TY - JOUR
T1 - An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development
AU - Bagadia, Prachi
AU - Huang, Xiao
AU - Liu, Tian Tian
AU - Durai, Vivek
AU - Grajales-Reyes, Gary E.
AU - Nitschké, Maximilian
AU - Modrusan, Zora
AU - Granja, Jeffrey M.
AU - Satpathy, Ansuman T.
AU - Briseño, Carlos G.
AU - Gargaro, Marco
AU - Iwata, Arifumi
AU - Kim, Sunkyung
AU - Chang, Howard Y.
AU - Shaw, Andrey S.
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
N1 - Funding Information:
We thank J. Chen and L. Goldstein for technical assistance. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by the National Cancer Institute’s Cancer Center Support grant no. P30 CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences/ Clinical and Translational Science Award grant no. UL1TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or NIH. This work benefitted from data assembled by the ImmGen consortium47. This work was supported by the Howard Hughes Medical Institute (K.M.M. and H.Y.C.), the National Science Foundation (grant no. DGE-1745038 to P.B.), the US NIH (grant nos. F30DK108498 to V.D., K08 CA23188-01 to A.T.S. and P50-HG007735 to H.Y.C.) and the Parker Institute for Cancer Immunotherapy (A.T.S. and H.Y.C.). A.T.S. was supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.
AB - Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.
UR - http://www.scopus.com/inward/record.url?scp=85070801599&partnerID=8YFLogxK
U2 - 10.1038/s41590-019-0449-3
DO - 10.1038/s41590-019-0449-3
M3 - Article
C2 - 31406377
AN - SCOPUS:85070801599
SN - 1529-2908
VL - 20
SP - 1174
EP - 1185
JO - Nature Immunology
JF - Nature Immunology
IS - 9
ER -