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 and Id2 CDPs to Zeb2 and Id2 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707889 | PMC |
| http://dx.doi.org/10.1038/s41590-019-0449-3 | DOI Listing |
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Article Synopsis
- The study discusses how autoactivation of specific transcription factors helps create distinct cell types crucial for developing complex body structures, especially in dendritic cells (cDC1 and cDC2) which have different immune roles.
- It highlights that the IRF8 gene, crucial for cDC1 identity, can accidentally activate in cDC2 progenitors when its enhancer is modified to have stronger binding sites, leading to mixed and abnormal cell types.
- These changes disrupt normal immune responses, showing the importance of specific genetic regulation in maintaining proper immune cell development and function.
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