H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair.

Bone Research
Rui ShaoWeiguo Zou

Abstract

Chondrocyte differentiation is a critical process for endochondral ossification, which is responsible for long bone development and fracture repair. Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation; however, epigenetic regulation of chondrocyte differentiation remains to be further studied. NSD1 is a H3K36 (histone H3 at lysine 36) methyltransferase. Here, we showed that mice with Nsd1 deficiency in Prx1+ mesenchymal progenitors but not in Col2+ chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation. Via combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we identified sex determining region Y box 9 (Sox9), the key transcription factor of chondrogenic differentiation, as a functional target gene of NSD1. Mechanistically, NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region, constituting a novel epigenetic regulatory mechanism of chondrogenesis. Moreover, we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α (HIF1α), which plays a vital role in chondrogenic differentiation th...Continue Reading

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Datasets Mentioned

BETA
AB5535

Methods Mentioned

BETA
Assay
PCR
transfections
ChIP-seq
ChIP-PCR
scraping
reverse transcription-PCR
X-ray
gene knockout
RNA-seq

Software Mentioned

GraphPad
ImageJ
DAVID Functional Annotation Bioinformatics Microarray Analysis
Heml
SOAP
Cufflinks
Cuffdiff
TopHat

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