Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

被引：112

作者：

Durai, Vivek ^{[1
]}

Bagadia, Prachi ^{[1
]}

Granja, Jeffrey M. ^{[2
,3
,4
]}

Satpathy, Ansuman T. ^{[2
,5
]}

Kulkarni, Devesha H. ^{[6
]}

Davidson, Jesse T. ^{[1
]}

Wu, Renee ^{[1
]}

Patel, Swapneel J. ^{[7
]}

Iwata, Arifumi ^{[1
]}

Liu, Tian-Tian ^{[1
,8
]}

Huang, Xiao ^{[1
]}

Briseno, Carlos G. ^{[1
]}

Grajales-Reyes, Gary E. ^{[1
]}

Wohner, Miriam ^{[9
]}

Tagoh, Hiromi ^{[9
]}

Kee, Barbara L. ^{[10
,11
]}

Newberry, Rodney D. ^{[6
]}

Busslinger, Meinrad ^{[9
]}

Chang, Howard Y. ^{[2
,12
]}

Murphy, Theresa L. ^{[1
]}

Murphy, Kenneth M. ^{[1
,8
]}

机构：

[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[2] Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Biophys Program, Stanford, CA 94305 USA

[5] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[6] Washington Univ, Sch Med, John T Milliken Dept Med, Div Gastroenterol, St Louis, MO USA

[7] Washington Univ, Sch Med, John T Milliken Dept Med, Div Rheumatol, St Louis, MO USA

[8] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA

[9] Res Inst Mol Pathol, Campus Vienna Bioctr 1, Vienna, Austria

[10] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[11] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA

[12] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA

来源：

NATURE IMMUNOLOGY | 2019年 / 20卷 / 09期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

DENDRITIC CELL PROGENITORS; CENTER B-CELL; TRANSCRIPTION-FACTOR; PHENOTYPIC ROBUSTNESS; GENE-EXPRESSION; I INTERFERON; PU.1; CHROMATIN; IDENTIFICATION; REGULATOR;

D O I：

10.1038/s41590-019-0450-x

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1161 / +

页数：20

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