Temporospatial induction of homeodomain gene cut dictates natural lineage reprogramming

Abstract

Understanding how cellular identity naturally interconverts with high efficiency and temporospatial precision is crucial for regenerative medicine. Here we revealed a natural midgut-to-renal lineage conversion event during Drosophila metamorphosis and identified the evolutionarily-conserved homeodomain protein Cut as a master switch in this process. A steep Wnt/Wingless morphogen gradient intersects with a pulse of steroid hormone ecdysone to induce cut expression in a subset of midgut progenitors and reprogram them into renal progenitors. Molecularly, ecdysone-induced temporal factor Broad physically interacts with cut enhancer-bound Wnt pathway effector TCF/β-catenin and likely bridges the distant enhancer and promoter region of cut through its self-association. Such long-range enhancer-promoter looping could subsequently trigger timely cut transcription. Our results therefore led us to propose an unexpected poising-and-bridging mechanism whereby spatial and temporal cues intersect, likely via chromatin looping, to turn on a master transcription factor and dictate efficient and precise lineage reprogramming.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ke Xu

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaodan Liu

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuchun Wang

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chouin Wong

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yan Song

    School of Life Sciences, Peking University, Beijing, China
    For correspondence
    yan.song@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1413-6123

Funding

National Natural Science Foundation of China

  • Yan Song

Peking-Tsinghua Center for Life Sciences

  • Yan Song

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Version history

  1. Received: November 29, 2017
  2. Accepted: April 30, 2018
  3. Accepted Manuscript published: May 1, 2018 (version 1)
  4. Version of Record published: June 4, 2018 (version 2)

Copyright

© 2018, 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. Ke Xu
  2. Xiaodan Liu
  3. Yuchun Wang
  4. Chouin Wong
  5. Yan Song
(2018)
Temporospatial induction of homeodomain gene cut dictates natural lineage reprogramming
eLife 7:e33934.
https://doi.org/10.7554/eLife.33934

Share this article

https://doi.org/10.7554/eLife.33934

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