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

Rica, Lorenzo de la; Rodríguez Ubreva, Javier; García, Mireia; Islam, Abul, 1978-; Urquiza, José M.; Hernando, Henar; Christensen, Jesper; Helin, Kristian; Gómez Vaquero, Carmen; Ballestar, Esteban

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 laca
dc.contributor.author Rodríguez Ubreva, Javierca
dc.contributor.author García, Mireiaca
dc.contributor.author Islam, Abul, 1978-ca
dc.contributor.author Urquiza, José M.ca
dc.contributor.author Hernando, Henarca
dc.contributor.author Christensen, Jesperca
dc.contributor.author Helin, Kristianca
dc.contributor.author Gómez Vaquero, Carmenca
dc.contributor.author Ballestar, Estebanca
dc.date.accessioned 2015-03-18T09:11:14Z
dc.date.available 2015-03-18T09:11:14Z
dc.date.issued 2013ca
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.en
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 fellowshipen
dc.format.mimetype application/pdfca
dc.identifier.citation de la Rica L, Rodríguez-Ubreva J, García M, Islam AB, Urquiza JM, Hernando H et al. 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-r99ca
dc.identifier.doi http://dx.doi.org/10.1186/gb-2013-14-9-r99
dc.identifier.issn 1465-6906ca
dc.identifier.uri http://hdl.handle.net/10230/23214
dc.language.iso engca
dc.publisher BioMed Centralca
dc.relation.ispartof Genome Biology. 2013;14:R99
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29635
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.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/2.0
dc.subject.other Proteïnes -- Metabolismeca
dc.subject.other Transcripció genèticaca
dc.subject.other RNA no missatgersca
dc.title PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiationen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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