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

Fabrice Darbellay, Anna Ramisch, Lucille Lopez-Delisle, Michael Kosicki, Antonella Rauseo, Zahra Jouini, Axel Visel and Guillaume Andrey ()
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Fabrice Darbellay: University of Geneva
Anna Ramisch: University of Geneva
Lucille Lopez-Delisle: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Michael Kosicki: Lawrence Berkeley Laboratory
Antonella Rauseo: University of Geneva
Zahra Jouini: University of Geneva
Axel Visel: Lawrence Berkeley Laboratory
Guillaume Andrey: University of Geneva

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49203-2

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