Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene epigenetically regulated

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• dc.contributor.author Martínez-Calle, Nicolás
• dc.contributor.author Pascual, Marien
• dc.contributor.author Ordóñez, Raquel
• dc.contributor.author San José-Enériz, Edurne
• dc.contributor.author Kulis, Marta
• dc.contributor.author Miranda, Estíbaliz
• dc.contributor.author Guruceaga, Elisabeth
• dc.contributor.author Segura, Víctor
• dc.contributor.author Larráyoz, María José
• dc.contributor.author Bellosillo Paricio, Beatriz
• dc.contributor.author Calasanz, María José
• dc.contributor.author Besses Raebel, Carles
• dc.contributor.author Rifón, José
• dc.contributor.author Martín-Subero, José Ignacio
• dc.contributor.author Agirre, Xabier
• dc.contributor.author Prosper, Felipe
• dc.date.accessioned 2019-05-09T06:47:14Z
• dc.date.available 2019-05-09T06:47:14Z
• dc.date.issued 2019
• dc.description.abstract In this study we have interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpGs corresponding to 10,253 genes between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, the majorities of differentially methylated CpGs were located outside gene promoter regions and showed a significant association with enhancer regions. This enhancer aberrant hypermethylation showed a negative correlation with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5' azacitidine treatment confirmed the functional relevance of the enhancer hypermethylation of ZFP36L1. Furthermore, in vitro rescue of ZFP36L1 expression had an impact in cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. We describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martínez-Calle N, Pascual M, Ordoñez R, San José-Enériz E, Kulis M, Miranda E. et al. Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene epigenetically regulated. Haematologica. 2019 Aug;104(8):1572-9. DOI: 10.3324/haematol.2018.204917
• dc.identifier.doi http://dx.doi.org/10.3324/haematol.2018.204917
• dc.identifier.issn 0390-6078
• dc.identifier.uri http://hdl.handle.net/10230/37194
• dc.language.iso eng
• dc.publisher Ferrata Storti Foundation
• dc.relation.ispartof Haematologica. 2019 Aug;104(8):1572-9
• dc.rights ©2018 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legal code. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Chronic Myeloproliferative Disorders
• dc.subject.keyword Cytogenetics and Molecular Genetics
• dc.subject.keyword DNA methylation
• dc.subject.keyword Enhancer
• dc.subject.keyword Epigenetic
• dc.title Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene epigenetically regulated
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion