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Cited by 179Genomics and Chromatin DynamicsOsteoarthritis Treatment and MechanismsDevelopmental Biology and Gene Regulation

Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte

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Ohba, Shinsuke, He, Xinjun, Hojo, Hironori, McMahon, Andrew P.·2015·Cell Reports
DOI 10.1016/j.celrep.2015.06.013PMC PMC4504750
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Abstract

Sox9 encodes an essential transcriptional regulator of chondrocyte specification and differentiation. When Sox9 nuclear activity was compared with markers of chromatin organization and transcriptional activity in primary chondrocytes, we identified two distinct categories of target association. Class I sites cluster around the transcriptional start sites of highly expressed genes with no chondrocyte-specific signature. Here, Sox9 association reflects protein-protein association with basal transcriptional components. Class II sites highlight evolutionarily conserved active enhancers that direct chondrocyte-related gene activity through the direct binding of Sox9 dimer complexes to DNA. Sox9 binds through sites with sub-optimal binding affinity; the number and grouping of enhancers into super-enhancer clusters likely determines the levels of target gene expression. Interestingly, comparison of Sox9 action in distinct chondrocyte lineages points to similar regulatory strategies. In addition to providing insights into Sox family action, our comprehensive identification of the chondrocyte regulatory genome will facilitate the study of skeletal development and human disease.

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Crossref · 10.1016/j.celrep.2015.06.013

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  • In mouse chondrocytes, a SOX motif was enriched in distal regions while promoter regions were enriched for motifs suggesting binding of SOX9 through the basal transcriptional machinery.

    “In mouse chondrocytes, a SOX motif was enriched in distal regions while promoter regions were enriched for motifs suggesting binding of SOX9 through the basal transcriptional machinery (62).”

    From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [62]

    The Results sections on Class I targets and Sox9 peaks report Sox motif enrichment away from promoters, but not in transcription-start-site-proximal regions. The Discussion proposes that Sox9 associates with promoters through protein–protein interactions with the basal transcription apparatus. It does not report enrichment of promoter motifs as the basis for that proposal. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Mouse H3K27Ac and Sox9 ChIP-seq profiles were previously described.

    “Mouse H3K27Ac and Sox9 ChIP-seq profiles were previously described51.”

    From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [51]

  • The identified SOX motifs are similar to previously identified motifs for SOX9.

    “which are similar to previously identified motifs for SOX9 (5,17,53,62).”

    From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [62]

  • Previous studies found that 20-30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes.

    “Previous studies of genome-wide chromatin binding by SOX9 found that 20–30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes (17,62).”

    From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [62]

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Research works printed but not linked: 71

