UNCLEAR. HERE, THE AUTHORS EXAMINE CD14+ BLOOD MONOCYTE'S TRANSCRIPTOME AND EPIGENOME SIGNATURES TO FIND DIFFERENTIAL METHYLATION AND EXPRESSION OF ARID5B TO BE ASSOCIATED WITH HUMAN ATHEROSCLEROSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7 3465  39 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS.	2019	
                                                                                                                                                                                                                                                                                                                                         
8 3390  38 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 1334  38 DEREGULATION OF AIOLOS EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE NEOPLASTIC B CELLS THAT ARE RESISTANT TO APOPTOSIS. AIOLOS, A MEMBER OF THE IKAROS FAMILY OF ZINC-FINGER TRANSCRIPTION FACTORS, PLAYS AN IMPORTANT ROLE IN THE CONTROL OF MATURE B LYMPHOCYTE DIFFERENTIATION AND MATURATION. IN THIS STUDY, WE SHOWED THAT AIOLOS EXPRESSION IS UP-REGULATED IN B-CLL CELLS. THIS OVEREXPRESSION DOES NOT IMPLICATE ISOFORM IMBALANCE OR DISTURB AIOLOS SUBCELLULAR LOCALIZATION. THE CHROMATIN STATUS AT THE AIOLOS PROMOTER IN CLL IS DEFINED BY THE DEMETHYLATION OF DNA AND AN ENRICHMENT OF EUCHROMATIN ASSOCIATED HISTONE MARKERS, SUCH AS THE DIMETHYLATION OF THE LYSINE 4 ON HISTONE H3. THESE EPIGENETIC MODIFICATIONS SHOULD ALLOW ITS UPSTREAM EFFECTORS, SUCH AS NUCLEAR FACTOR-KAPPAB, CONSTITUTIVELY ACTIVATED IN CLL, TO GAIN ACCESS TO PROMOTER, RESULTING UP-REGULATION OF AIOLOS. TO DETERMINE THE CONSEQUENCES OF AIOLOS DEREGULATION IN CLL, WE ANALYZED THE EFFECTS OF AIOLOS OVEREXPRESSION OR DOWN-REGULATION ON APOPTOSIS. AIOLOS IS INVOLVED IN CELL SURVIVAL BY REGULATING THE EXPRESSION OF SOME BCL-2 FAMILY MEMBERS. OUR RESULTS STRONGLY SUGGEST THAT AIOLOS DEREGULATION BY EPIGENETIC MODIFICATIONS MAY BE A HALLMARK OF CLL.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 5433  28 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 6059  33 THE DEVELOPMENT OF A SENSITIVE FLUORESCENT PROTEIN-BASED TRANSCRIPT REPORTER FOR HIGH THROUGHPUT SCREENING OF NEGATIVE MODULATORS OF LNCRNAS. WHILE THE HUMAN GENOME IS PERVASIVELY TRANSCRIBED, <2% OF THE HUMAN GENOME IS TRANSCRIBED INTO PROTEIN-CODING MRNAS, LEAVING MOST OF THE TRANSCRIPTS AS NONCODING RNAS, SUCH AS MICRORNAS AND LONG-NONCODING RNAS (LNCRNAS), WHICH ARE CRITICAL COMPONENTS OF EPIGENETIC REGULATION. LNCRNAS ARE EMERGING AS CRITICAL REGULATORS OF GENE EXPRESSION AND GENOMIC STABILITY. HOWEVER, IT REMAINS LARGELY UNKNOWN ABOUT HOW LNCRNAS ARE REGULATED. HERE, WE DEVELOP A HIGHLY SENSITIVE AND DYNAMIC REPORTER THAT ALLOWS US TO IDENTIFY AND/OR MONITOR NEGATIVE MODULATORS OF LNCRNA TRANSCRIPT LEVELS IN A HIGH THROUGHPUT FASHION. SPECIFICALLY, WE ENGINEER A FLUORESCENT