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IRF8 增强子的隐匿激活控制 cDC1 命运特化。

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification.

机构信息

Department of Pathology and Immunology, Washington University in St Louis, School of Medicine, St Louis, MO, USA.

Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.

出版信息

Nat Immunol. 2019 Sep;20(9):1161-1173. doi: 10.1038/s41590-019-0450-x. Epub 2019 Aug 12.

DOI:10.1038/s41590-019-0450-x
PMID:31406378
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6707878/
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.

摘要

转录因子 Irf8 在普通树突状细胞前体细胞（CDP）中的诱导对于经典的 1 型树突状细胞（cDC1）命运特化是必需的，但是控制这种诱导的机制尚不清楚。在本研究中，通过树突状细胞的染色质剖析鉴定了 Irf8 增强子，并使用 CRISPR/Cas9 基因组编辑来评估它们在 Irf8 调节中的作用。位于 Irf8 转录起始位点下游 32kb 的增强子（+32-kb Irf8）在成熟的 cDC1 中具有活性，对于该谱系的发育是必需的，但对于其特化不是必需的。相反，先前认为仅在浆细胞样树突状细胞中具有活性的+41-kb Irf8 增强子，在 cDC1 祖细胞中也被发现是瞬时可及的，并且删除该增强子可防止 CDP 中 Irf8 的诱导，并消除 cDC1 的特化。因此，树突状细胞祖细胞中+41-kb Irf8 增强子的隐匿性激活负责 cDC1 命运特化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/3e24be613f4f/nihms-1532197-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/a30d3c83cf97/nihms-1532197-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/a8c4b8d797eb/nihms-1532197-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/2eb07d6074db/nihms-1532197-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/feaf1b5009ba/nihms-1532197-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/12dbc3b1d344/nihms-1532197-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/896d345a896a/nihms-1532197-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/3e24be613f4f/nihms-1532197-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/a30d3c83cf97/nihms-1532197-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/a8c4b8d797eb/nihms-1532197-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/2eb07d6074db/nihms-1532197-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/feaf1b5009ba/nihms-1532197-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/12dbc3b1d344/nihms-1532197-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/896d345a896a/nihms-1532197-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3306/6707878/3e24be613f4f/nihms-1532197-f0007.jpg

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