Nature Communications (Jun 2024)

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,
  • Guillaume Andrey

DOI
https://doi.org/10.1038/s41467-024-49203-2
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 15

Abstract

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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.