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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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    1. Jason Ernst & Pouya Kheradpour & Tarjei S. Mikkelsen & Noam Shoresh & Lucas D. Ward & Charles B. Epstein & Xiaolan Zhang & Li Wang & Robbyn Issner & Michael Coyne & Manching Ku & Timothy Durham & Mano, 2011. "Mapping and analysis of chromatin state dynamics in nine human cell types," Nature, Nature, vol. 473(7345), pages 43-49, May.
    2. Jonas Malkmus & Laurène Ramos Martins & Shalu Jhanwar & Bonnie Kircher & Victorio Palacio & Rushikesh Sheth & Francisca Leal & Amandine Duchesne & Javier Lopez-Rios & Kevin A. Peterson & Robert Reinha, 2021. "Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Ying Litingtung & Randall D. Dahn & Yina Li & John F. Fallon & Chin Chiang, 2002. "Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity," Nature, Nature, vol. 418(6901), pages 979-983, August.
    4. Raphaël Margueron & Danny Reinberg, 2011. "The Polycomb complex PRC2 and its mark in life," Nature, Nature, vol. 469(7330), pages 343-349, January.
    5. Javier Lopez-Rios & Amandine Duchesne & Dario Speziale & Guillaume Andrey & Kevin A. Peterson & Philipp Germann & Erkan Ünal & Jing Liu & Sandrine Floriot & Sarah Barbey & Yves Gallard & Magdalena Mül, 2014. "Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs," Nature, Nature, vol. 511(7507), pages 46-51, July.
    6. Peng He & Brian A. Williams & Diane Trout & Georgi K. Marinov & Henry Amrhein & Libera Berghella & Say-Tar Goh & Ingrid Plajzer-Frick & Veena Afzal & Len A. Pennacchio & Diane E. Dickel & Axel Visel &, 2020. "The changing mouse embryo transcriptome at whole tissue and single-cell resolution," Nature, Nature, vol. 583(7818), pages 760-767, July.
    7. Xuanming Shi & Zilai Zhang & Xiaoming Zhan & Mou Cao & Takashi Satoh & Shizuo Akira & Karl Shpargel & Terry Magnuson & Qingtian Li & Rongfu Wang & Chaochen Wang & Kai Ge & Jiang Wu, 2014. "An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
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