232 results on '"Ballestar E"'
Search Results
2. POS1030 DNA-METHYLATION PROFILING IN THE BLOOD OF PATIENTS WITH RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
- Author
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Kaczmarczyk, B., primary, De la Calle-Fabregat, C., additional, Duarte, A. C., additional, Mena-Vázquez, N., additional, Fernandez-Nebro, A., additional, Triguero-Martinez, A., additional, Castañeda, S., additional, Dos-Santos, R., additional, Mera Varela, A., additional, Lopez-Pedrera, C., additional, Escudero Contreras, A., additional, Vela-Casasempere, P., additional, Molina Molina, M., additional, Narváez, J., additional, Retuerto-Guerrero, M., additional, Pablos, J. L., additional, Sarmiento-Monroy, J. C., additional, Sanmartí, R., additional, Gómez Carrera, L., additional, Bonilla, G., additional, Remuzgo Martinez, S., additional, González-Gay, M. A., additional, Leiro Fernandez, V., additional, Pérez Gómez, N., additional, Vadillo, C., additional, Abasolo, L., additional, Casafont-Solé, I., additional, Mateo Soria, L., additional, Castillo González, A. C., additional, Marras Fernandez Cid, C., additional, Perez-Pampín, E., additional, Ballestar, E., additional, and Gonzalez, A., additional
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- 2023
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3. POS0093 TRANSCRIPTOMIC AND METHYLOMIC PROFILING OF CD4+ T-CELLS IN GIANT CELL ARTERITIS WITH DIFFERENT DISEASE ACTIVITY
- Author
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Estupiñán-Moreno, E., primary, Hernández-Rodríguez, J., additional, LI, T., additional, Ciudad, L., additional, Andrés-León, E., additional, Terron-Camero, L. C., additional, Prieto-González, S., additional, Espígol-Frigolé, G., additional, Cid, M. C., additional, Márquez, A., additional, Martin Ibanez, J., additional, Ballestar, E., additional, and Ortiz-Fernández, L., additional
- Published
- 2023
- Full Text
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4. Epilepsy progression is associated with cumulative DNA methylation changes in inflammatory genes
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Martins-Ferreira, R, Leal, B, Chaves, J, Li, TL, Ciudad, L, Rangel, R, Santos, A, da Silva, AM, Costa, PP, and Ballestar, E
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Inflammation ,Epilepsy ,DNA methylation ,Neocortex ,Hippocampus - Abstract
Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common focal epilepsy in adults. It is characterized by alarming rates of pharmacoresistance. Epileptogenesis is associated with the occurrence of epigenetic alterations, and the few epigenetic studies carried out in MTLE-HS have mainly focused on the hippocampus. In this study, we obtained the DNA methylation profiles from both the hippocampus and anterior temporal neocortex of MTLE-HS patients subjected to resective epilepsy surgery and autopsied non epileptic controls. We assessed the progressive nature of DNA methylation changes in relation to epilepsy duration. We identified significantly altered hippocampal DNA methylation patterns encompassing multiple pathways known to be involved in epileptogenesis. DNA methylation changes were even more striking in the neocortex, wherein pathogenic pathways and genes were common to both tissues. Most importantly, DNA methylation changes at many genomic sites varied significantly with epilepsy duration. Such progressive changes were associated with inflammation-related genes in the hippocampus. Our results suggest that the neocortex, relatively spared of extensive histopathological damage, may also be involved in epilepsy development. These results also open the possibility that the observed neocortical impairment could represent a preliminary stage of epileptogenesis before the establishment of chronic lesions or a consequence of prolonged seizure exposure. Our two-tissue multi-level characterization of the MTLE-HS DNA methylome suggests the occurrence of a self propagating inflammatory wave of epigenetic dysregulation.
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- 2022
5. Epigenetic regulation of B cells and its role in autoimmune pathogenesis
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Xiao, F, Rui, K, Shi, XF, Wu, HJ, Cai, XY, Lui, KO, Lu, QJ, Ballestar, E, Tian, J, Zou, HJ, and Lu, LW
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B cells ,Autoimmune disease ,Biomarker ,Therapy ,Epigenetic regulation - Abstract
B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders, progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation. Epigenetic mechanisms, including those involving histone modifications, DNA methylation, and noncoding RNAs, regulate B-cell responses, and their dysregulation can contribute to the pathogenesis of autoimmune diseases. Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation. Moreover, many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients. In this review, we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets. Furthermore, we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases. Based on clinical and preclinical evidence, we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.
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- 2022
6. Epigenetic regulation of PRAME in acute myeloid leukemia is different compared to CD34+ cells from healthy donors: Effect of 5-AZA treatment
- Author
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Gutierrez-Cosío, S., de la Rica, L., Ballestar, E., Santamaría, C., Sánchez-Abarca, L.I., Caballero-Velazquez, T., Blanco, B., Calderón, C., Herrero-Sánchez, C., Carrancio, S., Ciudad, L., Cañizo, C., Miguel, J.F. San, and Pérez-Simón, J.A.
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- 2012
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7. Tolerogenic Dendritic Cells in Autoimmunity and Inflammatory Diseases
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Morante-Palacios, O, Fondelli, F, Ballestar, E, and Martinez-Caceres, EM
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inflammatory disease ,tolerogenic dendritic cells ,dendritic cells ,autoimmune disease ,epigenetics - Abstract
Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naive T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-beta, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions.
