40 results on '"Telese, F."'
Search Results
2. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control
- Author
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Wang, J, Telese, F, Tan, Y, Li, W, Jin, C, He, X, Basnet, H, Ma, Q, Merkurjev, D, Zhu, X, Liu, Z, Zhang, J, Ohgi, K, Taylor, H, White, RR, Tazearsalan, C, Suh, Y, Macfarlan, TS, Pfaff, SL, and Rosenfeld, MG
- Abstract
© 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. We found that a neuron-specific isoform of LSD1, LSD1n, which results from an alternative splicing event, acquires a new substrate specificity, targeting histone H4 Lys20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n led to deficits in spatial learning and memory, revealing the functional importance of LSD1n in neuronal activity–regulated transcription that is necessary for long-term memory formation. LSD1n occupied neuronal gene enhancers, promoters and transcribed coding regions, and was required for transcription initiation and elongation steps in response to neuronal activity, indicating the crucial role of H4K20 methylation in coordinating gene transcription with neuronal function. Our results indicate that this alternative splicing of LSD1 in neurons, which was associated with altered substrate specificity, serves as a mechanism acquired by neurons to achieve more precise control of gene expression in the complex processes underlying learning and memory.
- Published
- 2015
3. Reliability and validity of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index in Italian patients with osteoarthritis of the knee
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Salaffi, F., Leardini, G., Canesi, B., Mannoni, A., Fioravanti, A., Caporali, R., Lapadula, G., Punzi, L., Bucci, R., Cimmino, M. A., Ciocci, A., Colombo, F., Frizziero, L., Grattagliano, V., Magaro, M., Mascia, Maria Teresa, Minisola, G., Modena, V., Muratore, M., Nervetti, A., R, Olivieri, I., Perpignano, G., Rossi, S., Sabadini, L., Sarzi Puttini, P., Schiavon, F., Spano, A., Stancati, A., Stisi, S., Telese, F., and Tirri, G.
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Osteoarthritis of the knee ,WOMAC ,Wilcoxon signed-rank test ,Intraclass correlation ,Biomedical Engineering ,Pain ,Comorbidity ,Osteoarthritis ,trial methodology ,Health status ,Cohort Studies ,Disability Evaluation ,Trial methodology ,Physical medicine and rehabilitation ,Cronbach's alpha ,Rheumatology ,Surveys and Questionnaires ,medicine ,Humans ,Outpatient clinic ,Knee ,Orthopedics and Sports Medicine ,Muscle, Skeletal ,Aged ,Aged, 80 and over ,business.industry ,Discriminant validity ,Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index ,Reproducibility of Results ,Construct validity ,osteoarthritis ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,humanities ,Cross-Sectional Studies ,Italy ,Physical therapy ,Female ,business - Abstract
Objective : The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index is a tested questionnaire to assess symptoms and physical functional disability in patients with OA of the knee and the hip. We adapted the WOMAC for the Italian language and tested its metric properties in 304 patients with symptomatic OA of the knee. Methods : Three hundred and four consecutive patients, attending 29 rheumatologic outpatient clinic in northern, central, and southern Italy, were asked to answer two disease-specific questionnaires (WOMAC and Lequesne algofunctional index) and one generic instrument (Medical Outcomes Study SF-36 Health Survey—MOS SF-36). A sample of 258 patients was readministered the WOMAC 7–10 days after the first visit and the structured interview, which also assessed demographic and other characteristics. Internal consistency was assessed using Cronbach's alpha, reliability using intraclass correlation coefficients (ICCs), and construct and discriminant validity using Spearman's correlations, Wilcoxon rank sum test, and Kruskal–Wallis test. Results : All WOMAC subscales (pain, stiffness, and physical function) were internally consistent with Cronbach's coefficient alpha of 0.91, 0.81, and 0.84, respectively. Test–retest reliability was satisfactory with ICCs of 0.86, 0.68, and 0.89, respectively. In comparison with the SF-36, the expected correlations were found when comparing items measuring similar constructs, supporting the concepts of convergent construct validity. Very high correlations were also obtained between WOMAC scores and Lequesne OA algofunctional index. WOMAC physical function, but not WOMAC stiffness and pain subscales, was weakly associated with radiological OA severity ( P =0.03). Also, WOMAC pain score was inversely correlated ( P =0.01) with years of formal education. Examination of discriminant validity showed that the scores on the WOMAC and SF-36 followed hypothesized patterns: the WOMAC discriminated better among subjects with varying severity of knee problems, whereas the SF-36 discriminated better among subjects with varying levels of self-reported health status and comorbidity. Conclusion : The Italian version of WOMAC is a reliable and valid instrument for evaluating the severity of OA of the knee, with metric properties in agreement with the original, widely used version.
- Published
- 2003
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4. Identification of novel beta-secretase inhibitors through the inclusion of protein flexibility in virtual screening calculations
- Author
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COSCONATI, Sandro, Marinelli L, Telese F, Novellino E, Olson AJ, Cosconati, Sandro, Marinelli, L, Telese, F, Novellino, E, and Olson, Aj
- Published
- 2008
5. Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage
- Author
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Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M, Di Lauro R, Pacelli R, Brunetti A, Zambrano N, and Russo T.
- Subjects
Iron ,Amyloid Precursor Protein ,Alzheimer's Disease - Abstract
Fe65 interacts with the cytosolic domain of the Alzheimer amyloid precursor protein (APP). The functions of the Fe65 are still unknown. To address this point we generated Fe65 knockout (KO) mice. These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H2O2, an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged. Accordingly, brain extracts from Fe65 KO mice, exposed to non-lethal doses of ionizing radiations, showed high levels of gamma-H2AX and p53, thus demonstrating a higher sensitivity to X-rays than wild type mice. Nuclear Fe65 is necessary to rescue the observed phenotype, and few minutes after the exposure of MEFs to DNA damaging agents, Fe65 undergoes phosphorylation in the nucleus. With a similar timing, the proteolytic processing of APP is rapidly affected by the genotoxic stress: in fact, the cleavage of the APP COOH-terminal fragments by gamma-secretase is induced soon after the exposure of cells to etoposide, in a Fe65-dependent manner. These results demonstrate that Fe65 plays an essential role in the response of the cells to DNA damage.
- Published
- 2007
6. Essential roles for Fe65, Alzhaimer's amyloid precursor binding protein, in the cellular response to DNA damage
- Author
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Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M, Di Lauro M, Pacelli R, Brunetti A, Zambrano N, and Russo T.
