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Article: SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression

TitleSOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
Citation
Plos Genetics, 2011, v. 7 n. 11 How to Cite?
AbstractCartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise the precise spatiotemporal control of gene expression as chondrocytes progress through phases of differentiation, but how this is achieved is not clear. Here, we have identified a regulatory element upstream of Col10a1 that enhances its expression in hypertrophic chondrocytes in vivo. In immature chondrocytes, where Col10a1 is not expressed, SOX9 interacts with a conserved sequence within this element that is analogous to that within the intronic enhancer of the collagen II gene Col2a1, the known transactivation target of SOX9. By analysing a series of Col10a1 reporter genes in transgenic mice, we show that the SOX9 binding consensus in this element is required to repress expression of the transgene in non-hypertrophic chondrocytes. Forced ectopic Sox9 expression in hypertrophic chondrocytes in vitro and in mice resulted in down-regulation of Col10a1. Mutation of a binding consensus motif for GLI transcription factors, which are the effectors of Indian hedgehog signaling, close to the SOX9 site in the Col10a1 regulatory element, also derepressed transgene expression in non-hypertrophic chondrocytes. GLI2 and GLI3 bound to the Col10a1 regulatory element but not to the enhancer of Col2a1. In addition to Col10a1, paired SOX9-GLI binding motifs are present in the conserved non-coding regions of several genes that are preferentially expressed in hypertrophic chondrocytes and the occurrence of pairing is unlikely to be by chance. We propose a regulatory paradigm whereby direct concomitant positive and negative transcriptional control by SOX9 ensures differentiation phase-specific gene expression in chondrocytes. Discrimination between these opposing modes of transcriptional control by SOX9 may be mediated by cooperation with different partners such as GLI factors. © 2011 Leung et al.
Persistent Identifierhttp://hdl.handle.net/10722/147653
ISSN
2014 Impact Factor: 7.528
2020 SCImago Journal Rankings: 3.587
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council
University Grants Council of Hong KongHKU7222/97M
HKU2/02C
HKU 4/05C
AoE/M-04/04
Funding Information:

This work was supported by grants from the Research Grant Council and University Grants Council of Hong Kong (HKU7222/97M, HKU2/02C, HKU 4/05C, AoE/M-04/04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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DC FieldValueLanguage
dc.contributor.authorLeung, VYLen_HK
dc.contributor.authorGao, Ben_HK
dc.contributor.authorLeung, KKHen_HK
dc.contributor.authorMelhado, IGen_HK
dc.contributor.authorWynn, SLen_HK
dc.contributor.authorAu, TYKen_HK
dc.contributor.authorDung, NWFen_HK
dc.contributor.authorLau, JYBen_HK
dc.contributor.authorMak, ACYen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorCheah, KSEen_HK
dc.date.accessioned2012-05-29T06:05:16Z-
dc.date.available2012-05-29T06:05:16Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos Genetics, 2011, v. 7 n. 11en_HK
dc.identifier.issn1553-7390en_HK
dc.identifier.urihttp://hdl.handle.net/10722/147653-
dc.description.abstractCartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise the precise spatiotemporal control of gene expression as chondrocytes progress through phases of differentiation, but how this is achieved is not clear. Here, we have identified a regulatory element upstream of Col10a1 that enhances its expression in hypertrophic chondrocytes in vivo. In immature chondrocytes, where Col10a1 is not expressed, SOX9 interacts with a conserved sequence within this element that is analogous to that within the intronic enhancer of the collagen II gene Col2a1, the known transactivation target of SOX9. By analysing a series of Col10a1 reporter genes in transgenic mice, we show that the SOX9 binding consensus in this element is required to repress expression of the transgene in non-hypertrophic chondrocytes. Forced ectopic Sox9 expression in hypertrophic chondrocytes in vitro and in mice resulted in down-regulation of Col10a1. Mutation of a binding consensus motif for GLI transcription factors, which are the effectors of Indian hedgehog signaling, close to the SOX9 site in the Col10a1 regulatory element, also derepressed transgene expression in non-hypertrophic chondrocytes. GLI2 and GLI3 bound to the Col10a1 regulatory element but not to the enhancer of Col2a1. In addition to Col10a1, paired SOX9-GLI binding motifs are present in the conserved non-coding regions of several genes that are preferentially expressed in hypertrophic chondrocytes and the occurrence of pairing is unlikely to be by chance. We propose a regulatory paradigm whereby direct concomitant positive and negative transcriptional control by SOX9 ensures differentiation phase-specific gene expression in chondrocytes. Discrimination between these opposing modes of transcriptional control by SOX9 may be mediated by cooperation with different partners such as GLI factors. © 2011 Leung et al.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/en_HK
dc.relation.ispartofPLoS Geneticsen_HK
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.meshBone Development - genetics-
dc.subject.meshCartilage - growth and development-
dc.subject.meshChondrogenesis - genetics-
dc.subject.meshCollagen Type II - genetics-
dc.subject.meshCollagen Type X - genetics-
dc.titleSOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repressionen_HK
dc.typeArticleen_HK
dc.identifier.emailLeung, VYL: vicleung@hku.hken_HK
dc.identifier.emailLeung, KKH: keithlee@hku.hken_HK
dc.identifier.emailChan, D: chand@hkucc.hku.hken_HK
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hken_HK
dc.identifier.authorityLeung, VYL=rp01764en_HK
dc.identifier.authorityLeung, KKH=rp00298en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1371/journal.pgen.1002356en_HK
dc.identifier.pmid22072985en_HK
dc.identifier.pmcidPMC3207907-
dc.identifier.scopuseid_2-s2.0-81755183071en_HK
dc.identifier.hkuros200627-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-81755183071&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume7en_HK
dc.identifier.issue11en_HK
dc.identifier.eissn1553-7404-
dc.identifier.isiWOS:000297264500011-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectDevelopmental genomics and skeletal research-
dc.relation.projectGenomic approaches to uncover functionally relevant signalling pathways in craniofacial development-
dc.identifier.scopusauthoridLeung, VYL=35337438900en_HK
dc.identifier.scopusauthoridGao, B=55707317900en_HK
dc.identifier.scopusauthoridLeung, KKH=7401860467en_HK
dc.identifier.scopusauthoridMelhado, IG=55006348100en_HK
dc.identifier.scopusauthoridWynn, SL=36464623600en_HK
dc.identifier.scopusauthoridAu, TYK=54584851200en_HK
dc.identifier.scopusauthoridDung, NWF=54585215000en_HK
dc.identifier.scopusauthoridLau, JYB=54585591700en_HK
dc.identifier.scopusauthoridMak, ACY=36780323700en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK
dc.identifier.citeulike10777210-
dc.identifier.issnl1553-7390-

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