- Published
- 2021
8. What can clinical immunology learn from inborn errors of epigenetic regulators?
- Author
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Camacho-Ordonez, N, Ballestar, E, Timmers, HTM, and Grimbacher, B
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immune system ,lymphocyte differentiation ,immune response ,Epigenetic regulation ,inborn errors of epigenetic regulators - Abstract
The epigenome is at the interface between environmental factors and the genome, regulating gene transcription, DNA repair, and replication. Epigenetic modifications play a crucial role in establishing and maintaining cell identity and are especially crucial for neurology, musculoskeletal integrity, and the function of the immune system. Mutations in genes encoding for the components of the epigenetic machinery lead to the development of distinct disorders, especially involving the central nervous system and host defense. In this review, we focus on the role of epigenetic modifications for the function of the immune system. By studying the immune phenotype of patients with monogenic mutations in components of the epigenetic machinery (inborn errors of epigenetic regulators), we demonstrate the importance of DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and mRNA processing for immunity. Moreover, we give a short overview on therapeutic strategies targeting the epigenome.
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- 2021
9. Microglial innate memory and epigenetic reprogramming in neurological disorders
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Martins-Ferreira, R, Leal, B, Costa, PP, and Ballestar, E
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Innate immune memory ,DNA methylation ,Histone modifications ,Epigenetics ,Microglia ,Neurological disease - Abstract
Microglia are myeloid-derived cells recognized as brain-resident macrophages. They act as the first and main line of immune defense in the central nervous system (CNS). Microglia have high phenotypic plasticity and are essential for regulating healthy brain homeostasis, and their dysregulation underlies the onset and progression of several CNS pathologies through impaired inflammatory responses. Aberrant microglial activation, following an inflammatory insult, is associated with epigenetic dysregulation in various CNS pathologies. Emerging data suggest that certain stimuli to myeloid cells determine enhanced or attenuated responses to subsequent stimuli. These phenomena, generally termed innate immune memory (IIM), are highly dependent on epigenetic reprogramming. Microglial priming has been reported in several neurological diseases and corresponds to a state of increased permissiveness or exacerbated response, promoted by continuous exposure to a chronic proinflammatory environment. In this article, we provide extensive evidence of these epigenetic-mediated phenomena under neurological conditions and discuss their contribution to pathogenesis and their clinical implications, including those concerning potential novel therapeutic approaches.
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- 2021
10. Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation
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Jacinto, F V, Ballestar, E, and Esteller, M
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- 2009
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11. Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity
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Zubia, A, Ropero, S, Otaegui, D, Ballestar, E, Fraga, M F, Boix-Chornet, M, Berdasco, M, Martinez, A, Coll-Mulet, L, Gil, J, Cossío, F P, and Esteller, M
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- 2009
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12. Transforming pathways unleashed by a HDAC2 mutation in human cancer
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Ropero, S, Ballestar, E, Alaminos, M, Arango, D, Schwartz, Jr, S, and Esteller, M
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- 2008
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13. Unmasking of epigenetically silenced candidate tumor suppressor genes by removal of methyl-CpG-binding domain proteins
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Lopez-Serra, L, Ballestar, E, Ropero, S, Setien, F, Billard, L-M, Fraga, M F, Lopez-Nieva, P, Alaminos, M, Guerrero, D, Dante, R, and Esteller, M
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- 2008
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14. Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta
- Author
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Perrin, D, Ballestar, E, Fraga, M F, Frappart, L, Esteller, M, Guerin, J-F, and Dante, R
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- 2007
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15. Clinical value of DNA methylation markers in autoimmune rheumatic diseases
- Author
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Ballestar, E, Sawalha, AH, and Lu, QJ
- Abstract
Methylation of cytosine residues in DNA, the best studied epigenetic modification, is associated with gene transcription and nuclear organization, and ultimately the function of a cell. DNA methylation can be influenced by various factors, including changes in neighbouring genomic sites such as those induced by transcription factor binding. The DNA methylation profiles in relevant cell types are altered in most human diseases compared with the healthy state. Given the physical stability of DNA and methylated DNA compared with other epigenetic modifications, DNA methylation is an ideal marker for clinical purposes. However, few DNA methylation-based markers have made it into clinical practice, with the notable exception of some markers used in the field of oncology. Autoimmune rheumatic diseases are genetically complex entities that can vary widely in terms of prognosis, subtypes, progression and treatment responses. Increasing reports showing strong links between DNA methylation profiles and different clinical outcomes and other clinical aspects in autoimmune rheumatic diseases reinforce the usefulness of DNA methylation profiles as novel clinical markers. In this Review, we provide an updated discussion on DNA methylation alterations in autoimmune rheumatic diseases and the advantages and disadvantages of using these markers in clinical practice. The DNA methylation profile of various cells types are altered in autoimmune rheumatic diseases. Particular DNA methylation profiles are associated with the prognosis, subtype, progression and/or treatment responses of various rheumatic diseases and hence have potential as clinical biomarkers.
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- 2020
16. Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease
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Calle-Fabregat, CD, Morante-Palacios, O, and Ballestar, E
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rheumatoid arthritis ,B cells ,DNA methylation ,epigenetics ,T cells ,innate lymphoid cells ,NK cells ,granulocytes ,innate immune deficiencies ,Familial Mediterranean Fever ,immune system ,systemic lupus erythematosus ,cryopyrin-associated periodic fever syndrome ,monocytes ,primary immunodeficiencies - Abstract
Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases.
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- 2020
17. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer
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Aguilera, O, Fraga, M F, Ballestar, E, Paz, M F, Herranz, M, Espada, J, García, J M, Muñoz, A, Esteller, M, and González-Sancho, J M
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- 2006
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18. Towards defining the lymphoma methylome
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Martín-Subero, J I, Ballestar, E, Esteller, M, and Siebert, R
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- 2006
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19. miRNAs as Therapeutic Targets in Inflammatory Disease
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Lu, QJ, Wu, RF, Zhao, M, Garcia-Gomez, A, and Ballestar, E
- Abstract
In the past decade, we have witnessed considerable developments in understanding the roles and functions of miRNAs. In parallel, the identification of alterations in miRNA expression in inflammatory disease indicates their potential as therapeutic targets. Pharmacological treatments targeting abnormally expressed miRNAs for inflammatory diseases are not yet in clinical practice; however, some small compounds and nucleic acids targeting miRNAs have shown promise in preclinical development. Here, we focus on recent advances in understanding miRNA deregulation in inflammatory diseases and provide an overview of the current development of miRNA-based therapeutics in these diseases with an emphasis on newly discovered miRNA therapeutic targets.
