TY - JOUR
T1 - A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes
AU - Murakami, Koichi
AU - Sasaki, Haruka
AU - Nishiyama, Akira
AU - Kurotaki, Daisuke
AU - Kawase, Wataru
AU - Ban, Tatsuma
AU - Nakabayashi, Jun
AU - Kanzaki, Satoko
AU - Sekita, Yoichi
AU - Nakajima, Hideaki
AU - Ozato, Keiko
AU - Kimura, Tohru
AU - Tamura, Tomohiko
N1 - Funding Information:
The authors thank M. Ichino, I. Harada, M. Yoshinari, S. Honma, H. Sato, G. R. Sato and M. Tachikawa at Yokohama City University for their help with the experiments. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science/Ministry of Education, Culture, Sports, Science and Technology (MEXT; grant nos. 18K19345 and 15H04860 to T.T. and 19K07372 to A.N.); a Uehara Memorial Foundation Research Grant (to T.T.); a Japanese Society of Hematology Research Grant (to T.T.); and the MEXT Joint Usage/Research Center Program at the Advanced Medical Research Center, Yokohama City University (funding for Y.S., T.K. and T.T.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-021-00871-y
DO - 10.1038/s41590-021-00871-y
M3 - Article
C2 - 33603226
AN - SCOPUS:85101068832
SN - 1529-2908
VL - 22
SP - 301
EP - 311
JO - Nature Immunology
JF - Nature Immunology
IS - 3
ER -