- Published
- 2006
7. Prevalenza degli anticorpi anti-citrullina (CCP) nell’artrite reumatoide (A.R.): confronto con pazienti affetti da malattia di Still dell’Adulto. Studio preliminare
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Nunzi, Lianella, Cavallini, Ar, Dapporto, M., Govoni, Marcello, Guerra, Giovanni, Padovan, Melissa, Pizzicotti, S., Telese, F., Trotta, Francesco, and Rigolin, F.
- Published
- 2002
8. Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the "Magenta osteoarthritis study".
- Author
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M. Scarpellini, A. Lurati, G. Vignati, M. Marrazza, F. Telese, K. Re, A. Bellistri, Scarpellini, M, Lurati, A, Vignati, G, Marrazza, M G, Telese, F, Re, K, and Bellistri, A
- Subjects
OSTEOARTHRITIS ,ARTHRITIS ,CARTILAGE ,BONES ,COLLAGEN ,GLUCOSAMINE ,CHONDROITIN sulfates - Abstract
Background: The purpose of the present study was to determine relationship between disease activity, systemic markers of cartilage degradation, urinary C-terminal cross-linking telopeptides of type II collagen (uCTX-II), and bone degradation, urinary C-terminal cross-linking telopeptides of type I collagen (uCTX-I), structural progression of osteoarthritis (OA) and potential therapeutic efficacy of type II collagen (COLLII) in combination with glucosamine and chondroitin sulfate (GC).Materials and Methods: An observational retrospective study, 1-year follow-up, on 104 patients with OA (nodular osteoarthritis of the hand, erosive osteoarthritis of the hand, EOA, osteoarthritis of the knee or hip) who were treated with GC or glucosamine, chondroitin sulfate and collagen type II (GCC). The following information was collected at entry: demographics, BMI, characteristics of OA, patient global assessment (VAS), C-terminal cross-linking telopeptides of collagen types I (uCTX-I) and II (uCTX-II) and radiographs. After 6 months: VAS, uCTX-I and uCTX-II. After 1 year: VAS, uCTX-I, uCTX-II and radiographs.Results: After 6 months and 1 year of treatment VAS, uCTX-I and uCTX-II mean values were significantly lower than the baseline. 57 were treated with GCC and 47 with GC. The group that received GCC showed a similar VAS mean value after 6 months and 1 year when compared with the group treated with GC. uCTX-I and uCTX-II mean level was lower in the group treated with GCC (P < 0.05). Radiological score (Kellgren and Lawrence summarized score for hands) after 1 year showed a reduced progression compared to the baseline in the hand osteoarthritis group, especially after GCC treatment (P < 0.05). Finally, uCTX-I has better correlation with radiological score and with GC in the EOA subgroup (Pearson index: R = 0.44).Conclusions: (a) uCTX-I and uCTX-II proved to be useful biomarkers in OA monitoring; (b) uCTX-I is better correlated with hand EOA and could represent a potential further marker to assess the evolution of EOA bone damage; (c) GC slow down OA progression; (d) finally COLLII could represent a further protective factor in OA cartilage. [ABSTRACT FROM AUTHOR]- Published
- 2008
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9. Erratum: Fe65 is not involved in the platelet-derived growth factor-induced processing of Alzheimer's amyloid precursor protein, which activates its caspase-directed cleavage (Journal of Biological Chemistry (2004) 279 (16161-16169))
- Author
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Nicola Zambrano, Gianni, D., Bruni, P., Passaro, F., Telese, F., and Russo, T.
10. Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET
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Chiara D'Ambrosio, Andrea Scaloni, Michael G. Rosenfeld, Nicola Zambrano, Paola Bruni, Aldo Donizetti, Davide Gianni, Tommaso Russo, Francesca Telese, Telese, F, Bruni, P, Donizetti, Aldo, Gianni, D, D'Ambrosio, C, Scaloni, A, Zambrano, Nicola, Rosenfeld, Mg, and Russo, Tommaso
- Subjects
Transcriptional Activation ,Amyloid ,Transcription, Genetic ,Nucleosome assembly ,Chromosomal Proteins, Non-Histone ,Molecular Sequence Data ,Scientific Report ,Biology ,Kangai-1 Protein ,Biochemistry ,Cell Line ,Sp3 transcription factor ,Antigens, CD ,Proto-Oncogene Proteins ,Genetics ,Humans ,E2F1 ,Histone Chaperones ,Amino Acid Sequence ,Promoter Regions, Genetic ,Molecular Biology ,Sp1 transcription factor ,Membrane Glycoproteins ,General transcription factor ,Nuclear Proteins ,TCF4 ,Molecular biology ,Nucleosomes ,Cell biology ,DNA-Binding Proteins ,TAF4 ,TAF2 ,APP ,Tip60 ,chromatin immunoprecipitation ,KAI1 ,Alzheimer ,Protein Binding ,Transcription Factors - Abstract
Fe65 protein interacts with the cytosolic domain of the amyloid precursor APP. Its possible involvement in gene regulation is suggested by numerous observations, including those demonstrating that it activates transcription. Here, we show that the Fe65 transcription activation domain overlaps with the WW domain of Fe65 and binds to the nucleosome assembly factor SET. This protein is required for the Fe65-mediated transactivation of a reporter gene. Two-step chromatin immunoprecipitation experiments demonstrate that a complex including Fe65/AICD/Tip60 and SET is associated with the KAI1 gene promoter. Suppression of SET levels by RNA interference shows that this protein is required for full levels of basal transcription of the KAI1 gene. These results further support the function of Fe65 and APP in gene regulation and show a new role for the SET factor.
