Ablation of cDC2 development by triple mutations within the Zeb2 enhancer

Tian-Tian Liu, Sunkyung Kim, Pritesh Desai, Do-Hyun Kim, Xiao Huang, Stephen T. Ferris, Renee Wu, Feiya Ou, Takeshi Egawa, Steven J. Van Dyken, Michael S. Diamond, Peter F. Johnson, Masato Kubo, Theresa L. Murphy and Kenneth M. Murphy ()
Additional contact information
Tian-Tian Liu: Washington University in St Louis, School of Medicine
Sunkyung Kim: Washington University in St Louis, School of Medicine
Pritesh Desai: Washington University in St Louis, School of Medicine
Do-Hyun Kim: Washington University in St Louis, School of Medicine
Xiao Huang: Washington University in St Louis, School of Medicine
Stephen T. Ferris: Washington University in St Louis, School of Medicine
Renee Wu: Washington University in St Louis, School of Medicine
Feiya Ou: Washington University in St Louis, School of Medicine
Takeshi Egawa: Washington University in St Louis, School of Medicine
Steven J. Van Dyken: Washington University in St Louis, School of Medicine
Michael S. Diamond: Washington University in St Louis, School of Medicine
Peter F. Johnson: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute
Masato Kubo: Tokyo University of Science
Theresa L. Murphy: Washington University in St Louis, School of Medicine
Kenneth M. Murphy: Washington University in St Louis, School of Medicine

Nature, 2022, vol. 607, issue 7917, 142-148

Abstract: Abstract The divergence of the common dendritic cell progenitor1–3 (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages4,5 is poorly understood. Some transcription factors act in the commitment of already specified progenitors—such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer4,6—but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis7 suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the –165 kb Zeb2 enhancer8 at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPβ. In vivo mutational analysis using CRISPR–Cas9 targeting showed that these NFIL3–C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3–C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice did not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths9–11. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the –165 kb Zeb2 enhancer.

Date: 2022
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DOI: 10.1038/s41586-022-04866-z

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