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Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development

Author

Listed:
  • Fabrice Darbellay

    (University of Geneva
    University of Geneva
    Lawrence Berkeley Laboratory)

  • Anna Ramisch

    (University of Geneva)

  • Lucille Lopez-Delisle

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Michael Kosicki

    (Lawrence Berkeley Laboratory)

  • Antonella Rauseo

    (University of Geneva
    University of Geneva)

  • Zahra Jouini

    (University of Geneva
    University of Geneva)

  • Axel Visel

    (Lawrence Berkeley Laboratory
    Lawrence Berkeley Laboratory
    University of California)

  • Guillaume Andrey

    (University of Geneva
    University of Geneva)

Abstract

Chondrocyte differentiation controls skeleton development and stature. Here we provide a comprehensive map of chondrocyte-specific enhancers and show that they provide a mechanistic framework through which non-coding genetic variants can influence skeletal development and human stature. Working with fetal chondrocytes isolated from mice bearing a Col2a1 fluorescent regulatory sensor, we identify 780 genes and 2'704 putative enhancers specifically active in chondrocytes using a combination of RNA-seq, ATAC-seq and H3K27ac ChIP-seq. Most of these enhancers (74%) show pan-chondrogenic activity, with smaller populations being restricted to limb (18%) or trunk (8%) chondrocytes only. Notably, genetic variations overlapping these enhancers better explain height differences than those overlapping non-chondrogenic enhancers. Finally, targeted deletions of identified enhancers at the Fgfr3, Col2a1, Hhip and, Nkx3-2 loci confirm their role in regulating cognate genes. This enhancer map provides a framework for understanding how genes and non-coding variations influence bone development and diseases.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49203-2
    DOI: 10.1038/s41467-024-49203-2
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    References listed on IDEAS

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    Cited by:

    1. Samuel Abassah-Oppong & Matteo Zoia & Brandon J. Mannion & Raquel Rouco & Virginie Tissières & Cailyn H. Spurrell & Virginia Roland & Fabrice Darbellay & Anja Itum & Julie Gamart & Tabitha A. Festa-Da, 2024. "A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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