FUSION PROTEIN BY FUSING THREE COPIES OF THE PEST DESTRUCTION DOMAIN OF MOUSE ORNITHINE DECARBOXYLASE (MODC) TO THE C-TERMINAL END OF THE CODON-OPTIMIZED BILIRUBIN-INDUCIBLE FLUORESCENT PROTEIN, DESIGNATED AS DBIFP, AND SHOW THAT THE DBIFP PROTEIN IS HIGHLY DESTABILIZED, COMPARED WITH THE COMMONLY-USED EGFP PROTEIN. WE FURTHER DEMONSTRATE THAT THE DBIFP SIGNAL IS EFFECTIVELY DOWN-REGULATED WHEN THE DBIFP AND MOUSE LNCRNA H19 CHIMERIC TRANSCRIPT IS SILENCED BY MOUSE H19-SPECIFIC SIRNAS. THEREFORE, OUR RESULTS STRONGLY SUGGEST THAT THE DBIFP FUSION PROTEIN MAY SERVE AS A SENSITIVE AND DYNAMIC TRANSCRIPT REPORTER TO MONITOR THE INHIBITION OF LNCRNAS BY MICRORNAS, SYNTHETIC REGULATORY RNA MOLECULES, RNA BINDING PROTEINS, AND/OR SMALL MOLECULE INHIBITORS SO THAT NOVEL AND EFFICACIOUS INHIBITORS TARGETING THE EPIGENETIC CIRCUIT CAN BE DISCOVERED TO TREAT HUMAN DISEASES SUCH AS CANCER AND OTHER CHRONIC DISORDERS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12   26  35 A 6-ALKYLSALICYLATE HISTONE ACETYLTRANSFERASE INHIBITOR INHIBITS HISTONE ACETYLATION AND PRO-INFLAMMATORY GENE EXPRESSION IN MURINE PRECISION-CUT LUNG SLICES. LYSINE ACETYLATIONS ARE POST-TRANSLATIONAL MODIFICATIONS OF CELLULAR PROTEINS, THAT ARE CRUCIAL IN THE REGULATION OF MANY CELLULAR PROCESSES. LYSINE ACETYLATIONS ON HISTONE PROTEINS ARE PART OF THE EPIGENETIC CODE REGULATING GENE EXPRESSION AND ARE INSTALLED BY HISTONE ACETYLTRANSFERASES. OBSERVATIONS THAT INFLAMMATORY LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ARE CHARACTERIZED BY INCREASED HISTONE ACETYLTRANSFERASE ACTIVITY INDICATE THAT DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR THESE ENZYMES MIGHT BE A VALUABLE APPROACH TOWARDS NEW THERAPIES FOR THESE DISEASES. THE 6-ALKYLSALICYLATE MG149 IS A CANDIDATE TO EXPLORE THIS HYPOTHESIS BECAUSE IT HAS BEEN DEMONSTRATED TO INHIBIT THE MYST TYPE HISTONE ACETYLTRANSFERASES. IN THIS STUDY, WE DETERMINED THE K(I) VALUE FOR INHIBITION OF THE MYST TYPE HISTONE ACETYLTRANSFERASE KAT8 BY MG149 TO BE 39 +/- 7.7 MUM. UPON INVESTIGATING WHETHER THE INHIBITION OF HISTONE ACETYLTRANSFERASES BY MG149 CORRELATES WITH INHIBITION OF HISTONE ACETYLATION IN MURINE PRECISION-CUT LUNG SLICES, INHIBITION OF ACETYLATION WAS OBSERVED USING AN LC-MS/MS BASED ASSAY ON HISTONE H4 RES 4-17, WHICH CONTAINS THE TARGET LYSINE OF KAT8. FOLLOWING UP ON THIS, UPON TREATMENT WITH MG149, REDUCED PRO-INFLAMMATORY GENE EXPRESSION WAS OBSERVED IN LIPOPOLYSACCHARIDE AND INTERFERON GAMMA STIMULATED MURINE PRECISION-CUT LUNG SLICES. BASED ON THIS, WE PROPOSE THAT 6-ALKYLSALICYLATES SUCH AS MG149 HAVE POTENTIAL FOR DEVELOPMENT TOWARDS APPLICATIONS IN THE TREATMENT OF INFLAMMATORY LUNG DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13 3096  38 GENOMIC CHARACTERIZATION REVEALS NOVEL MECHANISMS UNDERLYING THE VALOSIN-CONTAINING PROTEIN-MEDIATED CARDIAC PROTECTION AGAINST HEART FAILURE. CHRONIC HYPERTENSION IS A KEY RISK FACTOR FOR HEART FAILURE. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS ARE NOT FULLY UNDERSTOOD. OUR PREVIOUS STUDIES FOUND THAT THE VALOSIN-CONTAINING PROTEIN (VCP), AN ATPASE-ASSOCIATED PROTEIN, WAS SIGNIFICANTLY DECREASED IN THE HYPERTENSIVE HEART TISSUES. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT RESTORATION OF VCP PROTECTED THE HEART AGAINST PRESSURE OVERLOAD-INDUCED HEART FAILURE. WITH A CARDIAC-SPECIFIC TRANSGENIC (TG) MOUSE MODEL, WE SHOWED THAT A MODERATE INCREASE OF VCP WAS ABLE TO ATTENUATE CHRONIC PRESSURE OVERLOAD-INDUCED MALADAPTIVE CARDIAC HYPERTROPHY AND DYSFUNCTION. RNA SEQUENCING AND A COMPREHENSIVE BIOINFORMATIC ANALYSIS FURTHER DEMONSTRATED THAT OVEREXPRESSION OF VCP IN THE HEART NORMALIZED THE PRESSURE OVERLOAD-STIMULATED HYPERTROPHIC SIGNALS AND REPRESSED THE STRESS-INDUCED INFLAMMATORY RESPONSE. IN ADDITION, VCP OVEREXPRESSION PROMOTED CELL SURVIVAL BY ENHANCING THE MITOCHONDRIA RESISTANCE TO THE OXIDATIVE STRESS VIA ACTIVATING THE RICTOR-MEDIATED-GENE NETWORKS. VCP WAS ALSO FOUND TO BE INVOLVED IN THE REGULATION OF THE ALTERNATIVE SPLICING AND DIFFERENTIAL ISOFORM EXPRESSION FOR SOME GENES THAT ARE RELATED TO ATP PRODUCTION AND PROTEIN SYNTHESIS BY INTERACTING WITH LONG NO-CODING RNAS AND HISTONE DEACETYLASES, INDICATING A NOVEL EPIGENETIC REGULATION OF VCP IN INTEGRATING CODING AND NONCODING GENOMIC NETWORK IN THE STRESSED HEART. IN SUMMARY, OUR STUDY DEMONSTRATED THAT THE RESCUING OF A DEFICIENT VCP IN THE HEART COULD PREVENT PRESSURE OVERLOAD-INDUCED HEART FAILURE BY RECTIFYING CARDIAC HYPERTROPHIC AND INFLAMMATORY SIGNALING AND ENHANCING THE CARDIAC RESISTANCE TO OXIDATIVE STRESS, WHICH BROUGHT IN NOVEL INSIGHTS INTO THE UNDERSTANDING OF THE MECHANISM OF VCP IN PROTECTING PATIENTS FROM HYPERTENSIVE HEART FAILURE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  102  28 A REGULATORY ROLE FOR CHD2 IN MYELOPOIESIS. THE TRANSCRIPTIONAL PROGRAM THAT DICTATES HAEMATOPOIETIC CELL FATE AND DIFFERENTIATION REQUIRES AN EPIGENETIC REGULATORY AND MEMORY FUNCTION, PROVIDED BY A NETWORK OF EPIGENETIC FACTORS THAT REGULATE DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE. DISTURBED EPIGENETIC REGULATION CAUSES PERTURBATIONS IN THE BLOOD CELL DIFFERENTIATION PROGRAM THAT RESULTS IN VARIOUS TYPES OF HAEMATOPOIETIC DISORDERS. THUS, ACCURATE EPIGENETIC REGULATION IS ESSENTIAL FOR FUNCTIONAL HAEMATOPOIESIS. IN THIS STUDY, WE USED A CRISPR-CAS9 SCREENING APPROACH TO IDENTIFY NEW EPIGENETIC REGULATORS IN MYELOID DIFFERENTIATION. WE DESIGNED A CHROMATIN-UMI CRISPR GUIDE LIBRARY TARGETING 1092 EPIGENETIC REGULATORS. PHORBOL 12-MYRISTATE 13-ACETATE (PMA) TREATMENT OF THE CHRONIC MYELOID LEUKAEMIA CELL LINE K-562 WAS USED AS A MEGAKARYOCYTIC MYELOID DIFFERENTIATION MODEL. BOTH PREVIOUSLY DESCRIBED DEVELOPMENTAL EPIGENETIC