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PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation

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dc.contributor.author Rica, Lorenzo de la
dc.contributor.author Rodríguez Ubreva, Javier
dc.contributor.author García, Mireia
dc.contributor.author Islam, Abul, 1978-
dc.contributor.author Urquiza, José M.
dc.contributor.author Hernando, Henar
dc.contributor.author Christensen, Jesper
dc.contributor.author Helin, Kristian
dc.contributor.author Gómez Vaquero, Carmen
dc.contributor.author Ballestar, Esteban
dc.date.accessioned 2015-03-18T09:11:14Z
dc.date.available 2015-03-18T09:11:14Z
dc.date.issued 2013
dc.identifier.citation de la Rica L, Rodríguez-Ubreva J, García M, Islam AB, Urquiza JM, Hernando H, Christensen J, Helin K, Gómez-Vaquero C, Ballestar E. PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation. Genome Biology. 2013; 14: R99. DOI 10.1186/gb-2013-14-9-r99
dc.identifier.issn 1465-6906
dc.identifier.uri http://hdl.handle.net/10230/23214
dc.description.abstract Background: DNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved. Results: Here we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an over-representation of PU.1, NF-κB, and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation. Conclusions: The work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.
dc.description.sponsorship This work was supported by grant SAF2011-29635 from the Spanish Ministry of Science and Innovation, grant CIVP16A1834 from Fundación Ramón Areces and grant 2009SGR184 from AGAUR (Catalan Government). LR is supported by a PFIS predoctoral fellowship
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Genome Biology. 2013; 14: R99
dc.rights © 2013 de la Rica et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/2.0
dc.subject.other Proteïnes -- Metabolisme
dc.subject.other Transcripció genètica
dc.subject.other RNA no missatgers
dc.title PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/gb-2013-14-9-r99
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29635
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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