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- 2019
20. THE ROLE OF EPIGENETIC ALTERATIONS IN CANCER
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Ballestar, E., Fraga, M. F., Ropero, S., Lopez-Serra, L., Jacinto, F. V., Lujambio, A., and Esteller, M.
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- 2007
21. The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding
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Mulero-Navarro, S., Carvajal-Gonzalez, J.M., Herranz, M., Ballestar, E., Fraga, M.F., Ropero, S., Esteller, M., and Fernandez-Salguero, P.M.
- Published
- 2006
22. S1A:5 Molecular stratification of autoimmune diseases based on epigenetic profiles
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Barturen, G, primary, Kerick, M, additional, Alvarez-Errico, D, additional, Quintares, R, additional, Carnero, E, additional, Gemperline, D, additional, Dow, E, additional, Beretta, L, additional, Pers, JO, additional, Renadineau, Y, additional, Frostegard, J, additional, Juarez, M, additional, Consortium, Clinical, additional, Group, Flow Cytometry, additional, Rao, S, additional, Chamberlain, C, additional, Wojcik, J, additional, Segura, A, additional, Martin, J, additional, Ballestar, E, additional, and Alarcón-Riquelme, ME, additional
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- 2018
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23. PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation
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de la Rica L, Rodrxedguez-Ubreva J, Garcxeda M, Islam AB, Urquiza JM, Hernando H, Christensen J, Helin K, Gxf3mez-Vaquero C, and Ballestar E.
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- 2013
24. Tet2 facilitates the derepression of myeloid target genes during CEBP\u03b1-induced transdifferentiation of pre-B cells
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Kallin EM, Rodrxedguez-Ubreva J, Christensen J, Cimmino L, Aifantis I, Helin K, Ballestar E, and Graf T.
- Published
- 2012
25. TRANSCRIPTOMIC AND METHYLOMIC PROFILING OF CD4+ T-CELLS IN GIANT CELL ARTERITIS WITH DIFFERENT DISEASE ACTIVITY.
- Author
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Estupiñán-Moreno, E., Hernández-Rodríguez, J., LI, T., Ciudad, L., Andrés-León, E., Terron-Camero, L. C., Prieto-González, S., Espígol-Frigolé, G., Cid, M. C., Márquez, A., Ibanez, J. Martin, Ballestar, E., and Ortiz-Fernández, L.
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- 2023
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26. Epigenetic control in immune function
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Elsen, P.J. van den, Eggermond, M.C.J.A. van, Wierda, R.J., and Ballestar, E.
- Subjects
chemical and pharmacologic phenomena - Abstract
This chapter describes recent advances in our understanding how epigenetic events control immune functions with emphasis on transcriptional regulation of major histocompatibility complex ClassI (MIC-I) and Class II (MHC-II) genes. MHC-I and MHC-II molecules play an essential role in the adaptive immune response by virtue of their ability to present peptides, respectively to CD8+ and CD4+ T cells. Central to the onset of an adequate immune response to pathogens is the presentation of pathogen-derived peptides in the context of MHC-II molecules by antigen presenting cells (APCs) to CD4+ T cells of the immune system. In particular dendritic cells are highly specialized APCs that are capable to activate naïve T cells. Given their central role in adaptive immunity, MHC-I and MHC-II genes are regulated in a tight fashion at the transcriptional level to meet with local requirements of an effective antigen-specific immune response. In these regulatory processes the MHC2TA encoded Class II transactivator (CIITA) plays a crucial role. CIITA is essential for transcriptional activation of all MHC-I genes, whereas it plays an ancillary function in the transcriptional control of MHC-I genes. The focus of this chapter therefore will be on the transcription factors that interact with conserved cis-acting promoter elements and epigenetic mechanisms that modulate cell type-specific regulation of MHC-I, MHC-I, and MHC2TA genes. Furthermore, we will also briefly discuss how genetic and epigenetic mechanisms contribute to T helper cell differentiation.
- Published
- 2011
27. BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia
- Author
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San-Jose, E. (Edurne), Roman-Gomez, J. (José), Cordeu, L. (Lucía), Ballestar, E. (E.), Garate, L. (Leire), Andreu, E.J. (Enrique José), Isidro, I. (Isabel), Guruceaga, E. (Elizabeth), Jimenez-Velasco, A. (A.), Heiniger, A. (A.), Torres, A. (Antonio), Calasanz-Abinzano, M.J. (Maria Jose), Esteller, M. (Manel), Gutierrez, N.C. (Norma C.), Rubio, A. (Ángel), Perez-Roger, I. (Ignacio), Agirre-Ena, X. (Xabier), and Prosper, F. (Felipe)
- Subjects
hemic and lymphatic diseases ,HSPA8 ,Signal transduction ,neoplasms ,Chronic myeloid leukaemia ,CD34+ - Abstract
In order to determine new signal transduction pathways implicated in chronic myeloid leukaemia (CML), we performed a gene expression profile comparison between CD34+ cells from CML patients and healthy donors. Functional studies were performed using the Mo7e and Mo7e-p210 cell lines. Expression of CCND1 (Cyclin D1), as well as the chaperone HSPA8, which is important for regulation of CCND1, were significantly upregulated in CD34+ CML cells. Upregulation of HSPA8 was dependent, at least in part, on STAT5 (signal transducer and activator of transcrition 5)-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation. The presence of HSPA8 in the nuclear protein fraction as well as its binding to CCND1 suggests that it may contribute to stabilization of the CCND1/CDK4 complex, which, in turn, may participate in proliferation of CML cells. Treatment of CML cells with the specific HSPA8 inhibitor 15-deoxyspergualin induced inhibition of CML cell viability but did not induce apoptosis. In conclusion, our studies suggest that STAT5-mediated activation of HSPA8 induces nuclear translocation and activation of the CCND1/CDK4 complex leading to increased proliferation of CML cells, deciphering a new pathway implicated in CML and supporting a potential role of chaperone inhibitors in the treatment of CML.
