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GLI transcriptional repression is inert prior to Hedgehog pathway activation

Author

Listed:
  • Rachel K. Lex

    (University of Texas at Austin)

  • Weiqiang Zhou

    (Johns Hopkins Bloomberg School of Public Health)

  • Zhicheng Ji

    (Johns Hopkins Bloomberg School of Public Health
    Duke University School of Medicine)

  • Kristin N. Falkenstein

    (University of Texas at Austin)

  • Kaleigh E. Schuler

    (University of Texas at Austin)

  • Kathryn E. Windsor

    (University of Texas at Austin)

  • Joseph D. Kim

    (University of Texas at Austin)

  • Hongkai Ji

    (Johns Hopkins Bloomberg School of Public Health)

  • Steven A. Vokes

    (University of Texas at Austin)

Abstract

The Hedgehog (HH) pathway regulates a spectrum of developmental processes through the transcriptional mediation of GLI proteins. GLI repressors control tissue patterning by preventing sub-threshold activation of HH target genes, presumably even before HH induction, while lack of GLI repression activates most targets. Despite GLI repression being central to HH regulation, it is unknown when it first becomes established in HH-responsive tissues. Here, we investigate whether GLI3 prevents precocious gene expression during limb development. Contrary to current dogma, we find that GLI3 is inert prior to HH signaling. While GLI3 binds to most targets, loss of Gli3 does not increase target gene expression, enhancer acetylation or accessibility, as it does post-HH signaling. Furthermore, GLI repression is established independently of HH signaling, but after its onset. Collectively, these surprising results challenge current GLI pre-patterning models and demonstrate that GLI repression is not a default state for the HH pathway.

Suggested Citation

  • Rachel K. Lex & Weiqiang Zhou & Zhicheng Ji & Kristin N. Falkenstein & Kaleigh E. Schuler & Kathryn E. Windsor & Joseph D. Kim & Hongkai Ji & Steven A. Vokes, 2022. "GLI transcriptional repression is inert prior to Hedgehog pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28485-4
    DOI: 10.1038/s41467-022-28485-4
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