A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes
- 18 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 22 (3), 301-311
- https://doi.org/10.1038/s41590-021-00871-y
Abstract
The transcription factor IRF8 is essential for the development of monocytes and dendritic cells (DCs), whereas it inhibits neutrophilic differentiation. It is unclear how Irf8 expression is regulated and how this single transcription factor supports the generation of both monocytes and DCs. Here, we identified a RUNX–CBFβ-driven enhancer 56 kb downstream of the Irf8 transcription start site. Deletion of this enhancer in vivo significantly decreased Irf8 expression throughout the myeloid lineage from the progenitor stages, thus resulting in loss of common DC progenitors and overproduction of Ly6C+ monocytes. We demonstrated that high, low or null expression of IRF8 in hematopoietic progenitor cells promotes differentiation toward type 1 conventional DCs, Ly6C+ monocytes or neutrophils, respectively, via epigenetic regulation of distinct sets of enhancers in cooperation with other transcription factors. Our results illustrate the mechanism through which IRF8 controls the lineage choice in a dose-dependent manner within the myeloid cell system.Keywords
Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (18K19345, 15H04860, 19K07372)
- Uehara Memorial Foundation Research Grant, Japanese Society of Hematology Research Grant, and MEXT Joint Usage/Research Center Program at the Advanced Medical Research Center, Yokohama City University
- MEXT Joint Usage/Research Center Program at the Advanced Medical Research Center, Yokohama City University
- MEXT Joint Usage/Research Center Program at the Advanced Medical Research Center, Yokohama City
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