- Published
- 2008
28. In vivo analysis of DNA methylation patterns recognized by specific proteins: coupling chromatin immunoprecipitation and bisulfite genomic sequencing
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Matarazzo M.R., Lembo F., Angrisano T., Ballestar E., Ferraro M., Pero R., De Bonis M.L., Bruni C.B., Esteller M., D'Esposito M., and Chiariotti L.
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CpG-Binding-Proteins ,MBD2 ,Domain ,Chromatin Structure ,Repression - Abstract
The three-way connection between DNA methylation, chromatin configuration, and transcriptional regulation is under increasing attention, but the fine rules governing the epigenetic control are still poorly understood. In several studies, the authors have concluded that the methylation status of CpG sites could be critical for the binding of factors to DNA and, consequently, for chromatin conformation. We tested the possibility that a novel technical approach combining chromatin immunoprecipitation and bisulfite genomic sequencing analysis (ChIP-BA) could provide useful information on the role of specific CpG methylation patterns in driving the association in vivo of proteins to given genomic regions. Our results show that ChIP-BA permits the establishment in vivo of the methylation patterns required for the binding of a methyl-CpG binding protein and, in addition, can potentially identify methylation patterns that do not allow a protein to bind specific genomic regions. Possible fields of application are discussed. We believe that wide use of ChIP-BA could make possible the exploration of a novel aspect of the intricate epigenetic web.
- Published
- 2004
29. Essentials in Rheumatology: Disease Management * I29. Recognition and Management of the Auto-Inflammatory Diseases
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McGonagle, D., primary, McKenna, F., additional, Maher, T., additional, Kavanagh, R., additional, Cunningham, A.-M., additional, Lee, M., additional, Grosart, R., additional, Wakefield, R., additional, Kane, D., additional, Schmidt, W., additional, Young, T., additional, Ndosi, M., additional, Lewis, M., additional, Hale, C., additional, Bird, H., additional, Ryan, S., additional, Quinn, H., additional, McIvor, E., additional, Taylor, J., additional, Burbage, G., additional, Bond, D., additional, White, J., additional, Chagadama, D., additional, Green, S., additional, Kay, L., additional, Pace, A. V., additional, Bejarano, V., additional, Emery, P., additional, Hill, J., additional, Hurley, M., additional, Porcheret, M., additional, Hart, O., additional, Oliver, D., additional, Coates, L., additional, Backhouse, M., additional, Pickles, D., additional, Chamberlain, V., additional, Partridge, K., additional, Keat, A., additional, Maddison, P., additional, Taylor, P., additional, Dillon, A., additional, Chapman, V., additional, Pincus, T., additional, Shelton, D., additional, Ballestar, E., additional, Loughlin, J., additional, Tak, P.-P., additional, Prinjha, R., additional, Regan, L., additional, D'Cruz, D., additional, Jones, G., additional, Lewis, J., additional, den Hollander, M., additional, Goossens, M., additional, de Jong, J., additional, Smeets, R., additional, Vlaeyen, J., additional, Ioannou, J., additional, McDonagh, J., additional, Clinch, J., additional, Pilkington, C., additional, Siebert, S., additional, Martindale, J., additional, Beevor, C., additional, Jeffries, C., additional, Deighton, C., additional, Nye, A., additional, Cook, D., additional, and Firth, J., additional
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- 2013
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30. The Wnt antagonist DICKKOPF-1 gene is induced by 1 ,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells
- Author
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Aguilera, O., primary, Pena, C., additional, Garcia, J. M., additional, Larriba, M. J., additional, Ordonez-Moran, P., additional, Navarro, D., additional, Barbachano, A., additional, Lopez de Silanes, I., additional, Ballestar, E., additional, Fraga, M. F., additional, Esteller, M., additional, Gamallo, C., additional, Bonilla, F., additional, Gonzalez-Sancho, J. M., additional, and Munoz, A., additional
- Published
- 2007
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31. Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells
- Author
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Espada, J., primary, Ballestar, E., additional, Santoro, R., additional, Fraga, M. F., additional, Villar-Garea, A., additional, Nemeth, A., additional, Lopez-Serra, L., additional, Ropero, S., additional, Aranda, A., additional, Orozco, H., additional, Moreno, V., additional, Juarranz, A., additional, Stockert, J. C., additional, Langst, G., additional, Grummt, I., additional, Bickmore, W., additional, and Esteller, M., additional
- Published
- 2007
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32. Multiple binding of methyl‐CpG and polycomb proteins in long‐term gene silencing events
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Matarazzo, M.R., primary, De Bonis, M.L., additional, Strazzullo, M., additional, Cerase, A., additional, Ferraro, M., additional, Vastarelli, P., additional, Ballestar, E., additional, Esteller, M., additional, Kudo, S., additional, and D'Esposito, M., additional
- Published
- 2006
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33. Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta
- Author
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Perrin, D, primary, Ballestar, E, additional, Fraga, M F, additional, Frappart, L, additional, Esteller, M, additional, Guerin, J-F, additional, and Dante, R, additional
- Published
- 2006
- Full Text
- View/download PDF
34. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer
- Author
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Ballestar, E., primary
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- 2003
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35. The impact of chromatin in human cancer: linking DNA methylation to gene silencing
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Ballestar, E., primary
- Published
- 2002
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36. Multiple binding of methyl-CpG and polycomb proteins in long-term gene silencing events.
