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An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth

Author

Listed:
  • Xuanming Shi

    (University of Texas Southwestern Medical Center)

  • Zilai Zhang

    (University of Texas Southwestern Medical Center)

  • Xiaoming Zhan

    (University of Texas Southwestern Medical Center)

  • Mou Cao

    (University of Texas Southwestern Medical Center)

  • Takashi Satoh

    (Laboratory of Host Defense, RIMD, Osaka University, Osaka)

  • Shizuo Akira

    (Laboratory of Host Defense, RIMD, Osaka University, Osaka)

  • Karl Shpargel

    (University of North Carolina School of Medicine)

  • Terry Magnuson

    (University of North Carolina School of Medicine)

  • Qingtian Li

    (Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute)

  • Rongfu Wang

    (Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute)

  • Chaochen Wang

    (NIDDK, NIH)

  • Kai Ge

    (NIDDK, NIH)

  • Jiang Wu

    (University of Texas Southwestern Medical Center)

Abstract

The Sonic hedgehog (Shh) signalling pathway plays important roles during development and in cancer. Here we report a Shh-induced epigenetic switch that cooperates with Gli to control transcription outcomes. Before induction, poised Shh target genes are marked by a bivalent chromatin domain containing a repressive histone H3K27me3 mark and an active H3K4me3 mark. Shh activation induces a local switch of epigenetic cofactors from the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) to an H3K27me3 demethylase Jmjd3/Kdm6b-centred coactivator complex. We also find that non-enzymatic activities of Jmjd3 are important and that Jmjd3 recruits the Set1/MLL H3K4 methyltransferase complexes in a Shh-dependent manner to resolve the bivalent domain. In vivo, changes of the bivalent domain accompanied Shh-activated cerebellar progenitor proliferation. Overall, our results reveal a regulatory mechanism that underlies the activation of Shh target genes and provides insight into the causes of various diseases and cancers exhibiting altered Shh signalling.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6425
    DOI: 10.1038/ncomms6425
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    Cited by:

    1. 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.
    2. David R. Ghasemi & Konstantin Okonechnikov & Anne Rademacher & Stephan Tirier & Kendra K. Maass & Hanna Schumacher & Piyush Joshi & Maxwell P. Gold & Julia Sundheimer & Britta Statz & Ahmet S. Rifaiog, 2024. "Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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