1. Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development
- Author
-
Darbellay, Fabrice, Ramisch, Anna, Lopez-Delisle, Lucille, Kosicki, Michael, Rauseo, Antonella, Jouini, Zahra, Visel, Axel, and Andrey, Guillaume
- Subjects
Biological Sciences ,Genetics ,Congenital Structural Anomalies ,Human Genome ,Arthritis ,Pediatric ,Musculoskeletal ,Animals ,Enhancer Elements ,Genetic ,Humans ,Chondrocytes ,Mice ,Chondrogenesis ,Receptor ,Fibroblast Growth Factor ,Type 3 ,Collagen Type II ,Gene Expression Regulation ,Developmental ,Bone Development ,Extremities ,Male ,Cell Differentiation ,Transcription Factors ,Female - 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.
- Published
- 2024