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Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud

Author

Listed:
  • Naoko Koyano-Nakagawa

    (University of Minnesota
    University of Minnesota
    Hamre, Schumann, Mueller & Larson, P.C.
    Mitchell Hamline School of Law)

  • Wuming Gong

    (University of Minnesota)

  • Satyabrata Das

    (University of Minnesota)

  • Joshua W. M. Theisen

    (University of Minnesota)

  • Tran B. Swanholm

    (University of Minnesota)

  • Daniel Ly

    (University of Minnesota)

  • Nikita Dsouza

    (University of Minnesota)

  • Bhairab N. Singh

    (University of Minnesota)

  • Hiroko Kawakami

    (University of Minnesota
    University of Minnesota)

  • Samantha Young

    (University of Minnesota)

  • Katherine Q. Chen

    (University of Minnesota)

  • Yasuhiko Kawakami

    (University of Minnesota
    University of Minnesota)

  • Daniel J. Garry

    (University of Minnesota
    University of Minnesota)

Abstract

Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.

Suggested Citation

  • Naoko Koyano-Nakagawa & Wuming Gong & Satyabrata Das & Joshua W. M. Theisen & Tran B. Swanholm & Daniel Ly & Nikita Dsouza & Bhairab N. Singh & Hiroko Kawakami & Samantha Young & Katherine Q. Chen & Y, 2022. "Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31848-6
    DOI: 10.1038/s41467-022-31848-6
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    References listed on IDEAS

    as
    1. Marie Kmita & Basile Tarchini & Jozsef Zàkàny & Malcolm Logan & Clifford J. Tabin & Denis Duboule, 2005. "Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function," Nature, Nature, vol. 435(7045), pages 1113-1116, June.
    2. Marco Osterwalder & Iros Barozzi & Virginie Tissières & Yoko Fukuda-Yuzawa & Brandon J. Mannion & Sarah Y. Afzal & Elizabeth A. Lee & Yiwen Zhu & Ingrid Plajzer-Frick & Catherine S. Pickle & Momoe Kat, 2018. "Enhancer redundancy provides phenotypic robustness in mammalian development," Nature, Nature, vol. 554(7691), pages 239-243, February.
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