- Published
- 2005
11. Fe65 is not involved in the platelet-derived growth factor-induced processing of Alzheimer's amyloid precursor protein, which activates its caspase-directed cleavage
- Author
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Francesca Telese, Fabiana Passaro, Paola Bruni, Davide Gianni, Tommaso Russo, Nicola Zambrano, Zambrano, Nicola, Gianni, D, Bruni, P, Passaro, Fabiana, Telese, F, and Russo, Tommaso
- Subjects
rac1 GTP-Binding Protein ,Mutant ,Molecular Sequence Data ,RAC1 ,Nerve Tissue Proteins ,Cleavage (embryo) ,Biochemistry ,Cell Line ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,mental disorders ,Animals ,Humans ,Receptors, Platelet-Derived Growth Factor ,Amino Acid Sequence ,Molecular Biology ,Caspase ,biology ,Neuropeptides ,Signal transducing adaptor protein ,Nuclear Proteins ,Cell Biology ,Cell biology ,rac GTP-Binding Proteins ,src-Family Kinases ,Alpha secretase ,Caspases ,Mutation ,biology.protein ,Protein Processing, Post-Translational ,Platelet-derived growth factor receptor ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction - Abstract
The proteolytic processing of the precursor of the β-amyloid peptides (APP) is believed to be a key event in the pathogenesis of Alzheimer's disease. This processing is activated through a pathway involving the PDGF receptor, Src, and Rac1. In this paper, we demonstrate that this pathway specifically acts on APP and requires the YENPTY motif present in the APP cytosolic domain. Considering that several results indicate that the adaptor proteins interacting with this domain affect the processing of APP, we examined their possible involvement in the PDGF-induced pathway. By using an APP-Gal4 reporter system, we observed that the overexpression of Fe65 activates APP-Gal4 cleavage, whereas X11 stabilizes APP. Although mDab1 and Jip1 have no effect, Shc induces a strong activation of APP cleavage, and the contemporary exposure of cells to PDGF causes a dramatic cooperative effect. The analysis of point mutations of the APP YENPTY motif indicates that Fe65 and PDGF function through different mechanisms. In fact, Fe65 requires the integrity of APP695 Tyr682 residue, whereas PDGF effect is dependent upon the integrity of Asn684. Furthermore, the mutation of Asp664 of APP, which is the target site for the caspase-directed APP cleavage, strongly decreases the effect of Fe65. This suggests that Fe65 activates the cleavage of APP by caspases, and in fact, caspase inhibitor Z-VEVD decreases the APP cleavage induced by Fe65. On the contrary, the effects of Shc overexpression, like those of PDGF, are completely absent in the presence of compound X and require the integrity of the Asn684 residue of APP695. The involvement of Shc in the pathway regulating APP processing is confirmed by the effects of constitutively active and dominant negative mutants of Src and Rac1.
- Published
- 2004
12. TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.
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Isaac R, Bandyopadhyay G, Rohm TV, Kang S, Wang J, Pokhrel N, Sakane S, Zapata R, Libster AM, Vinik Y, Berhan A, Kisseleva T, Borok Z, Zick Y, Telese F, Webster NJG, and Olefsky JM
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- Animals, Humans, Mice, Alternative Splicing, Mice, Inbred C57BL, Nuclear Proteins metabolism, Nuclear Proteins genetics, Hepatic Stellate Cells metabolism, Male, Fatty Liver metabolism, Fatty Liver pathology, Fatty Liver genetics, Mice, Knockout, TEA Domain Transcription Factors metabolism, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Liver Cirrhosis genetics, Transcription Factors metabolism, Transcription Factors genetics, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics
- Abstract
The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis., Competing Interests: Declaration of interests R.I. and J.M.O. are co-inventors on a provisional patent for the use of ASO 56 as an inhibitor of liver fibrosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats.
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de Jong TV, Pan Y, Rastas P, Munro D, Tutaj M, Akil H, Benner C, Chen D, Chitre AS, Chow W, Colonna V, Dalgard CL, Demos WM, Doris PA, Garrison E, Geurts AM, Gunturkun HM, Guryev V, Hourlier T, Howe K, Huang J, Kalbfleisch T, Kim P, Li L, Mahaffey S, Martin FJ, Mohammadi P, Ozel AB, Polesskaya O, Pravenec M, Prins P, Sebat J, Smith JR, Solberg Woods LC, Tabakoff B, Tracey A, Uliano-Silva M, Villani F, Wang H, Sharp BM, Telese F, Jiang Z, Saba L, Wang X, Murphy TD, Palmer AA, Kwitek AE, Dwinell MR, Williams RW, Li JZ, and Chen H
- Subjects
- Rats, Animals, Molecular Sequence Annotation, Whole Genome Sequencing, Genetic Variation genetics, Genome genetics, Genomics
- Abstract
The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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14. Genetic architecture distinguishes tinnitus from hearing loss.
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Clifford RE, Maihofer AX, Chatzinakos C, Coleman JRI, Daskalakis NP, Gasperi M, Hogan K, Mikita EA, Stein MB, Tcheandjieu C, Telese F, Zuo Y, Ryan AF, and Nievergelt CM
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- Humans, Cochlea, Tinnitus diagnosis, Tinnitus genetics, Deafness, Hearing Loss, Noise-Induced
- Abstract
Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
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15. Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.
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Clifford R, Munro D, Dochtermann D, Devineni P, Pyarajan S, Telese F, Palmer AA, Mohammadi P, and Friedman R
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- Humans, Aged, Dizziness genetics, Proto-Oncogene Proteins genetics, Vertigo, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Transcription Factors genetics, Genome-Wide Association Study, Protein-Tyrosine Kinases genetics
- Abstract
Purpose: Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown., Methods: The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits., Results: Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase., Conclusion: Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2023
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16. Author Correction: Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition.
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Zhou JL, de Guglielmo G, Ho AJ, Kallupi M, Pokhrel N, Li HR, Chitre AS, Munro D, Mohammadi P, Carrette LLG, George O, Palmer AA, McVicker G, and Telese F
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- 2023
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17. Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition.
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Zhou JL, de Guglielmo G, Ho AJ, Kallupi M, Pokhrel N, Li HR, Chitre AS, Munro D, Mohammadi P, Carrette LLG, George O, Palmer AA, McVicker G, and Telese F
- Subjects
- Humans, Rats, Animals, Amygdala physiology, Neurons, Chromatin metabolism, Cocaine-Related Disorders, Cocaine pharmacology
- Abstract
The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABA
A receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats., (© 2023. The Author(s).)- Published
- 2023
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18. Strain and sex-related behavioral variability of oxycodone dependence in rats.
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Doyle MR, Martinez AR, Qiao R, Dirik S, Di Ottavio F, Pascasio G, Martin-Fardon R, Benner C, George O, Telese F, and de Guglielmo G
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- Rats, Female, Male, Animals, Rats, Inbred ACI, Rats, Inbred F344, Rats, Inbred WKY, Analgesics, Opioid, Self Administration, Oxycodone, Opioid-Related Disorders drug therapy
- Abstract
Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices. In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration. The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism. In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid addiction process., Competing Interests: Declaration of competing interest This work was supported by the National Institute on Drug Abuse [DA051972 and DA056602 to FT, CB and GdG, DA044451 to OG and DA053443 to RM-F], by the National Institute on Alcohol Abuse and Alcoholism [T32 AA007456 to MRD, AA026999, AA028549 and AA006420 to RM-F] by the Brain & Behavior Research Foundation [2020 NARSAD Young Investigator Award to GdG] and from the Preclinical Addiction Research Consortium (PARC) at the University of California San Diego. The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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19. A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats.
