Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development

Ichiyama-Kobayashi, Sachi; Hata, Kenji; Wakamori, Kanta; Takahata, Yoshifumi; Murakami, Tomohiko; Yamanaka, Hitomi; Takano, Hiroshi; Yao, Ryoji; Uzawa, Narikazu; Nishimura, Riko

doi:https://doi.org/10.1172/jci.insight.175486

Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development

Ichiyama-Kobayashi, Sachi; Hata, Kenji; Wakamori, Kanta et al.

JCI Insight, 2024, 9(11), e175486

Number of Access:1,171（2025-07-22 20:40 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97270

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Title	Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development
Creator	CreatorName Ichiyama-Kobayashi, Sachi
	NRID 1000080444496 1000080444496 researchmap permalink read0107167 read0107167 Scopus Author ID 8952419300 8952419300 ORCID 0000-0003-4367-9343 0000-0003-4367-9343 CreatorName Hata, Kenji
	CreatorName Wakamori, Kanta
	NRID 1000060635845 1000060635845 researchmap permalink yoshifumitakahata yoshifumitakahata Scopus Author ID 22837135800 22837135800 ORCID 0000-0002-3322-0515 0000-0002-3322-0515 CreatorName Takahata, Yoshifumi
	NRID 1000050510723 1000050510723 researchmap permalink read0139290 read0139290 Scopus Author ID 8509095600 8509095600 CreatorName Murakami, Tomohiko
	CreatorName Yamanaka, Hitomi
	CreatorName Takano, Hiroshi
	CreatorName Yao, Ryoji
	NRID 1000030345285 1000030345285 researchmap permalink read0212957 read0212957 Scopus Author ID 6603144046 6603144046 CreatorName Uzawa, Narikazu
	NRID 1000060294112 1000060294112 ORCID 0000-0001-7279-8363 0000-0001-7279-8363 researchmap permalink MolBiology MolBiology Scopus Author ID 7201418320 7201418320 CreatorName Nishimura, Riko
Description	Ichiyama-Kobayashi S., Hata K., Wakamori K., et al. Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development. JCI Insight 9, e175486 (2024); https://doi.org/10.1172/jci.insight.175486.
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.
Publisher	American Society for Clinical Investigation
Source Title	JCI Insight
Volume (Issue)	9(11)
Page	e175486
Date of Issued	2024-06-10
Language	English
Handle URL	https://hdl.handle.net/11094/97270
eISSN	23793708
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1172/jci.insight.175486
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	JCI Insight. 2024, 9(11), p. e175486
DC.title	Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development
DC.creator	Ichiyama-Kobayashi, Sachi
	Hata, Kenji
	Wakamori, Kanta
	Takahata, Yoshifumi
	Murakami, Tomohiko
	Yamanaka, Hitomi
	Takano, Hiroshi
	Yao, Ryoji
	Uzawa, Narikazu
	Nishimura, Riko
DC.publisher	American Society for Clinical Investigation
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-06-10
DC.identifier	https://doi.org/10.1172/jci.insight.175486
DC.description	Ichiyama-Kobayashi S., Hata K., Wakamori K., et al. Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development. JCI Insight 9, e175486 (2024); https://doi.org/10.1172/jci.insight.175486.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	97270
citation_title	Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development
citation_author	Ichiyama-Kobayashi, Sachi
	Hata, Kenji
	Wakamori, Kanta
	Takahata, Yoshifumi
	Murakami, Tomohiko
	Yamanaka, Hitomi
	Takano, Hiroshi
	Yao, Ryoji
	Uzawa, Narikazu
	Nishimura, Riko
citation_publisher	American Society for Clinical Investigation
citation_language	English
citation_date	2024-06-10
citation_journal_title	JCI Insight
citation_volume	9
citation_issue	11
citation_firstpage	e175486
citation_doi	https://doi.org/10.1172/jci.insight.175486
citation_public_url	https://hdl.handle.net/11094/97270

Chromatin profiling identifies chondrocyte-specific Sox9 enhancers important for skeletal development

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