Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. Here we identified Irf8 enhancers via chromatin profiling of DCs and used CRI...

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Detalles Bibliográficos
Autores principales: Durai, Vivek, Bagadia, Prachi, Granja, Jeffrey M., Satpathy, Ansuman T., Kulkarni, Devesha H., Davidson, Jesse T., Wu, Renee, Patel, Swapneel J., Iwata, Arifumi, Liu, Tiantian, Huang, Xiao, Briseño, Carlos G., Grajales-Reyes, Gary E., Wöhner, Miriam, Tagoh, Hiromi, Kee, Barbara L., Newberry, Rodney D., Busslinger, Meinrad, Chang, Howard Y., Murphy, Theresa L., Murphy, Kenneth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707878/
https://www.ncbi.nlm.nih.gov/pubmed/31406378
http://dx.doi.org/10.1038/s41590-019-0450-x
Descripción
Sumario:Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. Here we identified Irf8 enhancers via chromatin profiling of DCs and used CRISPR/Cas9 genome editing to assess their roles in Irf8 regulation. An enhancer 32 kilobases downstream of the Irf8 transcriptional start site (+32 kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41 kb Irf8 enhancer previously thought to be active only in plasmacytoid DCs was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41 kb Irf8 enhancer in DC progenitors is responsible for cDC1 fate specification.

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