- Author
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de Jong TV, Pan Y, Rastas P, Munro D, Tutaj M, Akil H, Benner C, Chen D, Chitre AS, Chow W, Colonna V, Dalgard CL, Demos WM, Doris PA, Garrison E, Geurts AM, Gunturkun HM, Guryev V, Hourlier T, Howe K, Huang J, Kalbfleisch T, Kim P, Li L, Mahaffey S, Martin FJ, Mohammadi P, Ozel AB, Polesskaya O, Pravenec M, Prins P, Sebat J, Smith JR, Solberg Woods LC, Tabakoff B, Tracey A, Uliano-Silva M, Villani F, Wang H, Sharp BM, Telese F, Jiang Z, Saba L, Wang X, Murphy TD, Palmer AA, Kwitek AE, Dwinell MR, Williams RW, Li JZ, and Chen H
- Abstract
The seventh iteration of the reference genome assembly for Rattus norvegicus -mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared to its predecessor. Gene annotations are now more complete, significantly improving the mapping precision of genomic, transcriptomic, and proteomics data sets. We jointly analyzed 163 short-read whole genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ~20.0 million sequence variations, of which 18.7 thousand are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats., Competing Interests: Declaration of interests The authors declare no competing interests.
- Published
- 2023
- Full Text
- View/download PDF
20. The long non-coding RNA MALAT1 regulates intestine host-microbe interactions and polyposis.
- Author
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Long T, Hernandez JE, Ma S, Steele S, Luo C, Li Y, Xie Q, Telese F, Zhou B, and Huang WJM
- Abstract
The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains the integrity of the intestinal epithelial barrier and regulates local inflammation. However, its influences on intestinal microbial communities and tissue susceptibility to cancer development remain unexplored. Here, we report that MALAT1 regulates host anti-microbial response gene expression and the composition of mucosal-associated microbial communities in a region-specific manner. In the APC mutant mouse model of intestine tumorigenesis, knocking out MALAT1 results in higher polyp counts in the small intestine and colon. Interestingly, intestine polyps that developed in the absence of MALAT1 were smaller in size. These findings highlight the unexpected bivalent role of MALAT1 in restricting and promoting cancer progression at different disease stages. Among the 30 MALAT1-targets shared by both the small intestine and colon, ZNF638 and SENP8 levels are predictive of colon adenoma patient overall survival and disease-free survival. Genomic assays further revealed that MALAT1 modulates intestinal target expression and splicing through both direct and indirect mechanisms. This study expands the role of lncRNAs in regulating intestine homeostasis, microbial communities, and cancer pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Long, Hernandez, Ma, Steele, Luo, Li, Xie, Telese, Zhou and Huang.)
- Published
- 2023
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21. Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.
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Zapata RC, Zhang D, Libster A, Porcu A, Montilla-Perez P, Nur A, Xu B, Zhang Z, Correa SM, Liu C, Telese F, and Osborn O
- Subjects
- Animals, Humans, Mice, Agouti-Related Protein genetics, Agouti-Related Protein metabolism, Agouti-Related Protein pharmacology, Antipsychotic Agents adverse effects, Eating, Hypothalamus metabolism, Olanzapine adverse effects, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Cytoplasmic and Nuclear pharmacology, Receptors, Cytoplasmic and Nuclear therapeutic use, Weight Gain, Hyperphagia chemically induced, Hyperphagia genetics, Hyperphagia metabolism
- Abstract
Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain., (© 2023. The Author(s).)
- Published
- 2023
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22. Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions.
- Author
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Zuo Y, Iemolo A, Montilla-Perez P, Li HR, Yang X, and Telese F
- Subjects
- Adolescent, Animals, Brain, Cannabinoid Receptor Agonists pharmacology, Dronabinol metabolism, Endocannabinoids metabolism, Female, Gene Regulatory Networks, Humans, Male, Mice, Mice, Inbred C57BL, Shaw Potassium Channels metabolism, Cannabis adverse effects, Gene Expression, Hallucinogens pharmacology, Sex Factors
- Abstract
During adolescence, frequent and heavy cannabis use can lead to serious adverse health effects and cannabis use disorder (CUD). Rodent models of adolescent exposure to the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), mimic the behavioral alterations observed in adolescent users. However, the underlying molecular mechanisms remain largely unknown. Here, we treated female and male C57BL6/N mice with high doses of THC during early adolescence and assessed their memory and social behaviors in late adolescence. We then profiled the transcriptome of five brain regions involved in cognitive and addiction-related processes. We applied gene coexpression network analysis and identified gene coexpression modules, termed cognitive modules, that simultaneously correlated with THC treatment and memory traits reduced by THC. The cognitive modules were related to endocannabinoid signaling in the female dorsal medial striatum, inflammation in the female ventral tegmental area, and synaptic transmission in the male nucleus accumbens. Moreover, cross-brain region module-module interaction networks uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, we identified key driver genes of gene networks associated with THC in mice and genetic susceptibility to CUD in humans. This analysis revealed a common regulatory mechanism linked to CUD vulnerability in the nucleus accumbens of females and males, which shared four key drivers (Hapln4, Kcnc1, Elavl2, Zcchc12). These genes regulate transcriptional subnetworks implicated in addiction processes, synaptic transmission, brain development, and lipid metabolism. Our study provides novel insights into disease mechanisms regulated by adolescent exposure to THC in a sex- and brain region-specific manner., (© 2022. The Author(s).)
- Published
- 2022
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23. Reelin deficiency exacerbates cocaine-induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum.