- Author
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Matarazzo, M. R., De Bonis, M. L., Strazzullo, M., Cerase, A., Ferraro, M., Vastarelli, P., Ballestar, E., Esteller, M., Kudo, S., and D'Esposito, M.
- Subjects
GENE silencing ,PROTEINS ,GENE expression ,GENETIC regulation ,GENE transfection - Abstract
Epigenetic regulation is involved in the maintenance of long-term silencing phenomena, such as X-inactivation and genomic imprinting in mammals. Gene repression is mediated by several mechanisms, such as histone modifications, DNA methylation, and recruitment of Polycomb proteins. To understand the mechanistic relationships between these mechanisms for stable gene silencing, we analyzed the mechanisms of X- and Y-inactivation of the PAR2 gene SYBL1, previously showed to be regulated by concerted epigenetic mechanisms. Maintenance of stable repression occurs via the recruitment of both MBDPs and PRC2 complexes to SYBL1 promoter. Their binding is equally sensitive to defective DNA methylation seen in cells derived from ICF syndrome patients. Multiple occupancy is a feature shared within long-term repressed genes, such as the X-inactivated PGK1 and the imprinted IGF2. MBD2, MBD3, and MeCP2 occupy SYBL1 promoter simultaneously, as revealed by sequential ChIP. We did not find this co-occurring binding when looked for members of PRC2 complex together with any of the methyl-binding proteins. Furthermore, in co-transfection assays, MECP2 can silence methylated SYBL1 promoter, whereas the mutated protein fails. However, RNA interference of endogenous MECP2 does not induce the expression of the inactive SYBL1 alleles, suggesting that its silencing activity can be replaced by the other methyl-binding proteins. Our data suggest that maintenance of long-term silencing involves multiple layers of epigenetic control functionally redundant. PRC2 and MBD proteins could collaborate to different phases of this process, the former possibly recruiting DNMTs to the silenced promoters, the latter dictating the lock of the transcription. J. Cell. Physiol. 210: 711–719, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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37. Core histones are glutaminyl substrates for tissue transglutaminase.
- Author
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Ballestar, E, Abad, C, and Franco, L
- Abstract
Chicken erythrocyte core histones are glutaminyl substrates in the transglutaminase (TGase) reaction with monodansylcadaverine (DNC) as donor amine. The modification is very fast when compared with that of many native substrates of TGase. Out of the 18 glutamines of the four histones, nine (namely glutamine 95 of H2B; glutamines 5, 19, and 125 of H3; glutamines 27 and 93 of H4; and glutamines 24, 104, and 112 of H2A) are the amine acceptors in free histones. The use of Gln112 of H2A requires a temperature-dependent partial unfolding of the histone, showing that structural determinants are decisive for the glutamine specificity. The structures of H2A and H2B do not appreciably change upon modification with DNC as determined by circular dichroism, and core particles reconstituted from these DNC-modified histones are indistinguishable from native nucleosome cores. When the reaction is carried out with native nucleosomes, only glutamines 5 and 19 of H3, which are located in the N-terminal tail, and glutamine 22 of H2B, which is not labeled in free histone, are modified. Methylamine and putrescine also are incorporated into nucleosomes by the TGase reaction. Our results reveal several possibilities for the application of the TGase reaction in the chromatin field, and taking into account that histones are easily cross-linked or modified by polyamines in vitro, the possibility that they may be TGase substrates in vivo is discussed.
- Published
- 1996
38. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells (vol 67, pg 1424, 2007)
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Lujambic, A., Ropero, S., Ballestar, E., Fraga, M. F., Cerrato, C., Setien, F., Casado, S., Suarez-Gauthier, A., Sanchez-Cespedes, M., Git, A., Spiteri, I., Das, P. P., Carlos Caldas, Miska, E., and Esteller, M.
39. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature
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Teruel, María, Barturen, Guillermo, Martínez Bueno, Manuel, Castellini Pérez, Olivia, Barroso Gil, Miguel, Povedano, Elena, Kerick, Martin, Català Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Beretta, Lorenzo, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Rodriguez Maresca, Manuel, López Berrio, Antonio, Aguilar Quesada, Rocío, Navarro Linares, Héctor, Alvarez, Montserrat, Álvarez Errico, Damiana, Azevedo, Nancy, Barbarroja, Nuria, Cheng, Qingyu, Cremer, Jonathan, Groof, Aurélie de, Langhe, Ellen de, Ducreux, Julie, Dufour, Aleksandra, Hernández Fuentes, María, Khodadadi, Laleh, Kniesch, Katja, Li, Tianlu, López Pedrera, Chary, Marañón, Concepción, Muchmore, Brian, Neves, Esmeralda, Rouvière, Bénédicte, Simon, Quentin, Trombetta, Elena, Varela, Nieves, Witte, Torsten, Pers, Jacques-olivier, Ballestar, Esteban, Martin, Javier, Carnero Montoro, Elena, Alarcón Riquelme, Marta, Precisesads Clinical Consortium, Precisesads Flow Cytometry Study Group, Vigone, Barbara, Pers, Jacques Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Maudoux, Anne-lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Ángel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Rodríguez Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega Castro, Rafaela, Aguirre Zamorano, Mª Angeles, Escudero Contreras, Alejandro, Castro Villegas, Mª Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, Ramon, Enrique de, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Study Group, [Teruel,M, Barturen,G, Martínez-Bueno,M, Castellini-Pérez,O, Barroso-Gil,M, Povedano,E, Marañón,C, Carnero-Montoro,E, Alarcón-Riquelme,ME] GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain. [Kerick,M, Martin,J] IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científcas, Granada, Spain. [Català-Moll,F, Ballestar,E] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain. [Català-Moll,F, Ballestar,E] IDIBELL, Bellvitge Biomedical Research Institute L’Hospitalet de Llobregat, Barcelona, Spain. [Makowska,Z, Buttgereit,A] Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Pers,JO] Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France.[Alarcón-Riquelme,ME] Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden., and Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.
