PDF(Pubmed)
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.
摘要：
软骨细胞分化控制骨骼发育和身材。在这里，我们提供了软骨细胞特异性增强子的全面图谱，并表明它们提供了一个机制框架，通过该框架，非编码遗传变异可以影响骨骼发育和人类身材。使用从带有Col2a1荧光调节传感器的小鼠中分离出的胎儿软骨细胞，我们使用RNA-seq的组合鉴定了在软骨细胞中特异性活跃的780个基因和2'704个推定的增强子，ATAC-seq和H3K27acChIP-seq。大多数这些增强剂（74％）显示泛软骨形成活性，较小的群体仅限于肢体（18％）或躯干（8％）软骨细胞。值得注意的是,与重叠的非成软骨增强剂相比，重叠这些增强剂的遗传变异更好地解释了高度差异。最后,确定的增强子在Fgfr3，Col2a1，Hip和，Nkx3-2基因座证实了它们在调节同源基因中的作用。该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框架。