- Author
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de Guglielmo G, Iemolo A, Nur A, Turner A, Montilla-Perez P, Martinez A, Crook C, Roberts A, and Telese F
- Subjects
- Adult, Animals, Corpus Striatum, Humans, In Situ Hybridization, Fluorescence, Mice, Neostriatum, Reward, Cocaine pharmacology
- Abstract
The Reln gene encodes for the extracellular glycoprotein Reelin, which regulates several brain functions from development to adulthood, including neuronal migration, dendritic growth and branching and synapse formation and plasticity. Human studies have implicated Reelin signaling in several neurodevelopmental and psychiatric disorders. Mouse studies using the heterozygous Reeler (HR) mice have shown that reduced levels of Reln expression are associated with deficits in learning and memory and increased disinhibition. Although these traits are relevant to substance use disorders, the role of Reelin in cellular and behavioral responses to addictive drugs remains largely unknown. Here, we compared HR mice to wild-type (WT) littermate controls to investigate whether Reelin signaling contributes to the hyperlocomotor and rewarding effects of cocaine. After a single or repeated cocaine injections, HR mice showed enhanced cocaine-induced locomotor activity compared with WT controls. This effect persisted after withdrawal. In contrast, Reelin deficiency did not induce cocaine sensitization, and did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine-induced hyperlocomotion in HR mice was associated with increased protein Fos expression in the dorsal medial striatum (DMS) compared with WT. Lastly, we performed an RNA fluorescent in situ hybridization experiment and found that Reln was highly co-expressed with the Drd1 gene, which encodes for the dopamine receptor D1, in the DMS. These findings show that Reelin signaling contributes to the locomotor effects of cocaine and improve our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine., (© 2022 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
- Published
- 2022
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24. RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.
- Author
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Long T, Abbasi N, Hernandez JE, Li Y, Sayed IM, Ma S, Iemolo A, Yee BA, Yeo GW, Telese F, Ghosh P, Das S, and Huang WJM
- Subjects
- Animals, Carcinogenesis metabolism, DEAD-box RNA Helicases genetics, Disease Susceptibility, Inflammation metabolism, Mice, RNA-Binding Proteins metabolism, rho GTP-Binding Proteins metabolism, DEAD-box RNA Helicases metabolism, Intestinal Mucosa metabolism
- Abstract
Objective: Tuft cells residing in the intestinal epithelium have diverse functions. In the small intestine, they provide protection against inflammation, combat against helminth and protist infections, and serve as entry portals for enteroviruses. In the colon, they had been implicated in tumourigenesis. Commitment of intestinal progenitor cells to the tuft cell lineage requires Rho GTPase Cell Division Cycle 42 (CDC42), a Rho GTPase that acts downstream of the epidermal growth factor receptor and wingless-related integration site signalling cascades, and the master transcription factor POU class 2 homeobox 3 (POU2F3). This study investigates how this pathway is regulated by the DEAD box containing RNA binding protein DDX5 in vivo., Design: We assessed the role of DDX5 in tuft cell specification and function in control and epithelial cell-specific Ddx5 knockout mice (DDX5
ΔIEC ) using transcriptomic approaches., Results: DDX5ΔIEC mice harboured a loss of intestinal tuft cell populations, modified microbial repertoire, and altered susceptibilities to ileal inflammation and colonic tumourigenesis. Mechanistically, DDX5 promotes CDC42 protein synthesis through a post-transcriptional mechanism to license tuft cell specification. Importantly, the DDX5-CDC42 axis is parallel but distinct from the known interleukin-13 circuit implicated in tuft cell hyperplasia, and both pathways augment Pou2f3 expression in secretory lineage progenitors. In mature tuft cells, DDX5 not only promotes integrin signalling and microbial responses, it also represses gene programmes involved in membrane transport and lipid metabolism., Conclusion: RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine., Competing Interests: Competing interests: G.W.Y. is a co-founder, a member of the Board of Directors, a scientific advisor, an equity holder and a paid consultant for Locanabio and Eclipse BioInnovations. G.W.Y. is a visiting professor at the National University of Singapore. G.W.Y.’s interests have been reviewed and approved by the University of California San Diego, in accordance with its conflict-of-interest policies. The authors declare no other competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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25. Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction.
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Duttke SH, Montilla-Perez P, Chang MW, Li H, Chen H, Carrette LLG, de Guglielmo G, George O, Palmer AA, Benner C, and Telese F
- Abstract
Substance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, including glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Duttke, Montilla-Perez, Chang, Li, Chen, Carrette, Guglielmo, George, Palmer, Benner and Telese.)
- Published
- 2022
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26. The Cannabinoid Receptor Agonist, WIN-55212-2, Suppresses the Activation of Proinflammatory Genes Induced by Interleukin 1 Beta in Human Astrocytes.
- Author
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Fields JA, Swinton MK, Montilla-Perez P, Ricciardelli E, and Telese F
- Subjects
- Animals, Anti-Inflammatory Agents metabolism, Benzoxazines, Endocannabinoids pharmacology, Humans, Inflammation drug therapy, Interleukin-1beta metabolism, Morpholines, Naphthalenes, Peroxisome Proliferator-Activated Receptors metabolism, Astrocytes, Cannabinoid Receptor Agonists pharmacology
- Abstract
Background: Alterations of astrocyte function play a crucial role in neuroinflammatory diseases due to either the loss of their neuroprotective role or the gain of their toxic inflammatory properties. Accumulating evidence highlights that cannabinoids and cannabinoid receptor agonists, such as WIN55,212-2 (WIN), reduce inflammation in cellular and animal models. Thus, the endocannabinoid system has become an attractive target to attenuate chronic inflammation in neurodegenerative diseases. However, the mechanism of action of WIN in astrocytes remains poorly understood. Objective: We studied the immunosuppressive property of WIN by examining gene expression patterns that were modulated by WIN in reactive astrocytes. Materials and Methods: Transcriptomic analysis by RNA-seq was carried out using primary human astrocyte cultures stimulated by the proinflammatory cytokine interleukin 1 beta (IL1β) in the presence or absence of WIN. Real-time quantitative polymerase chain reaction analysis was conducted on selected transcripts to characterize the dose-response effects of WIN, and to test the effect of selective antagonists of cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptors (PPAR). Results: Transcriptomic analysis showed that the IL1β-induced inflammatory response is robustly inhibited by WIN pretreatment. WIN treatment alone also induced substantial gene expression changes. Pathway analysis revealed that the anti-inflammatory properties of WIN were linked to the regulation of kinase pathways and gene targets of neuroprotective transcription factors, including PPAR and SMAD (mothers against decapentaplegic homolog). The inhibitory effect of WIN was dose-dependent, but it was not affected by selective antagonists of CB1 or PPAR. Conclusions: This study suggests that targeting the endocannabinoid system may be a promising strategy to disrupt inflammatory pathways in reactive astrocytes. The anti-inflammatory activity of WIN is independent of CB1, suggesting that alternative receptors mediate the effects of WIN. These results provide mechanistic insights into the anti-inflammatory activity of WIN and highlight that astrocytes are a potential therapeutic target to ameliorate neuroinflammation in the brain.