- Subjects
Epigenomics ,Male ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings] ,Autoimmune diseases ,Gene Expression ,Quantitative trait ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings] ,0302 clinical medicine ,Rheumatic diseases ,HLA Antigens ,Genetics ,Regulation of gene expression ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,Malalties autoimmunitàries ,Molecular medicine ,Epigenetic ,Autoanticuerpos ,Genomics ,Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings] ,3. Good health ,Sjogren's Syndrome ,DNA methylation ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings] ,Medicine ,Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings] ,Epigenetics ,Female ,Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings] ,Extracellular matrix organization ,Science ,Population ,Check Tags::Male [Medical Subject Headings] ,Human leukocyte antigen ,Biology ,Variación genética ,Article ,03 medical and health sciences ,Rheumatology ,Enfermedades autoinmunes ,Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings] ,Immunogenetics ,Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid::Sjogren's Syndrome [Medical Subject Headings] ,Humans ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [Medical Subject Headings] ,education ,Gene ,030304 developmental biology ,Autoantibodies ,030203 arthritis & rheumatology ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings] ,Genetic Variation ,DNA Methylation ,Epigenètica ,Check Tags::Female [Medical Subject Headings] ,Gene Expression Regulation ,Epigenómica ,Síndrome de Sjögren ,Interferons ,Expresión génica - Abstract
Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support., Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population., Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565, EFPIA companies, Junta de Andalucia PI/0017/2016, Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme, EFPIA, Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652
- Published
- 2021
40. Epigenetic Deregulation in Rheumatoid Arthritis
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Emmanuel Karouzakis, Renate E. Gay, Steffen Gay, Michel Neidhart, University of Zurich, Ballestar, E, and Neidhart, M
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biology ,business.industry ,10051 Rheumatology Clinic and Institute of Physical Medicine ,Arthritis ,610 Medicine & health ,Bioinformatics ,medicine.disease_cause ,medicine.disease ,Autoimmunity ,Histone ,medicine.anatomical_structure ,1300 General Biochemistry, Genetics and Molecular Biology ,10076 Center for Integrative Human Physiology ,Rheumatoid arthritis ,DNA methylation ,biology.protein ,medicine ,570 Life sciences ,sense organs ,Epigenetics ,Synovial membrane ,skin and connective tissue diseases ,business ,Epigenetic therapy - Abstract
In this chapter, we discuss the current understanding of the possible epigenetics changes that occur in rheumatoid arthritis. In particular, we describe that deregulation ofDNA methylation and histone modifications can occur in the immune system and lead to rheumatoid arthritis. In addition, we discuss the role of rheumatoid arthritis synovial fibroblasts in autoimmunity. Examples of changes in DNA methylation and histone modification occurring in synovial fibroblasts during the disease process are reviewed in this chapter. In conclusion, we discuss the possible use of epigenetic therapy and describe future experiments that can elucidate further the epigenetic changes observed in the disease.
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- 2011
41. Combinatorial effects of splice variants modulate function of Aiolos
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Rogelio González-Sarmiento, Miguel Alaminos, Fernando Setien, Manuel Boix-Chornet, Lidia Lopez-Serra, Mario F. Fraga, María C. Montoya, Rosalia Caballero, Eva María Sánchez-Tapia, Diego Megías, Manel Esteller, Santiago Ropero, Esteban Ballestar, [Caballero,R, Setien,F, Lopez-Serra,L, Boix-Chornet,M, Fraga, MF, Ropero, S, Esteller,M, Ballestar,E] Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [Caballero,R, Sanchez-Tapia,EM, Gonzalez-Sarmiento,R] Molecular Medicine Unit-Department of Medicine, Center for Cancer Research (CIC), University of Salamanca, Salamanca, Spain. [Boix-Chornet,M] Leukaemia Research Fund Centre at the Institute of Cancer Research, London, UK. [Megias,MD, Montoya, MC]Confocal Microscopy and Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [Alaminos, M]Department of Histology (University of Granada) and Fundación Hospital Clínico, Granada, Spain., and This work was supported by grants BFU2004-02073/BMC, CSD2006-49 and PM 99-0070 from the Spanish Ministry of Education and Science (MEC) and Mutua Madrileña Foundation. R.C. was funded by a Predoctoral Fellowship from the Spanish Ministry of Education and Science (PM 99-0070).
