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

TitleH3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair.
Publication TypeJournal Article
Year of Publication2021
AuthorsShao R, Zhang Z, Xu Z, Ouyang H, Wang L, Ouyang H, Greenblatt M, Chen X, Zou W
JournalBone Res
Volume9
Issue1
Pagination30
Date Published2021 Jun 07
ISSN2095-4700
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 through its regulation of Sox9 expression. Collectively, the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation, skeletal growth, and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.

DOI10.1038/s41413-021-00148-y
Alternate JournalBone Res
PubMed ID34099628
PubMed Central IDPMC8185073
Grant List81725010 / / National Natural Science Foundation of China (National Science Foundation of China) /
81672119 / / National Natural Science Foundation of China (National Science Foundation of China) /
81902212 / / National Natural Science Foundation of China (National Science Foundation of China) /
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700