An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Prachi Bagadia; Xiao Huang; Tian Tian Liu; Vivek Durai; Gary E. Grajales-Reyes; Maximilian Nitschké; Zora Modrusan; Jeffrey M. Granja; Ansuman T. Satpathy; Carlos G. Briseño; Marco Gargaro; Arifumi Iwata; Sunkyung Kim; Howard Y. Chang; Andrey S. Shaw; Theresa L. Murphy; Kenneth M. Murphy

doi:10.1038/s41590-019-0449-3

An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Prachi Bagadia, Xiao Huang, Tian Tian Liu, Vivek Durai, Gary E. Grajales-Reyes, Maximilian Nitschké, Zora Modrusan, Jeffrey M. Granja, Ansuman T. Satpathy, Carlos G. Briseño, Marco Gargaro, Arifumi Iwata, Sunkyung Kim, Howard Y. Chang, Andrey S. Shaw, Theresa L. Murphy, Kenneth M. Murphy

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Abstract

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 Zeb2^hi and Id2^lo CDPs to Zeb2^lo and Id2^hi 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.

Original language	English
Pages (from-to)	1174-1185
Number of pages	12
Journal	Nature immunology
Volume	20
Issue number	9
DOIs	https://doi.org/10.1038/s41590-019-0449-3
State	Published - Sep 1 2019

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Bagadia, P., Huang, X., Liu, T. T., Durai, V., Grajales-Reyes, G. E., Nitschké, M., Modrusan, Z., Granja, J. M., Satpathy, A. T., Briseño, C. G., Gargaro, M., Iwata, A., Kim, S., Chang, H. Y., Shaw, A. S., Murphy, T. L., & Murphy, K. M. (2019). An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development. Nature immunology, 20(9), 1174-1185. https://doi.org/10.1038/s41590-019-0449-3

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title = "An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development",

abstract = "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.",

author = "Prachi Bagadia and Xiao Huang and Liu, {Tian Tian} and Vivek Durai and Grajales-Reyes, {Gary E.} and Maximilian Nitschk{\'e} and Zora Modrusan and Granja, {Jeffrey M.} and Satpathy, {Ansuman T.} and Brise{\~n}o, {Carlos G.} and Marco Gargaro and Arifumi Iwata and Sunkyung Kim and Chang, {Howard Y.} and Shaw, {Andrey S.} and Murphy, {Theresa L.} and Murphy, {Kenneth M.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = sep,

day = "1",

doi = "10.1038/s41590-019-0449-3",

language = "English",

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Bagadia, P, Huang, X, Liu, TT, Durai, V, Grajales-Reyes, GE, Nitschké, M, Modrusan, Z, Granja, JM, Satpathy, AT, Briseño, CG, Gargaro, M, Iwata, A, Kim, S, Chang, HY, Shaw, AS, Murphy, TL & Murphy, KM 2019, 'An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development', Nature immunology, vol. 20, no. 9, pp. 1174-1185. https://doi.org/10.1038/s41590-019-0449-3

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.

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.

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M3 - Article

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AN - SCOPUS:85070801599

SN - 1529-2908

VL - 20

SP - 1174

EP - 1185

JO - Nature immunology

JF - Nature immunology

IS - 9

ER -

An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development

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