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Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Histones [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Histones ,Factores de Transcripción ,Histonas ,Anatomy::Cells::Antibody-Producing Cells::B-Lymphocytes [Medical Subject Headings] ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Protein Isoforms ,Regulación de la Expresión Génica ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Kruppel-Like Transcription Factors::Ikaros Transcription Factor [Medical Subject Headings] ,Cellular localization ,Genetics ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Molecular Conformation::Protein Conformation::Protein Structure, Secondary::Amino Acid Motifs::Zinc Fingers [Medical Subject Headings] ,B-Lymphocytes ,Histona Desacetilasas ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein Isoforms [Medical Subject Headings] ,Dedos de Zinc ,Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured::Cell Line, Tumor [Medical Subject Headings] ,Zinc Fingers ,Aiolos ,IKZF3 ,Empalme Alternativo ,Chromatin ,Cell biology ,Humanos ,Histone ,Mi-2/NuRD ,RNA splicing ,Epigenetics ,Linfocitos B ,Dimerization ,Gene isoform ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Amidohydrolases::Histone Deacetylases [Medical Subject Headings] ,Línea Celular ,Biology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings] ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative Splicing [Medical Subject Headings] ,Histone Deacetylases ,Cell Line ,Ikaros Transcription Factor ,Cell Line, Tumor ,Dimerización ,Animals ,Humans ,Ikaros ,Transcription factor ,Factor de Transcripción Ikaros ,Alternative splicing ,Cell Biology ,Alternative Splicing ,Gene Expression Regulation ,Línea Celular Tumoral ,Animales ,Phenomena and Processes::Chemical Phenomena::Chemical Processes::Dimerization [Medical Subject Headings] ,biology.protein ,Phenomena and Processes::Physiological Phenomena [Medical Subject Headings] ,Histone deacetylase ,Isoformas de Proteínas ,Isoforms ,Transcription Factors - Abstract
Journal Article; Research Support, Non-U.S. Gov't; The transcription factor Aiolos (also known as IKZF3), a member of the Ikaros family of zinc-finger proteins, plays an important role in the control of B lymphocyte differentiation and proliferation. Previously, multiple isoforms of Ikaros family members arising from differential splicing have been described and we now report a number of novel isoforms of Aiolos. It has been demonstrated that full-length Ikaros family isoforms localize to heterochromatin and that they can associate with complexes containing histone deacetylase (HDAC). In this study, for the first time we directly investigate the cellular localization of various Aiolos isoforms, their ability to heterodimerize with Ikaros and associate with HDAC-containing complexes, and the effects on histone modification and binding to putative targets. Our work demonstrates that the cellular activities of Aiolos isoforms are dependent on combinations of various functional domains arising from the differential splicing of mRNA transcripts. These data support the general principle that the function of an individual protein is modulated through alternative splicing, and highlight a number of potential implications for Aiolos in normal and aberrant lymphocyte function. Yes
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- 2007
42. In vivo analysis of DNA methylation patterns recognized by specific proteins: Coupling ChIP and bisulfite analysis
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Manel Esteller, Marcella Ferraro, Maria R. Matarazzo, Carmelo B. Bruni, Lorenzo Chiariotti, Esteban Ballestar, Francesca Lembo, Maurizio D'Esposito, Tiziana Angrisano, Raffaela Pero, Maria Luigia De Bonis, Matarazzo, Mr, Lembo, Francesca, Angrisano, Tiziana, Ballestar, E, Ferraro, M, Pero, Raffaela, De Bonis, Ml, Bruni, CARMELO BRUNO, Esteller, M, D'Esposito, M, and Chiariotti, Lorenzo
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Bisulfite sequencing ,Computational biology ,chromatin immunoprecipitation ,Biology ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,bisulfite genomic sequencing analysis ,Epigenetics of physical exercise ,Methylated DNA immunoprecipitation ,Epigenetics ,Cloning, Molecular ,Epigenomics ,Genetics ,DNA methylation ,Base Sequence ,Sulfates ,DNA ,Genomics ,Sequence Analysis, DNA ,DNA Fingerprinting ,Culture Media ,Chromatin ,DNA-Binding Proteins ,Illumina Methylation Assay ,Biotechnology - Abstract
The three-way connection between DNA methylation, chromatin configuration, and transcriptional regulation is under increasing attention, but the fine rules governing the epi-genetic control are still poorly understood. In several studies, the authors have concluded that the methylation status of CpG sites could be critical for the binding of factors to DNA and, consequently, for chromatin conformation. We tested the possibility that a novel technical approach combining chromatin immunoprecipitation and bisulfite genomic sequencing analysis (ChIP-BA) could provide useful information on the role of specific CpG methylation patterns in driving the association in vivo of proteins to given genomic regions. Our results show that ChIP-BA permits the establishment in vivo of the methylation patterns required for the binding of a methyl-CpG binding protein and, in addition, can potentially identify methylation patterns that do not allow a protein to bind specific genomic regions. Possible fields of application are discussed. We believe that wide use of ChIP-BA could make possible the exploration of a novel aspect of the intricate epigenetic web.
43. Opposing effects of the purinergic P2X7 receptor on seizures in neurons and microglia in male mice.
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Alves M, Gil B, Villegas-Salmerón J, Salari V, Martins-Ferreira R, Arribas Blázquez M, Menéndez Méndez A, Da Rosa Gerbatin R, Smith J, de Diego-Garcia L, Conte G, Sierra-Marquez J, Merino Serrais P, Mitra M, Fernandez Martin A, Wang Y, Kesavan J, Melia C, Parras A, Beamer E, Zimmer B, Heiland M, Cavanagh B, Parcianello Cipolat R, Morgan J, Teng X, Prehn JHM, Fabene PF, Bertini G, Artalejo AR, Ballestar E, Nicke A, Olivos-Oré LA, Connolly NMC, Henshall DC, and Engel T
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- Animals, Male, Mice, Female, Mice, Inbred C57BL, Kainic Acid, Epilepsies, Myoclonic metabolism, Epilepsies, Myoclonic genetics, Hippocampus metabolism, Status Epilepticus metabolism, Status Epilepticus genetics, Mice, Knockout, Pentylenetetrazole, Signal Transduction, GABAergic Neurons metabolism, Epilepsy metabolism, Epilepsy genetics, Brain metabolism, Microglia metabolism, Receptors, Purinergic P2X7 metabolism, Receptors, Purinergic P2X7 genetics, Seizures metabolism, Seizures genetics, Neurons metabolism, Disease Models, Animal
- Abstract
Background: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood., Methods: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter., Results: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome., Conclusions: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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44. Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states.
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Martins-Ferreira R, Calafell-Segura J, Chaves J, Ciudad L, Martins da Silva A, Pinho E Costa P, Leal B, and Ballestar E
- Abstract
Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)
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- 2024
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45. Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.