- Published
- 2022
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27. Functional validation of a finding from a mouse genome-wide association study shows that Azi2 influences the acute locomotor stimulant response to methamphetamine.
- Author
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Zhou X, Barkley-Levenson AM, Montilla-Perez P, Telese F, and Palmer AA
- Subjects
- Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Dopamine Plasma Membrane Transport Proteins drug effects, Dopamine Plasma Membrane Transport Proteins genetics, Genome-Wide Association Study methods, Mice, Inbred C57BL, Motor Activity genetics, Ventral Tegmental Area drug effects, Ventral Tegmental Area metabolism, Mice, Adaptor Proteins, Signal Transducing genetics, Central Nervous System Stimulants pharmacology, Methamphetamine pharmacology, Motor Activity drug effects
- Abstract
In a previous genome-wide association study (GWAS) using outbred Carworth Farms White (CFW) mice, we identified a locus that influenced the stimulant response to methamphetamine and colocalized with an eQTL for Azi2. Based on those findings, we hypothesized that heritable differences in Azi2 expression were causally related to the differential response to methamphetamine. To test that hypothesis, we created a mutant Azi2 allele on an inbred C57BL/6J background. The mutant allele enhanced the locomotor response to methamphetamine. However, the GWAS had suggested that lower Azi2 would decrease the locomotor response to methamphetamine. We also sought to explore the mechanism by which Azi2 influenced methamphetamine sensitivity. A recent publication reported that the 3'UTR of Azi2 mRNA downregulates the expression of Slc6a3, which encodes the dopamine transporter, which is a key target of methamphetamine. We evaluated the relationship between Azi2, Azi2 3'UTR and Slc6a3 expression in the ventral tegmental area of wildtype, mutant Azi2 heterozygotes and mutant Azi2 homozygotes and in a new cohort of outbred CFW mice where both allele mapped in our prior GWAS were segregating. We did not observe any correlation between Azi2 and Slc6a3 in either cohort. However, RNA sequencing confirmed that the Azi2 mutation altered Azi2 expression and also revealed a number of potentially important genes and pathways that were regulated by Azi2, including the metabotropic glutamate receptor group III pathway and nicotinic acetylcholine receptor signaling pathway. Our results support a role for Azi2 in methamphetamine sensitivity; however, the exact mechanism does not appear to involve regulation of Slc6a3., (© 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
- Published
- 2021
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28. Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice.
- Author
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Iemolo A, Montilla-Perez P, Nguyen J, Risbrough VB, Taffe MA, and Telese F
- Subjects
- Animals, Anxiety, Behavior, Animal physiology, Locomotion drug effects, Locomotion genetics, Mice, Mice, Neurologic Mutants, Open Field Test, Reelin Protein deficiency, Reelin Protein metabolism, Behavior, Animal drug effects, Dronabinol pharmacology, Reelin Protein genetics, Social Interaction drug effects
- Abstract
Cannabis use is widespread among adolescents and has been associated with long-term negative outcomes on neurocognitive functions. However, the factors that contribute to the long-term detrimental effects of cannabis use remain poorly understood. Here, we studied how Reelin deficiency influences the behavior of mice exposed to cannabis during adolescence. Reelin is a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically injected during adolescence with high doses (10 mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Two weeks after the last injection of THC, mice were tested with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed impaired social behaviors, elevated disinhibitory phenotypes and increased reactivity to aversive situations, in a sex-specific manner. Overall, these findings show that Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence and suggest that elucidating Reelin signaling will improve our understanding of neurobiological mechanisms underlying behavioral traits relevant to the development of psychiatric conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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29. The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short- and long-access cocaine self-administration.
- Author
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Caffino L, Mottarlini F, Van Reijmersdal B, Telese F, Verheij MMM, Fumagalli F, and Homberg JR
- Subjects
- Animals, Male, Rats, Synaptic Transmission drug effects, Cocaine pharmacology, Glutamic Acid drug effects, Prefrontal Cortex drug effects, Serotonin Plasma Membrane Transport Proteins drug effects
- Abstract
Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT
-/- ) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine-seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine-exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT-/- rats, which compared to wild-type (SERT+/+ ) rats show increased ShA and LgA intake short-access (ShA) and long-access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT-/- rats, we observed a sharp increase in glial glutamate transporter 1 (GLT-1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA-induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed., (© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)- Published
- 2021
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30. A cell type-specific expression map of NCoR1 and SMRT transcriptional co-repressors in the mouse brain.
- Author
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Iemolo A, Montilla-Perez P, Lai IC, Meng Y, Nolan S, Wen J, Rusu I, Dulcis D, and Telese F
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Receptor Co-Repressor 1 genetics, Nuclear Receptor Co-Repressor 2 genetics, Transcription, Genetic physiology, Brain cytology, Brain metabolism, Gene Expression Profiling methods, Nuclear Receptor Co-Repressor 1 biosynthesis, Nuclear Receptor Co-Repressor 2 biosynthesis
- Abstract
The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid-hormone receptors (SMRT) are the best characterized transcriptional co-repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type-specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type-specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain., (© 2020 Wiley Periodicals, Inc.)
- Published
- 2020
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31. Mitochondrial biogenesis is altered in HIV+ brains exposed to ART: Implications for therapeutic targeting of astroglia.
- Author
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Swinton MK, Carson A, Telese F, Sanchez AB, Soontornniyomkij B, Rad L, Batki I, Quintanilla B, Pérez-Santiago J, Achim CL, Letendre S, Ellis RJ, Grant I, Murphy AN, and Fields JA
- Subjects
- Anti-HIV Agents pharmacology, Astrocytes drug effects, Astrocytes pathology, Brain drug effects, Brain pathology, Cells, Cultured, DNA-Binding Proteins metabolism, HIV Seropositivity drug therapy, HIV Seropositivity pathology, Humans, Inflammation metabolism, Inflammation pathology, Interleukin-1beta pharmacology, Mitochondria drug effects, Mitochondria pathology, Mitochondrial Proteins metabolism, Neurons drug effects, Neurons metabolism, Neurons pathology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Transcription Factors metabolism, Anti-HIV Agents therapeutic use, Astrocytes metabolism, Brain metabolism, HIV Seropositivity metabolism, Mitochondria metabolism, Organelle Biogenesis
- Abstract
The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1β. To determine how IL-1β affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1β. IL-1β induced mitochondrial activity within 30 min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1β-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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32. Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program.
