Suchergebnisse

We thank all participating subjects with AS and healthy individuals who provided the DNA and clinical information necessary for this study. This work was in part funded by grants from Arthritis Research UK (19536 and 18797), the NIHR Oxford comprehensive Biomedical Research Centre (immunity and inflammation theme A93081) and NIHR Thames Valley collaborative research network and National Ankylosing Spondylitis Society (UK). SPARCC was established through the support of the Arthritis Society of Canada. Support was received from National Institutes of Health/National Institute of Allergy and Infectious Diseases grant 1U01AI09090-01. This work was supported in part by grant PI12/02587 (Inst. Carlos III, Spain) and by European Union 'Fondos FEDER'. Support was received from Agence Nationale de la Recherche (grant ANR 2010 GEMISA and Investissements d'Avenir programme ANR-11-IDEX-0005-02), the Socie´te´ Franc¸aise de Rhumatologie (SFR) and the Arthritis Foundation. M.W. is funded by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. M.A.B. is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. D.M.E. is funded by an Australian Research Council Future Fellowship (FT130101709). P.I.W.d.B. is funded in part by the Netherlands Organization for Scientific Research (VIDI Vernieuwingsimpuls project 016.126.354) and by the National Institutes of Health (1R01AR062886-1) ; Cortes, A., Pulit, S.L., Leo, P.J., Pointon, J.J., Robinson, P.C., Weisman, M.H., Ward, M., Gensler, L.S., Zhou, X., Garchon, H.-J., Chiocchia, G., Nossent, J., Lie, B.A., Førre, Ø., Tuomilehto, J., Laiho, K., Bradbury, L.A., Elewaut, D., Burgos-Vargas, R., Stebbings, S., Appleton, L., Farrah, C., Lau, J., Haroon, N., Mulero, J., Blanco, F.J., Gonzalez-Gay, M.A., Lopez-Larrea, C., Bowness, P., Gaffney, K., Gaston, H., Gladman, D.D., Rahman, P., Maksymowych, W.P., Crusius, J.B.A., Van Der Horst-Bruinsma, I.E., Valle-Oñate, ...

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis. ; Plan Nacional de [I+D+I 2008–2011]; Instituto de Salud Carlos III [grant number PI12/02587]; Red Española de Investigación Renal (REDinREN) [grant number RD12/0021/0018 and RD12/0021/0021]; Spanish Ministry of Science and Innovation [grant number SAF2010- 15106 and PLE2009-0110]; European Union [Fondos FEDER] ; Peer Reviewed

This work was supported by the Red de Investigación Renal (REDinREN) and FIS-Fondos FEDER European Union PI080566 and PI1202527 from the Instituto Carlos III.

Clinical trial was supported by the grants from the Instituto de Salud Carlos III (PI12/02587), Red de Investigación Renal (REDiNREN RD12/0021/0021), European Union FEDER funds, Principado de Asturias (Plan de Ciencia, Tecnologia e Innovacion), FICYT (GRUPIN 14-069), and Hackensack University Medical Center Foundation ; Delgado, E., Perez-Basterrechea, M., Suarez-Alvarez, B., Zhou, H., Revuelta, E.M., Garcia-Gala, J.M., Perez, S., Alvarez-Viejo, M., Menendez, E., Lopez-Larrea, C., Tang, R., Zhu, Z., Hu, W., Moss, T., Guindi, E., Otero, J., Zhao, Y.

This work is supported by Plan Nacional de I+D+I 2008–2011 and European Union Fondos Feder; Instituto de Salud Carlos III (grant number PI12/02587 and PI16/01318); Red Española de Investigación Renal (REDinREN) (grant number RD12/0021/0018 and 0021, and RD16/0009/0020), Plan de Ciencia, Tecnología e Innovación 2013-2017 del Principado de Asturias (reference GRUPIN-14-030), by the Government of the Basque Country (Etortek Research Programs 2008/2015) the Innovation Technology Department of Bizkaia.

We wish to thank Pablo Martinez Camblor for the critical review of the statistical part of the study. This work is supported by Spanish grants PI12-02587 from the Instituto de Salud Carlos III, RETICS REDiNREN (RD12/0021/0021) from the Instituto de Salud Carlos III and by the European Union Fondos FEDER.

