A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation

Abstract

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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE198651 and GenBank under accession codes ON134061 and ON134062.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Huaming Xu

    Department of Cell Biology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhijian Li

    Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Chao-Chung Kuo

    Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Katrin Goetz

    Department of Cell Biology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Look

    Department of Cell Biology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Marcelo AS de Toldeo

    Department of Cell Biology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Kristin Sere

    Department of Cell Biology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Ivan G Costa

    Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2890-8697
  9. Martin Zenke

    Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany
    For correspondence
    martin.zenke@rwth-aachen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1107-3251

Funding

German Research Foundation

  • Martin Zenke

German Ministry of Science and Technology (Fibromap)

  • Ivan G Costa

Interdisciplinary Center for Clinical Research Aachen

  • Ivan G Costa
  • Martin Zenke

China Scholarship Council (202008080170)

  • Huaming Xu

CAPES-Alexander von Humboldt Foundation (99999.001703/2014-05)

  • 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.

Reviewing Editor

  1. Florent Ginhoux, Agency for Science Technology and Research, Singapore

Ethics

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).

Version history

  1. Preprint posted: August 12, 2022 (view preprint)
  2. Received: September 8, 2022
  3. Accepted: March 13, 2023
  4. Accepted Manuscript published: March 14, 2023 (version 1)
  5. Version of Record published: March 27, 2023 (version 2)

Copyright

© 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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  1. Huaming Xu
  2. Zhijian Li
  3. Chao-Chung Kuo
  4. Katrin Goetz
  5. Thomas Look
  6. Marcelo AS de Toldeo
  7. Kristin Sere
  8. Ivan G Costa
  9. Martin Zenke
(2023)
A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation
eLife 12:e83342.
https://doi.org/10.7554/eLife.83342

Share this article

https://doi.org/10.7554/eLife.83342

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