  1. Akiyama H Kim JE Nakashima K Balmes G Iwai N Deng JM Zhang Z Martin JF Behringer RR Nakamura T 2005 Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors Proc Natl Acad Sci U S A 102 14665 14670 16203988 PMC1239942
  2. Akiyama H Lefebvre V 2011 Unraveling the transcriptional regulatory machinery in chondrogenesis J Bone Miner Metab 29 390 395 21594584 PMC3354916
  3. Arango NA Lovell-Badge R Behringer RR 1999 Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development Cell 99 409 419 10571183
  4. Bailey TL Boden M Buske FA Frith M Grant CE Clementi L Ren J Li WW Noble WS 2009 MEME SUITE: tools for motif discovery and searching Nucleic Acids Res 37 W202 208 19458158 PMC2703892
  5. Behrens A Haigh J Mechta-Grigoriou F Nagy A Yaniv M Wagner EF 2003 Impaired intervertebral disc formation in the absence of Jun Development 130 103 109 12441295
  6. Bell DM Leung KK Wheatley SC Ng LJ Zhou S Ling KW Sham MH Koopman P Tam PP Cheah KS 1997 SOX9 directly regulates the type-II collagen gene Nat Genet 16 174 178 9171829
  7. Bernard P Tang P Liu S Dewing P Harley VR Vilain E 2003 Dimerization of SOX9 is required for chondrogenesis, but not for sex determination Hum Mol Genet 12 1755 1765 12837698
  8. Bessa J Tena JJ de la Calle-Mustienes E Fernandez-Minan A Naranjo S Fernandez A Montoliu L Akalin A Lenhard B Casares F 2009 Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish Dev Dyn 238 2409 2417 19653328
  9. Bhandari RK Haque MM Skinner MK 2012 Global genome analysis of the downstream binding targets of testis determining factor SRY and SOX9 PLoS One 7 e43380 22984422 PMC3440412
  10. Bi W Deng JM Zhang Z Behringer RR de Crombrugghe B 1999 Sox9 is required for cartilage formation Nat Genet 22 85 89 10319868
  11. Bi W Huang W Whitworth DJ Deng JM Zhang Z Behringer RR de Crombrugghe B 2001 Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization Proc Natl Acad Sci U S A 98 6698 6703 11371614 PMC34415
  12. Bridgewater LC Lefebvre V de Crombrugghe B 1998 Chondrocyte-specific enhancer elements in the Col11a2 gene resemble the Col2a1 tissue-specific enhancer J Biol Chem 273 14998 15006 9614107
  13. Bridgewater LC Walker MD Miller GC Ellison TA Holsinger LD Potter JL Jackson TL Chen RK Winkel VL Zhang Z 2003 Adjacent DNA sequences modulate Sox9 transcriptional activation at paired Sox sites in three chondrocyte-specific enhancer elements Nucleic Acids Res 31 1541 1553 12595563 PMC149823
  14. Consortium EP Birney E Stamatoyannopoulos JA Dutta A Guigo R Gingeras TR Margulies EH Weng Z Snyder M Dermitzakis ET 2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project Nature 447 799 816 17571346 PMC2212820
  15. Coustry F Oh CD Hattori T Maity SN de Crombrugghe B Yasuda H 2010 The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template Nucleic Acids Res 38 6018 6028 20484372 PMC2952863
  16. De Santa Barbara P Bonneaud N Boizet B Desclozeaux M Moniot B Sudbeck P Scherer G Poulat F Berta P 1998 Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene Mol Cell Biol 18 6653 6665 9774680 PMC109250
  17. Dy P Wang W Bhattaram P Wang Q Wang L Ballock RT Lefebvre V 2012 Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes Dev Cell 22 597 609 22421045 PMC3306603
  18. Foster JW Dominguez-Steglich MA Guioli S Kwok C Weller PA Stevanovic M Weissenbach J Mansour S Young ID Goodfellow PN 1994 Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene Nature 372 525 530 7990924
  19. Furumatsu T Tsuda M Yoshida K Taniguchi N Ito T Hashimoto M Ito T Asahara H 2005 Sox9 and p300 cooperatively regulate chromatin-mediated transcription J Biol Chem 280 35203 35208 16109717
  20. Genzer MA Bridgewater LC 2007 A Col9a1 enhancer element activated by two interdependent SOX9 dimers Nucleic Acids Res 35 1178 1186 17264118 PMC1851653
  21. Gross S Krause Y Wuelling M Vortkamp A 2012 Hoxa11 and Hoxd11 regulate chondrocyte differentiation upstream of Runx2 and Shox2 in mice PLoS One 7 e43553 22916278 PMC3423364
  22. Han Y Lefebvre V 2008 L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer Mol Cell Biol 28 4999 5013 18559420 PMC2519711
  23. He HH Meyer CA Shin H Bailey ST Wei G Wang Q Zhang Y Xu K Ni M Lupien M 2010 Nucleosome dynamics define transcriptional enhancers Nat Genet 42 343 347 20208536 PMC2932437
  24. Helms JA Schneider RA 2003 Cranial skeletal biology Nature 423 326 331 12748650
  25. Hu G Codina M Fisher S 2012 Multiple enhancers associated with ACAN suggest highly redundant transcriptional regulation in cartilage Matrix Biol 31 328 337 22820679 PMC3508301
  26. Huang BL Brugger SM Lyons KM 2010 Stage-specific control of connective tissue growth factor (CTGF/CCN2) expression in chondrocytes by Sox9 and beta-catenin J Biol Chem 285 27702 27712 20571031 PMC2934638
  27. Ikeda T Kamekura S Mabuchi A Kou I Seki S Takato T Nakamura K Kawaguchi H Ikegawa S Chung UI 2004 The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage Arthritis Rheum 50 3561 3573 15529345
  28. Jenkins E Moss JB Pace JM Bridgewater LC 2005 The new collagen gene COL27A1 contains SOX9-responsive enhancer elements Matrix Biol 24 177 184 15922909 PMC3205994
