RRC ID 80964
Author Ichiyama-Kobayashi S, Hata K, Wakamori K, Takahata Y, Murakami T, Yamanaka H, Takano H, Yao R, Uzawa N, Nishimura R.
Title Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development.
Journal JCI Insight
Abstract The transcription factor SRY-related HMG box 9 (Sox9) is essential for chondrogenesis. Mutations in and around SOX9 cause campomelic dysplasia (CD) characterized by skeletal malformations. Although the function of Sox9 in this context is well studied, the mechanisms that regulate Sox9 expression in chondrocytes remain to be elucidated. Here, we have used genome-wide profiling to identify 2 Sox9 enhancers located in a proximal breakpoint cluster responsible for CD. Enhancer activity of E308 (located 308 kb 5' upstream) and E160 (located 160 kb 5' upstream) correlated with Sox9 expression levels, and both enhancers showed a synergistic effect in vitro. While single deletions in mice had no apparent effect, simultaneous deletion of both E308 and E160 caused a dwarf phenotype, concomitant with a reduction of Sox9 expression in chondrocytes. Moreover, bone morphogenetic protein 2-dependent chondrocyte differentiation of limb bud mesenchymal cells was severely attenuated in E308/E160 deletion mice. Finally, we found that an open chromatin region upstream of the Sox9 gene was reorganized in the E308/E160 deletion mice to partially compensate for the loss of E308 and E160. In conclusion, our findings reveal a mechanism of Sox9 gene regulation in chondrocytes that might aid in our understanding of the pathophysiology of skeletal disorders.
Volume 9(11)
Published 2024-6-10
DOI 10.1172/jci.insight.175486
PII 175486
PMID 38855864
MeSH Animals Bone Development / genetics Bone Morphogenetic Protein 2 / genetics Bone Morphogenetic Protein 2 / metabolism Campomelic Dysplasia* / genetics Campomelic Dysplasia* / metabolism Campomelic Dysplasia* / pathology Cell Differentiation* / genetics Chondrocytes* / metabolism Chondrogenesis* / genetics Chromatin / genetics Chromatin / metabolism Enhancer Elements, Genetic / genetics Gene Expression Regulation, Developmental Humans Mice Mice, Knockout SOX9 Transcription Factor* / genetics SOX9 Transcription Factor* / metabolism
Human and Animal Cells 10T1/2(RCB0247) ATDC5(RCB0565) C2C12(RCB0987) 293(RCB1637)