Referencia

Genome Biology 14, R99.

Autores

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

Resumen

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.

Descripción

Los osteoclastos son células gigantes cuya función es degradar hueso, y se diferencian a partir de monocitos circulantes en sangre. En las articulaciones de pacientes con artritis reumatoide, este proceso de diferenciación está exacerbado. El aumento de osteoclastos en la articulación de los pacientes, provoca una excesiva resorción ósea, que da lugar a fracturas, y a la pérdida de función de la misma. En este estudio, el empleo de estrategias de análisis epigenético nos ha permitido describir por primera vez los cambios que suceden en genes clave para la función del osteoclasto, como la catepsina K (CTSK), la fosfatasa ácida resistente a tartrato (TRACP), o el receptor de la fractalina (CX3CR1). Además se ha determinado el papel dual del factor de transcripción PU.1 en la diferenciación de los osteoclastos, a través de la interacción con dos componentes clave de la maquinaria epigenética: las enzimas TET2 y DNMT3b. El bloqueo de la expresión de PU.1 impidió que se produjeran los cambios epigenéticos necesarios para la diferenciación de monocito a osteoclastos, abriendo una nueva vía de inhibición terapéutica que reduzca la severidad de las lesiones artríticas.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Cromatina y Enfermedad del Institut d'Investigació Biomèdica de Bellvitge está dirigido por el Dr Esteban Ballestar y centra su actividad investigadora en el estudio de mecanismos de desregulación epigenética en el sistema inmune, especialmente en el contexto de enfermedad autoinmune y en distintos modelos de diferenciación relevantes en enfermedades del sistema inmune. En los últimos años el laboratorio ha publicado diversos trabajos relacionados con la adquisición de alteraciones epigenéticas en distintos tipos celulares de enfermedades autoinmunes como el lupus eritematoso sistémico y la artritis reumatoide. Asimismo, el grupo ha realizado diversas contribuciones describiendo los mecanismos de adquisición de alteraciones. http://www.idibell.cat/modul/chromatin-and-disease/en

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