REGULATORS AND NOVEL FACTORS WERE IDENTIFIED IN OUR SCREEN. IN THIS STUDY, WE VALIDATED AND CHARACTERIZED A ROLE FOR THE CHROMATIN REMODELLER CHD2 IN MYELOID PROLIFERATION AND MEGAKARYOCYTIC DIFFERENTIATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  669  31 BONE MARROW STROMAL CELL ANTIGEN-1 (CD157) REGULATED BY SPHINGOSINE KINASE 2 MEDIATES KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE IS A PROGRESSIVE DISEASE THAT MAY LEAD TO END-STAGE RENAL DISEASE. INTERSTITIAL FIBROSIS DEVELOPS AS THE DISEASE PROGRESSES. THERAPIES THAT FOCUS ON FIBROSIS TO DELAY OR REVERSE PROGRESSIVE RENAL FAILURE ARE LIMITED. WE AND OTHERS SHOWED THAT SPHINGOSINE KINASE 2-DEFICIENT MICE (SPHK2 (-/-)) DEVELOP LESS FIBROSIS IN MOUSE MODELS OF KIDNEY FIBROSIS. SPHINGOSINE KINASE2 (SPHK2), ONE OF TWO SPHINGOSINE KINASES THAT PRODUCE SPHINGOSINE 1-PHOSPHATE (S1P), IS PRIMARILY LOCATED IN THE NUCLEUS. S1P PRODUCED BY SPHK2 INHIBITS HISTONE DEACETYLASE (HDAC) AND CHANGES HISTONE ACETYLATION STATUS, WHICH CAN LEAD TO ALTERED TARGET GENE EXPRESSION. WE HYPOTHESIZED THAT SPHK2 EPIGENETICALLY REGULATES DOWNSTREAM GENES TO INDUCE FIBROSIS, AND WE PERFORMED A COMPREHENSIVE ANALYSIS USING THE COMBINATION OF RNA-SEQ AND CHIP-SEQ. BST1/CD157 WAS IDENTIFIED AS A GENE THAT IS REGULATED BY SPHK2 THROUGH A CHANGE IN HISTONE ACETYLATION LEVEL, AND BST1 (-/-) MICE WERE FOUND TO DEVELOP LESS RENAL FIBROSIS AFTER UNILATERAL ISCHEMIA-REPERFUSION INJURY, A MOUSE MODEL OF KIDNEY FIBROSIS. ALTHOUGH BST1 IS A CELL-SURFACE MOLECULE THAT HAS A WIDE VARIETY OF FUNCTIONS THROUGH ITS VARIED ENZYMATIC ACTIVITIES AND DOWNSTREAM INTRACELLULAR SIGNALING PATHWAYS, NO STUDIES ON THE ROLE OF BST1 IN KIDNEY DISEASES HAVE BEEN REPORTED PREVIOUSLY. IN THE CURRENT STUDY, WE DEMONSTRATED THAT BST1 IS A GENE THAT IS REGULATED BY SPHK2 THROUGH EPIGENETIC CHANGE AND IS CRITICAL IN KIDNEY FIBROSIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 6230  32 THE LONG NONCODING RNA LANDSCAPE IN HYPOXIC AND INFLAMMATORY RENAL EPITHELIAL INJURY. LONG NONCODING RNAS (LNCRNAS) ARE EMERGING AS KEY SPECIES-SPECIFIC REGULATORS OF CELLULAR AND DISEASE PROCESSES. TO IDENTIFY POTENTIAL LNCRNAS RELEVANT TO ACUTE AND CHRONIC RENAL EPITHELIAL INJURY, WE PERFORMED UNBIASED WHOLE TRANSCRIPTOME PROFILING OF HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS (PTECS) IN HYPOXIC AND INFLAMMATORY CONDITIONS. RNA SEQUENCING REVEALED THAT THE PROTEIN-CODING AND NONCODING TRANSCRIPTOMIC LANDSCAPE DIFFERED BETWEEN HYPOXIA-STIMULATED AND CYTOKINE-STIMULATED HUMAN PTECS. HYPOXIA- AND INFLAMMATION-MODULATED LNCRNAS WERE PRIORITIZED FOR FOCUSED FOLLOWUP ACCORDING TO THEIR DEGREE OF INDUCTION BY THESE STRESS STIMULI, THEIR EXPRESSION IN HUMAN KIDNEY TISSUE, AND WHETHER EXPOSURE OF HUMAN PTECS TO PLASMA OF CRITICALLY ILL SEPSIS PATIENTS WITH ACUTE KIDNEY INJURY MODULATED THEIR EXPRESSION. FOR THREE