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research article

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

Darbellay, Fabrice
•
Ramisch, Anna
•
Lopez-Delisle, Lucille  
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December 1, 2024
Nature Communications

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.

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10.1038_s41467-024-49203-2.pdf

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Main Document

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Published version

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openaccess

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CC BY

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2.68 MB

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892caf1e94965ab9d8ea564c9aefc687

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