Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

Vivek Durai; Prachi Bagadia; Jeffrey M. Granja; Ansuman T. Satpathy; Devesha H. Kulkarni; Jesse T. Davidson; Renee Wu; Swapneel J. Patel; Arifumi Iwata; Tian Tian Liu; Xiao Huang; Carlos G. Briseño; Gary E. Grajales-Reyes; Miriam Wöhner; Hiromi Tagoh; Barbara L. Kee; Rodney D. Newberry; Meinrad Busslinger; Howard Y. Chang; Theresa L. Murphy; Kenneth M. Murphy

doi:10.1038/s41590-019-0450-x

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

Vivek Durai, Prachi Bagadia, Jeffrey M. Granja, Ansuman T. Satpathy, Devesha H. Kulkarni, Jesse T. Davidson, Renee Wu, Swapneel J. Patel, Arifumi Iwata, Tian Tian Liu, Xiao Huang, Carlos G. Briseño, Gary E. Grajales-Reyes, Miriam Wöhner, Hiromi Tagoh, Barbara L. Kee, Rodney D. Newberry, Meinrad Busslinger, Howard Y. Chang, Theresa L. MurphyKenneth M. Murphy^*

^*Corresponding author for this work

Surgery, Transplant Surgery Division

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.

Original language	English (US)
Pages (from-to)	1161-1173
Number of pages	13
Journal	Nature Immunology
Volume	20
Issue number	9
DOIs	https://doi.org/10.1038/s41590-019-0450-x
State	Published - Sep 1 2019

Funding

was supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund. This work benefitted from data assembled by the ImmGen consortium48. We thank the Genome Technology Access Center in the Department of Genetics at Washington University in St Louis 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 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 the NIH. This work was supported by the Howard Hughes Medical Institute (K.M. and H.C.), the US National Institutes of Health (NIH: F30 DK108498 to V.D.; K08 CA230188 to A.S.; P50 HG007735 to H.C.; R01 AI106352 to B.K.; R01 DK097317 to R.N.), the National Science Foundation (DGE-1745038 to P.B.), the Parker Institute for Cancer Immunotherapy (A.S. and H.C.) and Boehringer Ingelheim (M.W., H.T. and M.B.). A.S.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Durai, V., Bagadia, P., Granja, J. M., Satpathy, A. T., Kulkarni, D. H., Davidson, J. T., Wu, R., Patel, S. J., Iwata, A., Liu, T. T., Huang, X., Briseño, C. G., Grajales-Reyes, G. E., Wöhner, M., Tagoh, H., Kee, B. L., Newberry, R. D., Busslinger, M., Chang, H. Y., ... Murphy, K. M. (2019). Cryptic activation of an Irf8 enhancer governs cDC1 fate specification. Nature Immunology, 20(9), 1161-1173. https://doi.org/10.1038/s41590-019-0450-x

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title = "Cryptic activation of an Irf8 enhancer governs cDC1 fate specification",

abstract = "Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.",

author = "Vivek Durai and Prachi Bagadia and Granja, {Jeffrey M.} and Satpathy, {Ansuman T.} and Kulkarni, {Devesha H.} and Davidson, {Jesse T.} and Renee Wu and Patel, {Swapneel J.} and Arifumi Iwata and Liu, {Tian Tian} and Xiao Huang and Brise{\~n}o, {Carlos G.} and Grajales-Reyes, {Gary E.} and Miriam W{\"o}hner and Hiromi Tagoh and Kee, {Barbara L.} and Newberry, {Rodney D.} and Meinrad Busslinger and Chang, {Howard Y.} 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/s41590-019-0450-x",

language = "English (US)",

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Durai, V, Bagadia, P, Granja, JM, Satpathy, AT, Kulkarni, DH, Davidson, JT, Wu, R, Patel, SJ, Iwata, A, Liu, TT, Huang, X, Briseño, CG, Grajales-Reyes, GE, Wöhner, M, Tagoh, H, Kee, BL, Newberry, RD, Busslinger, M, Chang, HY, Murphy, TL & Murphy, KM 2019, 'Cryptic activation of an Irf8 enhancer governs cDC1 fate specification', Nature Immunology, vol. 20, no. 9, pp. 1161-1173. https://doi.org/10.1038/s41590-019-0450-x

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T1 - Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

AU - Durai, Vivek

AU - Bagadia, Prachi

AU - Granja, Jeffrey M.

AU - Satpathy, Ansuman T.

AU - Kulkarni, Devesha H.

AU - Davidson, Jesse T.

AU - Wu, Renee

AU - Patel, Swapneel J.

AU - Iwata, Arifumi

AU - Liu, Tian Tian

AU - Huang, Xiao

AU - Briseño, Carlos G.

AU - Grajales-Reyes, Gary E.

AU - Wöhner, Miriam

AU - Tagoh, Hiromi

AU - Kee, Barbara L.

AU - Newberry, Rodney D.

AU - Busslinger, Meinrad

AU - Chang, Howard Y.

AU - Murphy, Theresa L.

AU - Murphy, Kenneth M.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.

AB - Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.

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JO - Nature Immunology

JF - Nature Immunology

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Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

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