IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31848-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31848-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31848-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Andrea Wilderman & Eva D’haene & Machteld Baetens & Tara N. Yankee & Emma Wentworth Winchester & Nicole Glidden & Ellen Roets & Jo Dorpe & Sandra Janssens & Danny E. Miller & Miranda Galey & Kari M. B, 2024. "A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Jan-Renier Moonen & James Chappell & Minyi Shi & Tsutomu Shinohara & Dan Li & Maxwell R. Mumbach & Fan Zhang & Ramesh V. Nair & Joseph Nasser & Daniel H. Mai & Shalina Taylor & Lingli Wang & Ross J. M, 2022. "KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Raquel Rouco & Olimpia Bompadre & Antonella Rauseo & Olivier Fazio & Rodrigue Peraldi & Fabrizio Thorel & Guillaume Andrey, 2021. "Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Daniela Michelatti & Sven Beyes & Chiara Bernardis & Maria Luce Negri & Leonardo Morelli & Naiara Garcia Bediaga & Vittoria Poli & Luca Fagnocchi & Sara Lago & Sarah D’Annunzio & Nicole Cona & Ilaria , 2024. "Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    5. Xuemeng Zhou & Tsz Wing Sam & Ah Young Lee & Danny Leung, 2021. "Mouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    6. Markus Götz & Olivier Messina & Sergio Espinola & Jean-Bernard Fiche & Marcelo Nollmann, 2022. "Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Jin Woo Oh & Michael A. Beer, 2024. "Gapped-kmer sequence modeling robustly identifies regulatory vocabularies and distal enhancers conserved between evolutionarily distant mammals," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Matthew J Harder & Julie Hix & Wendy M Reeves & Michael T Veeman, 2021. "Ciona Brachyury proximal and distal enhancers have different FGF dose-response relationships," PLOS Genetics, Public Library of Science, vol. 17(1), pages 1-23, January.
    9. Christopher Chase Bolt & Lucille Lopez-Delisle & Aurélie Hintermann & Bénédicte Mascrez & Antonella Rauseo & Guillaume Andrey & Denis Duboule, 2022. "Context-dependent enhancer function revealed by targeted inter-TAD relocation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Fabrice Darbellay & Anna Ramisch & Lucille Lopez-Delisle & Michael Kosicki & Antonella Rauseo & Zahra Jouini & Axel Visel & Guillaume Andrey, 2024. "Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. Matthieu Santos & Stéphanie Backer & Frédéric Auradé & Matthew Man-Kin Wong & Maud Wurmser & Rémi Pierre & Francina Langa & Marcio Cruzeiro & Alain Schmitt & Jean-Paul Concordet & Athanassia Sotiropou, 2022. "A fast Myosin super enhancer dictates muscle fiber phenotype through competitive interactions with Myosin genes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    12. Marta Losa & Iros Barozzi & Marco Osterwalder & Viviana Hermosilla-Aguayo & Angela Morabito & Brandon H. Chacón & Peyman Zarrineh & Ausra Girdziusaite & Jean Denis Benazet & Jianjian Zhu & Susan Macke, 2023. "A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    13. Sandra Kessler & Maryline Minoux & Onkar Joshi & Yousra Zouari & Sebastien Ducret & Fiona Ross & Nathalie Vilain & Adwait Salvi & Joachim Wolff & Hubertus Kohler & Michael B. Stadler & Filippo M. Rijl, 2023. "A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31848-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.