LNCRNAS (MIR210HG, LINC-ATP13A4-8, AND LINC-KIAA1737-2) THAT FULFILLED OUR CRITERIA, WE VALIDATED THEIR EXPRESSION PATTERNS, EXAMINED THEIR LOCI FOR CONSERVATION AND SYNTENY, AND DEFINED THEIR ASSOCIATED EPIGENETIC MARKS. THE LNCRNA LANDSCAPE CHARACTERIZED HERE PROVIDES INSIGHTS INTO NOVEL TRANSCRIPTOMIC VARIATIONS IN THE RENAL EPITHELIAL CELL RESPONSE TO HYPOXIC AND INFLAMMATORY STRESS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 5101  38 POLYCOMB FACTOR PHF19 CONTROLS CELL GROWTH AND DIFFERENTIATION TOWARD ERYTHROID PATHWAY IN CHRONIC MYELOID LEUKEMIA CELLS. POLYCOMB GROUP (PCG) OF PROTEINS ARE A GROUP OF HIGHLY CONSERVED EPIGENETIC REGULATORS INVOLVED IN MANY BIOLOGICAL FUNCTIONS, SUCH AS EMBRYONIC DEVELOPMENT, CELL PROLIFERATION, AND ADULT STEM CELL DETERMINATION. PHD FINGER PROTEIN 19 (PHF19) IS AN ASSOCIATED FACTOR OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2), OFTEN UPREGULATED IN HUMAN CANCERS. IN PARTICULAR, MYELOID LEUKEMIA CELL LINES SHOW INCREASED LEVELS OF PHF19, YET LITTLE IS KNOWN ABOUT ITS FUNCTION. HERE, WE HAVE CHARACTERIZED THE ROLE OF PHF19 IN MYELOID LEUKEMIA CELLS. WE DEMONSTRATED THAT PHF19 DEPLETION DECREASES CELL PROLIFERATION AND PROMOTES CHRONIC MYELOID LEUKEMIA (CML) DIFFERENTIATION. MECHANISTICALLY, WE HAVE SHOWN HOW PHF19 REGULATES THE PROLIFERATION OF CML THROUGH A DIRECT REGULATION OF THE CELL CYCLE INHIBITOR P21. FURTHERMORE, WE OBSERVED THAT MTF2, A PHF19 HOMOLOG, PARTIALLY COMPENSATES FOR PHF19 DEPLETION IN A SUBSET OF TARGET GENES, INSTRUCTING SPECIFIC ERYTHROID DIFFERENTIATION. TAKEN TOGETHER, OUR RESULTS SHOW THAT PHF19 IS A KEY TRANSCRIPTIONAL REGULATOR FOR CELL FATE DETERMINATION AND COULD BE A POTENTIAL THERAPEUTIC TARGET FOR MYELOID LEUKEMIA TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18 1806  39 EFFECT OF TRANSCRIPTION INHIBITION AND GENERATION OF SUPPRESSIVE VIRAL NON-CODING RNAS. BACKGROUND: HIV-1 PATIENTS RECEIVING COMBINATION ANTIRETROVIRAL THERAPY (CART) SURVIVE INFECTION BUT REQUIRE LIFE-LONG ADHERENCE AT HIGH EXPENSE. IN CHRONIC CART-TREATED PATIENTS WITH UNDETECTABLE VIRAL TITERS, CELL-ASSOCIATED VIRAL RNA IS STILL DETECTABLE, POINTING TO LOW-LEVEL VIRAL TRANSCRIPTIONAL LEAKINESS. TO DATE, THERE ARE NO FDA-APPROVED DRUGS AGAINST HIV-1 TRANSCRIPTION. WE HAVE PREVIOUSLY SHOWN THAT F07#13, A THIRD GENERATION TAT PEPTIDE MIMETIC WITH COMPETITIVE ACTIVITY AGAINST CDK9/T1-TAT BINDING SITES, INHIBITS HIV-1 TRANSCRIPTION IN VITRO AND IN VIVO. RESULTS: HERE, WE DEMONSTRATE THAT INCREASING CONCENTRATIONS OF F07#13 (0.01, 0.1, 1 MICROM) CAUSE A DECREASE IN TAT LEVELS IN A DOSE-DEPENDENT MANNER BY INHIBITING THE CDK9/T1-TAT COMPLEX FORMATION AND SUBSEQUENT UBIQUITIN-MEDIATED TAT SEQUESTRATION AND DEGRADATION. OUR DATA INDICATE THAT COMPLEXES I AND IV CONTAIN DISTINCT PATTERNS OF UBIQUITINATED TAT AND THAT TRANSCRIPTIONAL INHIBITION INDUCED BY F07#13 