- Author
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Yang F, Ma Q, Liu Z, Li W, Tan Y, Jin C, Ma W, Hu Y, Shen J, Ohgi KA, Telese F, Liu W, and Rosenfeld MG
- Subjects
- Binding Sites, Breast Neoplasms genetics, Breast Neoplasms pathology, Dexamethasone pharmacology, Down-Regulation, Enhancer Elements, Genetic, Estradiol pharmacology, Estrogen Receptor alpha agonists, Estrogen Receptor alpha genetics, Female, HEK293 Cells, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, MCF-7 Cells, Multiprotein Complexes, Mutation, Nuclear Receptor Co-Repressor 1 genetics, Nuclear Receptor Co-Repressor 1 metabolism, Nuclear Receptor Co-Repressor 2 genetics, Nuclear Receptor Co-Repressor 2 metabolism, Protein Binding, RNA Interference, Receptors, Glucocorticoid agonists, Receptors, Glucocorticoid genetics, Signal Transduction, Sumoylation, Transcriptome, Transfection, Breast Neoplasms metabolism, Estrogen Receptor alpha metabolism, Gene Expression Regulation, Neoplastic drug effects, Receptor Cross-Talk drug effects, Receptors, Glucocorticoid metabolism, Transcription, Genetic drug effects
- Abstract
The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E
2 program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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33. Genome-wide epigenetic analysis of MEF2A and MEF2C transcription factors in mouse cortical neurons.
- Author
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Ma Q and Telese F
- Abstract
The transcription factors of the myocyte enhancer factor 2 family (MEF2 A-D) are highly expressed in the brain and play a key role in neuronal survival/apoptosis, differentiation and synaptic plasticity. However, the precise genome-wide mapping of different members of the family has not yet been fully elucidated. Here, we report the comparative analysis of MEF2A and MEF2C genome-wide mapping in mouse cortical neurons by ChIP-seq, a powerful approach to elucidate the genomic functions of transcription factors and to identify their transcriptional targets. Our analysis reveals that MEF2A and MEF2C each orchestrate similar epigenomic programs mainly through the binding of enhancer regulatory elements in proximity of target genes involved in neuronal plasticity and calcium signaling. We highlight the differences in the enhancer networks and molecular pathways regulated by MEF2A and MEF2C, which might be determined by the combinatorial action of different transcription factors.
- Published
- 2015
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34. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control.
- Author
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Wang J, Telese F, Tan Y, Li W, Jin C, He X, Basnet H, Ma Q, Merkurjev D, Zhu X, Liu Z, Zhang J, Ohgi K, Taylor H, White RR, Tazearslan C, Suh Y, Macfarlan TS, Pfaff SL, and Rosenfeld MG
- Subjects
- Animals, Cells, Cultured, Cerebral Cortex metabolism, Female, Gene Deletion, Male, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Histone Demethylases genetics, Histone Demethylases metabolism, Histones genetics, Histones metabolism, Memory, Long-Term physiology, Transcription, Genetic physiology
- Abstract
We found that a neuron-specific isoform of LSD1, LSD1n, which results from an alternative splicing event, acquires a new substrate specificity, targeting histone H4 Lys20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n led to deficits in spatial learning and memory, revealing the functional importance of LSD1n in neuronal activity-regulated transcription that is necessary for long-term memory formation. LSD1n occupied neuronal gene enhancers, promoters and transcribed coding regions, and was required for transcription initiation and elongation steps in response to neuronal activity, indicating the crucial role of H4K20 methylation in coordinating gene transcription with neuronal function. Our results indicate that this alternative splicing of LSD1 in neurons, which was associated with altered substrate specificity, serves as a mechanism acquired by neurons to achieve more precise control of gene expression in the complex processes underlying learning and memory.
- Published
- 2015
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35. LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.
- Author
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Telese F, Ma Q, Perez PM, Notani D, Oh S, Li W, Comoletti D, Ohgi KA, Taylor H, and Rosenfeld MG
- Subjects
- Animals, Bicuculline pharmacology, CREB-Binding Protein metabolism, Cell Adhesion Molecules, Neuronal genetics, Cells, Cultured, Embryo, Mammalian, Enzyme Inhibitors pharmacology, Excitatory Amino Acid Antagonists pharmacology, Extracellular Matrix Proteins genetics, Histone Deacetylases metabolism, Humans, LDL-Receptor Related Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, N-Acetylglucosaminyltransferases genetics, Nerve Tissue Proteins genetics, Receptors, N-Methyl-D-Aspartate metabolism, Reelin Protein, Serine Endopeptidases genetics, Signal Transduction genetics, Synaptic Transmission drug effects, Synaptic Transmission genetics, Cell Adhesion Molecules, Neuronal metabolism, Conditioning, Classical physiology, Extracellular Matrix Proteins metabolism, LDL-Receptor Related Proteins metabolism, Memory physiology, Nerve Tissue Proteins metabolism, Neurons physiology, Serine Endopeptidases metabolism
- Abstract
One of the exceptional properties of the brain is its ability to acquire new knowledge through learning and to store that information through memory. The epigenetic mechanisms linking changes in neuronal transcriptional programs to behavioral plasticity remain largely unknown. Here, we identify the epigenetic signature of the neuronal enhancers required for transcriptional regulation of synaptic plasticity genes during memory formation, linking this to Reelin signaling. The binding of Reelin to its receptor, LRP8, triggers activation of this cohort of LRP8-Reelin-regulated neuronal (LRN) enhancers that serve as the ultimate convergence point of a novel synapse-to-nucleus pathway. Reelin simultaneously regulates NMDA-receptor transmission, which reciprocally permits the required γ-secretase-dependent cleavage of LRP8, revealing an unprecedented role for its intracellular domain in the regulation of synaptically generated signals. These results uncover an in vivo enhancer code serving as a critical molecular component of cognition and relevant to psychiatric disorders linked to defects in Reelin signaling., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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36. "Seq-ing" insights into the epigenetics of neuronal gene regulation.
- Author
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Telese F, Gamliel A, Skowronska-Krawczyk D, Garcia-Bassets I, and Rosenfeld MG
- Subjects
- Gene Expression Regulation, Humans, Neurons metabolism, Brain physiology, Epigenesis, Genetic, Neuronal Plasticity genetics
- Abstract
The epigenetic control of neuronal gene expression patterns has emerged as an underlying regulatory mechanism for neuronal function, identity, and plasticity, in which short- to long-lasting adaptation is required to dynamically respond and process external stimuli. To achieve a comprehensive understanding of the physiology and pathology of the brain, it becomes essential to understand the mechanisms that regulate the epigenome and transcriptome in neurons. Here, we review recent advances in the study of regulated neuronal gene expression, which are dramatically expanding as a result of the development of new and powerful contemporary methodologies, based on next-generation sequencing. This flood of new information has already transformed our understanding of many biological processes and is now driving discoveries elucidating the molecular mechanisms of brain function in cognition, behavior, and disease and may also inform the study of neuronal identity, diversity, and neuronal reprogramming., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
37. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.
