Reference

Genome Biology CoverGenome Biology 17:4.

Authors

Roser Vento-Tormo, Carlos Company *, Javier Rodríguez-Ubreva* , Lorenzo de la Rica, José M. Urquiza, Biola M. Javierre, Radhakrishnan Sabarinathan, Ana Luque, Manel Esteller, Josep M. Aran, Damiana Álvarez-Errico and Esteban Ballestar.

Abstract

BACKGROUND:
The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation.
RESULTS:
Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes.
CONCLUSIONS:
Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.

Description

La diferenciación terminal de monocitos a macrófagos y células dendríticas es un proceso relevante para las respuestas inflamatorias, que puede ser recapitulado in vitro mediante la adición de citoquinas en el medio. En este estudio, utilizando estos modelos de diferenciación terminal, caracterizamos los mecanismos que conectan la estimulación extracelular y la consecuente activación de rutas de señalización celulares, con el mecanismo epigenetico de desmetilación activa del DNA. En concreto, describimos como la citoquina diferencial entre ambas diferenciaciones, la IL-4, a través de la ruta JAK3-STAT6, es capaz de establecer patrones de metilación específicos que determinarán la diferenciación a células dendríticas.

 

Ballestar group 2

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Cromatina y Enfermedad del Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) 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, autoinflamatoria, inmunodeficiencia 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 relevantes en el contexto inmunológico. http://www.idibell.cat/modul/chromatin-and-disease/en .

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