Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland.
Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211, Geneva, Switzerland.
Nat Commun. 2024 Jun 6;15(1):4820. doi: 10.1038/s41467-024-49203-2.
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.
软骨细胞分化控制骨骼发育和身高。在这里，我们提供了一个全面的软骨细胞特异性增强子图谱，并表明它们提供了一个机制框架，通过这个框架，非编码遗传变异可以影响骨骼发育和人类身高。我们与携带 Col2a1 荧光调控传感器的小鼠的胎儿软骨细胞一起工作，使用 RNA-seq、ATAC-seq 和 H3K27ac ChIP-seq 的组合，鉴定了 780 个基因和 2'704 个在软骨细胞中特异性激活的假定增强子。这些增强子中的大多数（74%）表现出多向软骨生成活性，而只有一小部分（18%）局限于肢体或（8%）躯干软骨细胞。值得注意的是，与非软骨生成性增强子重叠的遗传变异更好地解释了身高差异，而与这些增强子重叠的遗传变异更好地解释了身高差异。最后，靶向删除 Fgfr3、Col2a1、Hhip 和 Nkx3-2 基因座上鉴定出的增强子，证实了它们在调节同源基因中的作用。这个增强子图谱为理解基因和非编码变异如何影响骨骼发育和疾病提供了一个框架。
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