Transcription factors play a determining role in lineage commitment and cell differentiation. Interferon regulatory factor 8 (IRF8) is a lineage determining transcription factor in hematopoiesis and master regulator of dendritic cells (DC), an important immune cell for immunity and tolerance. IRF8 is prominently upregulated in DC development by autoactivation and controls both DC differentiation and function. However, it is unclear how Irf8 autoactivation is controlled and eventually limited. Here we identified a novel long non-coding RNA transcribed from the +32 kb enhancer downstream of Irf8 transcription start site and expressed specifically in mouse plasmacytoid DC (pDC), referred to as lncIrf8. The lncIrf8 locus interacts with the lrf8 promoter and shows differential epigenetic signatures in pDC versus classical DC type 1 (cDC1). Interestingly, a sequence element of the lncIrf8 promoter, but not lncIrf8 itself, is crucial for mouse pDC and cDC1 differentiation, and this sequence element confers feedback inhibition of Irf8 expression. Taken together, in DC development Irf8 autoactivation is first initiated by flanking enhancers and then second controlled by feedback inhibition through the lncIrf8 promoter element in the +32 kb enhancer. Our work reveals a previously unrecognized negative feedback loop of Irf8 that orchestrates its own expression and thereby controls DC differentiation.
Sequencing data have been deposited in GEO under accession code GSE198651 and GenBank under accession codes ON134061 and ON134062.
A lncRNA identifies IRF8 enhancer element in negative feedback control of dendritic cell differentiationNCBI Gene Expression Omnibus, GSE198651.
- Martin Zenke
- Ivan G Costa
- Ivan G Costa
- Martin Zenke
- Huaming Xu
- Marcelo AS de Toldeo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All the animal experiments were approved by the local authorities of the German Federal State North Rhine-Westphalia, Germany according to the German animal protection law (reference number 81-02.04.2018.A228).
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
© 2023, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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