- Author
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Cook PJ, Ju BG, Telese F, Wang X, Glass CK, and Rosenfeld MG
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins metabolism, Cell Line, Cell Survival, DNA Damage, DNA Repair, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Histones deficiency, Histones genetics, Humans, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Mice, Nuclear Proteins deficiency, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phosphorylation, Phosphotyrosine metabolism, Protein Binding, Protein Serine-Threonine Kinases metabolism, Protein Tyrosine Phosphatases deficiency, Protein Tyrosine Phosphatases genetics, Protein Tyrosine Phosphatases metabolism, Substrate Specificity, Tumor Suppressor Proteins metabolism, Apoptosis, Histones metabolism, Tyrosine metabolism
- Abstract
Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. Although the regulatory mechanisms and signalling pathways controlling DNA repair and apoptosis are well characterized, the precise molecular strategies that determine the ultimate choice of DNA repair and survival or apoptotic cell death remain incompletely understood. Here we report that a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage-signal-dependent dephosphorylation of an H2AX carboxy-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of serine phosphorylated histone H2AX (gamma-H2AX) and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.
- Published
- 2009
- Full Text
- View/download PDF
38. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors.
- Author
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Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, Ju BG, Ohgi KA, Wang J, Escoubet-Lozach L, Rose DW, Glass CK, Fu XD, and Rosenfeld MG
- Subjects
- Cell Line, Tumor, Chromatin Immunoprecipitation, Estradiol metabolism, Genome, Human, Histone Code, Histone Demethylases, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Humans, Ligands, Methylation, Promoter Regions, Genetic, Transcriptional Activation, Estrogen Receptor alpha metabolism, Gene Expression Regulation, Histones metabolism, Oxidoreductases, N-Demethylating metabolism
- Abstract
Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals. This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression. These events link an inhibitory methylation component of the histone code to a broadly used strategy that circumvents pathological constitutive gene induction by physiologically regulated transcription factors.
- Published
- 2007
- Full Text
- View/download PDF
39. Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET.
- Author
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Telese F, Bruni P, Donizetti A, Gianni D, D'Ambrosio C, Scaloni A, Zambrano N, Rosenfeld MG, and Russo T
- Subjects
- Amino Acid Sequence, Amyloid metabolism, Antigens, CD genetics, Antigens, CD metabolism, Cell Line, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins, Histone Chaperones, Humans, Kangai-1 Protein, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Molecular Sequence Data, Nuclear Proteins chemistry, Nuclear Proteins genetics, Promoter Regions, Genetic genetics, Protein Binding, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Transcription Factors genetics, Transcriptional Activation genetics, Chromosomal Proteins, Non-Histone metabolism, Nuclear Proteins metabolism, Nucleosomes metabolism, Transcription Factors metabolism, Transcription, Genetic genetics
- Abstract
Fe65 protein interacts with the cytosolic domain of the amyloid precursor APP. Its possible involvement in gene regulation is suggested by numerous observations, including those demonstrating that it activates transcription. Here, we show that the Fe65 transcription activation domain overlaps with the WW domain of Fe65 and binds to the nucleosome assembly factor SET. This protein is required for the Fe65-mediated transactivation of a reporter gene. Two-step chromatin immunoprecipitation experiments demonstrate that a complex including Fe65/AICD/Tip60 and SET is associated with the KAI1 gene promoter. Suppression of SET levels by RNA interference shows that this protein is required for full levels of basal transcription of the KAI1 gene. These results further support the function of Fe65 and APP in gene regulation and show a new role for the SET factor.
- Published
- 2005
- Full Text
- View/download PDF
40. Fe65 is not involved in the platelet-derived growth factor-induced processing of Alzheimer's amyloid precursor protein, which activates its caspase-directed cleavage.
- Author
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Zambrano N, Gianni D, Bruni P, Passaro F, Telese F, and Russo T
- Subjects
- Alzheimer Disease metabolism, Amino Acid Sequence, Animals, Caspases metabolism, Cell Line, Humans, Molecular Sequence Data, Mutation, Neuropeptides genetics, Neuropeptides metabolism, Protein Processing, Post-Translational, Signal Transduction, rac GTP-Binding Proteins genetics, rac GTP-Binding Proteins metabolism, rac1 GTP-Binding Protein, src-Family Kinases genetics, src-Family Kinases metabolism, Amyloid beta-Protein Precursor metabolism, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism, Receptors, Platelet-Derived Growth Factor metabolism
- Abstract
The proteolytic processing of the precursor of the beta-amyloid peptides (APP) is believed to be a key event in the pathogenesis of Alzheimer's disease. This processing is activated through a pathway involving the PDGF receptor, Src, and Rac1. In this paper, we demonstrate that this pathway specifically acts on APP and requires the YENPTY motif present in the APP cytosolic domain. Considering that several results indicate that the adaptor proteins interacting with this domain affect the processing of APP, we examined their possible involvement in the PDGF-induced pathway. By using an APP-Gal4 reporter system, we observed that the overexpression of Fe65 activates APP-Gal4 cleavage, whereas X11 stabilizes APP. Although mDab1 and Jip1 have no effect, Shc induces a strong activation of APP cleavage, and the contemporary exposure of cells to PDGF causes a dramatic cooperative effect. The analysis of point mutations of the APP YENPTY motif indicates that Fe65 and PDGF function through different mechanisms. In fact, Fe65 requires the integrity of APP695 Tyr682 residue, whereas PDGF effect is dependent upon the integrity of Asn684. Furthermore, the mutation of Asp664 of APP, which is the target site for the caspase-directed APP cleavage, strongly decreases the effect of Fe65. This suggests that Fe65 activates the cleavage of APP by caspases, and in fact, caspase inhibitor Z-VEVD decreases the APP cleavage induced by Fe65. On the contrary, the effects of Shc overexpression, like those of PDGF, are completely absent in the presence of compound X and require the integrity of the Asn684 residue of APP695. The involvement of Shc in the pathway regulating APP processing is confirmed by the effects of constitutively active and dominant negative mutants of Src and Rac1.
- Published
- 2004
- Full Text
- View/download PDF
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