Supported by Spanish grant PI12-02587 from the Instituto de Salud Carlos III, RETICS REDiNREN (RD12/0021/0021) from the Instituto de Salud Carlos III and by European Union ''Fondos FEDER ''

This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias-Fondos FEDER European Union (FIS PI12/0287) del Plan Nacional de I+D+I 2008–2011, Red de Investigación Renal (REDinREN RD12/0021/0018 and RD12/0021/0021), and the PCTI 2013–2017 (GRUPIN 14-030) from the Principado de Asturias, Spain.

A. Horrillo, A. Hmadcha, and B.S. are supported by Red TerCel and the Consejeria de Salud Junta de Andalucía (FPS). M.F.F. is funded by Spanish Ministry of Health Grants PI061267 and PS09/02454 and Spanish National Research Council (Consejo Superior de Investigaciones Cientificas) Grant 200820I172. This work was supported primarily by European Union Grant (ESTOOLS) LSHG-CT-2006-018739

In recent years, the macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage CSF (GM-CSF) cytokines have been identified as opposing regulators of the inflammatory program. However, the two cytokines are simultaneously present in the inflammatory milieu, and it is not clear how cells integrate these signals. In order to understand the regulatory networks associated with the GM/M-CSF signaling axis, we analyzed DNA methylation in human monocytes. Our results indicate that GM-CSF induces activation of the inflammatory program and extensive DNA methylation changes, while M-CSF-polarized cells are in a less differentiated state. This inflammatory program is mediated via JAK2 associated with the GM-CSF receptor and the downstream extracellular signal-regulated (ERK) signaling. However, PI3K signaling is associated with a negative regulatory loop of the inflammatory program and M-CSF autocrine signaling in GM-CSF-polarized monocytes. Our findings describe the regulatory networks associated with the GM/M-CSF signaling axis and how they contribute to the establishment of the inflammatory program associated with monocyte activation. ; This work was supported by grants from the Plan Nacional de I+D+I 2013– 2016 ISCIII (Institute of Health Carlos III; PI16/01318, PI17/01244, PI17/ 0119, PI16/1900, and PI19/00184); the Gobierno del Principado de Asturias; the PCTI-Plan de Ciencia, Tecnologı´a e Innovacio´ n 2013-2017 (grant IDI/ 2018/144); FEDER ''Funding Program of the European Union''; the Red Española de Investigación Renal (REDinREN) (RD16/0009/0020, RD016/0009/002, and RD016/0009/001); the Agencia Estatal de Investigación (AEI) (ayuda Juan de la Cierva-Incorporaciόn; IJCI-2017-33347 to R.M.R.); and the Instituto de Salud Carlos III (Contratos Sara Borrell; CD16/00033 to C.H.). CIC bioGUNE support was provided by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs), the Innovation Technology Department of Bizkaia County, the CIBERehd Network, and Spanish MINECO, the Severo Ochoa Excellence Accreditation (SEV-2016-0644)

19 p.-6 fig. ; In recent years, the macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage CSF (GM-CSF) cytokines have been identified as opposing regulators of the inflammatory program. However, the two cytokines are simultaneously present in the inflammatory milieu, and it is not clear how cells integrate these signals. In order to understand the regulatory networks associated with the GM/M-CSF signaling axis, we analyzed DNA methylation in human monocytes. Our results indicate that GM-CSF induces activation of the inflammatory program and extensive DNA methylation changes, while M-CSF-polarized cells are in a less differentiated state. This inflammatory program is mediated via JAK2 associated with the GM-CSF receptor and the downstream extracellular signal-regulated (ERK) signaling. However, PI3K signaling is associated with a negative regulatory loop of the inflammatory program and M-CSF autocrine signaling in GM-CSF-polarized monocytes. Our findings describe the regulatory networks associated with the GM/M-CSF signaling axis and how they contribute to the establishment of the inflammatory program associated with monocyte activation. ; This work was supported by grants from the Plan Nacional de I+D+I 2013– 2016 ISCIII (Institute of Health Carlos III; PI16/01318, PI17/01244, PI17/ 0119, PI16/1900, and PI19/00184); the Gobierno del Principado de Asturias; the PCTI-Plan de Ciencia, Tecnología e Innovación 2013-2017 (grant IDI/ 2018/144); FEDER ''Funding Program of the European Union''; the Red Española de Investigación Renal (REDinREN) (RD16/0009/0020, RD016/0009/002, and RD016/0009/001); the Agencia Estatal de Investigación (AEI) (ayuda Juan de la Cierva-Incorporaciόn; IJCI-2017-33347 to R.M.R.); and the Instituto de Salud Carlos III (Contratos Sara Borrell; CD16/00033 to C.H.). CIC bioGUNE support was provided by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs), the Innovation Technology Department of Bizkaia County, the CIBERehd Network, and Spanish MINECO, the Severo Ochoa Excellence Accreditation (SEV-2016-0644). ; Peer reviewed

Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation. ; This work was primarily supported by the European Union (LSHG-CT-2006-018739; ESTOOLS). MFF is funded by the Spanish Ramon & Cajal Programme and the Health Department of the Spanish Government (PI061267). The Cancer Epigenetics group at the CNIO is supported by the Health (FIS01-04) and Education and Science (I+D+I MCYT08-03, FU2004-02073/BMC and Consolider MEC09-05) Departments of the Spanish Government, the European Grant TRANSFOG LSHC-CT-2004-503438, and the Spanish Association Against Cancer (AECC). VC is a recipient of a Fellowship from the FPU Spanish Research Programme. CLL and BSA are supported by the Health Department of the Spanish Government (PI051707). The BACM is supported by the Consejería de Salud de la Junta de Andalucía (0029 and, 0030/2006 to PM) and, the Spanish Ministry of Health to PM (FIS PI070026). CB is supported by the International Jose Carreras Foundation against Leukemia (EDThomas-05) and the ISCIII (FIS 3+3 contract). The Institute of Reconstructive Neurobiology received additional funding from the DFG and the Hertie Foundation. BS, AbH and AnH are supported by the Fundación Progreso y Salud and Instituto de Salud Carlos III-Red Española de Terapia Celular (RD06/0010/0025 ). PWA, NH and HDM are also supported by the MRC.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death. ; Plan Nacional de I+D+I co-funding FEDER [PI15/00892 and PI18/01527 to M.F.F. and A.F.F.; PI16/01318 and PI14/01244 to C.L.]; ISCIII-Subdireccion General de Evaluacion y Fomento de la Investigacion, and Plan Nacional de I+D+I 2008–2011/FEDER [CP11/00131 to A.F.F.]; IUOPA (to G.F.B. and M.I.S.); Fundacion Cientifica de la AECC (to R.G.U.); Ministry of Economy and Competitiveness Juan de la Cierva postdoctoral fellowships [FJCI-2015-26965 to J.R.T., IJCI-2015- 23316 to V.L.]; Fundacion Ramon Areces (to M.F.F); FICYT (to E.G.T., M.G.G., A.C.); Asturias Regional Government [GRUPIN14-052 to M.F.F.]; Gobierno del Principado de Asturias, PCTI-Plan de Ciencia, Tecnologia e Innovacion co-funding Fondos FEDER (grant number IDI/2018/146 to M.F.F. and IDI/2018/144 to C.L.); Deutsche Forschungsgemeinschaft (DFG) [SFB960 to A.V.G., R.D.]; European Research Council [CoG-2014-646903]; Spanish Ministry of Economy and Competitiveness [SAF-SAF2013-43065 to P.M.]; Asociacion Española Contra el Cancer [AECC-CI-2015]; FERO Foundation, and the ISCIII [PI14-01191 to C.B.]; P.M. acknowledges financial support from The Obra Social La Caixa Fundacio Josep Carreras and The Generalitat de Catalunya (SGR330). P.M. an investigator from the Spanish Cell Therapy cooperative network (TERCEL). The IUOPA is supported by the Obra Social Liberbank-Cajastur, Spain. Funding for open access charge: Plan Nacional de I+D+I co-funding FEDER [PI18/01527].