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Castellini-Pérez O, Povedano E, Barturen G, Martínez-Bueno M, Iakovliev A, Kerick M, López-Domínguez R, Marañón C, Martín J, Ballestar E, Borghi MO, Qiu W, Zhu C, Shankara S, Spiliopoulou A, de Rinaldis E, Carnero-Montoro E, and Alarcón-Riquelme ME
- Abstract
The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered., (© 2024. The Author(s).)
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- 2024
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46. Disease activity drives divergent epigenetic and transcriptomic reprogramming of monocyte subpopulations in systemic lupus erythematosus.
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Ferreté-Bonastre AG, Martínez-Gallo M, Morante-Palacios O, Calvillo CL, Calafell-Segura J, Rodríguez-Ubreva J, Esteller M, Cortés-Hernández J, and Ballestar E
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- Humans, Female, Adult, Male, Cell Differentiation genetics, Middle Aged, Case-Control Studies, Disease Progression, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Monocytes metabolism, Monocytes immunology, DNA Methylation, Epigenesis, Genetic, Transcriptome
- Abstract
Objectives: Systemic lupus erythematosus (SLE) is characterised by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classic monocytes into intermediate and non-classic monocytes, assuming diverse roles and changing their proportions in inflammation. In this study, we investigated the epigenetic and transcriptomic profiles of these and novel monocyte subsets in SLE in relation to activity and progression., Methods: We obtained the DNA methylomes and transcriptomes of classic, intermediate, non-classic monocytes in patients with SLE (at first and follow-up visits) and healthy donors. We integrated these data with single-cell transcriptomics of SLE and healthy donors and interrogated their relationships with activity and progression., Results: In addition to shared DNA methylation and transcriptomic alterations associated with a strong interferon signature, we identified monocyte subset-specific alterations, especially in DNA methylation, which reflect an impact of SLE on monocyte differentiation. SLE classic monocytes exhibited a proinflammatory profile and were primed for macrophage differentiation. SLE non-classic monocytes displayed a T cell differentiation-related phenotype, with Th17-regulating features. Changes in monocyte proportions, DNA methylation and expression occurred in relation to disease activity and involved the STAT pathway. Integration of bulk with single-cell RNA sequencing datasets revealed disease activity-dependent expansion of SLE-specific monocyte subsets, further supported the interferon signature for classic monocytes, and associated intermediate and non-classic populations with exacerbated complement activation., Conclusions: Disease activity in SLE drives a subversion of the epigenome and transcriptome programme in monocyte differentiation, impacting the function of different subsets and allowing to generate predictive methods for activity and progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
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- 2024
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47. Decoding CD4 + T cell transcriptome in giant cell arteritis: Novel pathways and altered cross-talk with monocytes.
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Estupiñán-Moreno E, Hernández-Rodríguez J, Li T, Ciudad L, Andrés-León E, Terron-Camero LC, Prieto-González S, Espígol-Frigolé G, Cid MC, Márquez A, Martin J, Ballestar E, and Ortiz-Fernández L
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- Humans, Female, Male, Aged, DNA Methylation, Middle Aged, Aged, 80 and over, Epigenesis, Genetic, Cell Communication immunology, Gene Expression Regulation, Giant Cell Arteritis immunology, Giant Cell Arteritis genetics, Monocytes immunology, Monocytes metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Transcriptome, Signal Transduction, Gene Expression Profiling
- Abstract
Background: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4
+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis., Methods: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes., Results: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA., Conclusions: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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48. MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.
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Wang T, Song D, Li X, Luo Y, Yang D, Liu X, Kong X, Xing Y, Bi S, Zhang Y, Hu T, Zhang Y, Dai S, Shao Z, Chen D, Hou J, Ballestar E, Cai J, Zheng F, and Yang JY
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- Humans, Mice, Animals, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 metabolism, Toll-Like Receptor 8 genetics, Toll-Like Receptor 8 metabolism, Kidney metabolism, Mice, Transgenic, Lupus Nephritis genetics, MicroRNAs genetics
- Abstract
Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
49. Single-cell multi-omics analysis of COVID-19 patients with pre-existing autoimmune diseases shows aberrant immune responses to infection.
- Author
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Barmada A, Handfield LF, Godoy-Tena G, de la Calle-Fabregat C, Ciudad L, Arutyunyan A, Andrés-León E, Hoo R, Porter T, Oszlanczi A, Richardson L, Calero-Nieto FJ, Wilson NK, Marchese D, Sancho-Serra C, Carrillo J, Presas-Rodríguez S, Ramo-Tello C, Ruiz-Sanmartin A, Ferrer R, Ruiz-Rodriguez JC, Martínez-Gallo M, Munera-Campos M, Carrascosa JM, Göttgens B, Heyn H, Prigmore E, Casafont-Solé I, Solanich X, Sánchez-Cerrillo I, González-Álvaro I, Raimondo MG, Ramming A, Martin J, Martínez-Cáceres E, Ballestar E, Vento-Tormo R, and Rodríguez-Ubreva J
- Subjects
- Humans, SARS-CoV-2, Leukocytes, Mononuclear, Multiomics, Autoimmunity, Single-Cell Analysis, COVID-19, Autoimmune Diseases
- Abstract
In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
- Published
- 2024
- Full Text
- View/download PDF
50. Single-cell transcriptomic profiling reveals a pathogenic role of cytotoxic CD4 + T cells in giant cell arteritis.
- Author
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Carmona EG, Callejas-Rubio JL, Raya E, Ríos-Fernández R, Villanueva-Martín G, Cid MC, Hernández-Rodríguez J, Ballestar E, Timmermann B, Ortego-Centeno N, Martín J, and Márquez A
- Subjects
- Humans, T-Lymphocytes, Regulatory, T-Lymphocytes, Cytotoxic pathology, Gene Expression Profiling, Giant Cell Arteritis
- Abstract
Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4
+ T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4+ T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4+ T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4+ T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4+ T cells in GCA and suggest targeting CTLs as a potential therapeutic option., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
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