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




PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Genome Biology

, 14:R99

First Online: 12 September 2013Received: 07 May 2013Accepted: 12 September 2013

Abstract

BackgroundDNA 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.

ResultsHere 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.

ConclusionsThe work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.

Abbreviations5azadC5-aza-2′-deoxycytidine

5hmC5-hydroxymethylcytosine

5mC5-methylcytosine

AUMAAmplification of unmethylated Alu repeats.

Electronic supplementary materialThe online version of this article doi:10.1186-gb-2013-14-9-r99 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Autor: Lorenzo de la Rica - Javier Rodríguez-Ubreva - Mireia García - Abul BMMK Islam - José M Urquiza - Henar Hernando - Jesp

Fuente: https://link.springer.com/







Documentos relacionados