CAUSES AN OVERALL REDUCTION IN TAT LEVELS. THIS REDUCTION MAY BE TRIGGERED BY F07#13 BUT ULTIMATELY IS MEDIATED BY TAR-GAG VIRAL RNAS THAT BIND SUPPRESSIVE TRANSCRIPTION FACTORS (SIMILAR TO 7SK, NRON, HOTAIR, AND XIST LNCRNAS) TO ENHANCE TRANSCRIPTIONAL GENE SILENCING AND LATENCY. THESE RNAS COMPLEX WITH PRC2, SIN3A, AND CUL4B, RESULTING IN EPIGENETIC MODIFICATIONS. FINALLY, WE OBSERVED AN F07#13-MEDIATED DECREASE OF VIRAL BURDEN BY TARGETING THE R REGION OF THE LONG TERMINAL REPEAT (HIV-1 PROMOTER REGION, LTR), PROMOTING BOTH PAUSED POLYMERASES AND INCREASED EFFICIENCY OF CRISPR/CAS9 EDITING IN INFECTED CELLS. THIS IMPLIES THAT GENE EDITING MAY BE BEST PERFORMED UNDER A REPRESSED TRANSCRIPTIONAL STATE. CONCLUSIONS: COLLECTIVELY, OUR RESULTS INDICATE THAT F07#13, WHICH CAN TERMINATE RNA POLYMERASE II AT DISTINCT SITES, CAN GENERATE SCAFFOLD RNAS, WHICH MAY ASSEMBLE INTO SPECIFIC SETS OF "RNA MACHINES" THAT CONTRIBUTE TO GENE REGULATION. IT REMAINS TO BE SEEN WHETHER THESE EFFECTS CAN ALSO BE SEEN IN VARIOUS CLADES THAT HAVE VARYING PROMOTER STRENGTH, MUTANT LTRS, AND IN PATIENT SAMPLES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 6012  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 1293  33 DECREASED ERK AND JNK SIGNALING CONTRIBUTE TO GENE OVEREXPRESSION IN "SENESCENT" CD4+CD28- T CELLS THROUGH EPIGENETIC MECHANISMS. AN INFLAMMATORY AND CYTOTOXIC CD4+CD28- T CELL SUBSET INFILTRATES ATHEROSCLEROTIC PLAQUES AND IS IMPLICATED IN PLAQUE RUPTURE AND MYOCARDIAL INFARCTIONS. THIS PATHOLOGIC SUBSET DEVELOPS WITH REPLICATIVE STRESS AND IS FOUND IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES SUCH AS RA AS WELL AS WITH AGING. CD4+CD28- CELLS OVEREXPRESS GENES NORMALLY SUPPRESSED BY DNA METHYLATION IN CD4+CD28+ T CELLS, SUCH AS KIR, PERFORIN, AND CD70. HOW THIS SUBSET OVER EXPRESSES METHYLATION-SENSITIVE GENES IS UNKNOWN. DNA METHYLATION PATTERNS ARE MAINTAINED IN PROLIFERATING CELLS BY DNMTS, WHICH ARE UP-REGULATED DURING MITOSIS BY THE ERK AND JNK SIGNALING PATHWAYS. WE HYPOTHESIZED THAT DEFECTS IN THESE SIGNALING PATHWAYS CONTRIBUTE TO ALTERED GENE EXPRESSION IN HUMAN CD4+CD28- CELLS THROUGH EFFECTS ON DNA METHYLATION. WE REPORT THAT SIGNALING THROUGH THE ERK AND JNK PATHWAYS IS DECREASED IN CD4+CD28- RELATIVE TO CD4+CD28+ CELLS FROM THE SAME INDIVIDUALS AND THAT ERK AND JNK PATHWAY INHIBITION DECREASES DNMT1 AND -3A LEVELS, WHICH IN TURN, CAUSES DEMETHYLATION AND OVEREXPRESSION OF THE TNFSF7 (CD70) GENE. WE ALSO REPORT THAT CD4+CD28- T CELLS OVEREXPRESS PP5, A STRESS-INDUCED INHIBITOR OF THE ERK AND JNK SIGNALING PATHWAYS THAT MAY CONTRIBUTE TO THE SIGNALING DEFECTS. WE CONCLUDE THAT DECREASED ERK AND JNK SIGNALING IN THE CD4+CD28- SUBSET, ARISING WITH REPLICATIVE STRESS, CAN LEAD TO THE OVEREXPRESSION OF NORMALLY SUPPRESSED GENES THROUGH EFFECTS ON DNMTS AND CONSEQUENTLY, CHROMATIN STRUCTURE.	2010