  29. Ji H Jiang H Ma W Johnson DS Myers RM Wong WH 2008 An integrated software system for analyzing ChIP-chip and ChIP-seq data Nat Biotechnol 26 1293 1300 18978777 PMC2596672
  30. Kan A Ikeda T Saito T Yano F Fukai A Hojo H Ogasawara T Ogata N Nakamura K Chung UI 2009 Screening of chondrogenic factors with a real-time fluorescence-monitoring cell line ATDC5-C2ER: identification of sorting nexin 19 as a novel factor Arthritis Rheum 60 3314 3323 19877062
  31. Karreth F Hoebertz A Scheuch H Eferl R Wagner EF 2004 The AP1 transcription factor Fra2 is required for efficient cartilage development Development 131 5717 5725 15509771
  32. Kimura A Inose H Yano F Fujita K Ikeda T Sato S Iwasaki M Jinno T Ae K Fukumoto S 2010 Runx1 and Runx2 cooperate during sternal morphogenesis Development 137 1159 1167 20181744 PMC2835330
  33. Komori T Yagi H Nomura S Yamaguchi A Sasaki K Deguchi K Shimizu Y Bronson RT Gao YH Inada M 1997 Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts Cell 89 755 764 9182763
  34. Kou I Ikegawa S 2004 SOX9-dependent and -independent transcriptional regulation of human cartilage link protein J Biol Chem 279 50942 50948 15456769
  35. Kronenberg HM 2003 Developmental regulation of the growth plate Nature 423 332 336 12748651
  36. Lefebvre V 2010 The SoxD transcription factors--Sox5, Sox6, and Sox13--are key cell fate modulators Int J Biochem Cell Biol 42 429 432 19647094 PMC2826538
  37. Lefebvre V Dumitriu B Penzo-Mendez A Han Y Pallavi B 2007 Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors Int J Biochem Cell Biol 39 2195 2214 17625949 PMC2080623
  38. Lefebvre V Li P de Crombrugghe B 1998 A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene Embo J 17 5718 5733 9755172 PMC1170900
  39. Lefebvre V Zhou G Mukhopadhyay K Smith CN Zhang Z Eberspaecher H Zhou X Sinha S Maity SN de Crombrugghe B 1996 An 18-base-pair sequence in the mouse proalpha1(II) collagen gene is sufficient for expression in cartilage and binds nuclear proteins that are selectively expressed in chondrocytes Mol Cell Biol 16 4512 4523 8754852 PMC231450
  40. Leung KK Ng LJ Ho KK Tam PP Cheah KS 1998 Different cis-regulatory DNA elements mediate developmental stage- and tissue-specific expression of the human COL2A1 gene in transgenic mice J Cell Biol 141 1291 1300 9628886 PMC2132792
  41. Leung VY Gao B Leung KK Melhado IG Wynn SL Au TY Dung NW Lau JY Mak AC Chan D 2011 SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression PLoS Genet 7 e1002356 22072985 PMC3207907
  42. Liu Y Li H Tanaka K Tsumaki N Yamada Y 2000 Identification of an enhancer sequence within the first intron required for cartilage-specific transcription of the alpha2(XI) collagen gene J Biol Chem 275 12712 12718 10777565
  43. Maher B 2012 ENCODE: The human encyclopaedia Nature 489 46 48 22962707
  44. Mead TJ Wang Q Bhattaram P Dy P Afelik S Jensen J Lefebvre V 2013 A far-upstream (−70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration Nucleic Acids Res 41 4459 4469 23449223 PMC3632127
  45. Nagy A Kenesi E Rentsendorj O Molnar A Szenasi T Sinko I Zvara A Oommen ST Barta E Puskas LG 2011 Evolutionarily conserved, growth plate zone-specific regulation of the matrilin-1 promoter: L-Sox5/Sox6 and Nfi factors bound near TATA finely tune activation by Sox9 Mol Cell Biol 31 686 699 21173167 PMC3028657
  46. Nakashima K Zhou X Kunkel G Zhang Z Deng JM Behringer RR de Crombrugghe B 2002 The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation Cell 108 17 29 11792318
  47. Nifuji A Miura N Kato N Kellermann O Noda M 2001 Bone morphogenetic protein regulation of forkhead/winged helix transcription factor Foxc2 (Mfh1) in a murine mesodermal cell line C1 and in skeletal precursor cells J Bone Miner Res 16 1765 1771 11585339
  48. Odom DT Zizlsperger N Gordon DB Bell GW Rinaldi NJ Murray HL Volkert TL Schreiber J Rolfe PA Gifford DK 2004 Control of pancreas and liver gene expression by HNF transcription factors Science 303 1378 1381 14988562 PMC3012624
  49. Oh CD Maity SN Lu JF Zhang J Liang S Coustry F de Crombrugghe B Yasuda H 2010 Identification of SOX9 interaction sites in the genome of chondrocytes PLoS One 5 e10113 20404928 PMC2852419
  50. Olsen BR Reginato AM Wang W 2000 Bone development Annu Rev Cell Dev Biol 16 191 220 11031235
  51. Rentsendorj O Nagy A Sinko I Daraba A Barta E Kiss I 2005 Highly conserved proximal promoter element harbouring paired Sox9-binding sites contributes to the tissue- and developmental stage-specific activity of the matrilin-1 gene Biochem J 389 705 716 15804237 PMC1180720
  52. Rodova M Lu Q Li Y Woodbury BG Crist JD Gardner BM Yost JG Zhong XB Anderson HC Wang J 2011 Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation J Bone Miner Res 26 1974 1986 21452283 PMC3353550
  53. Rosenbloom KR Dreszer TR Pheasant M Barber GP Meyer LR Pohl A Raney BJ Wang T Hinrichs AS Zweig AS 2010 ENCODE whole-genome data in the UCSC Genome Browser Nucleic Acids Res 38 D620 625 19920125 PMC2808953
  54. Schafer AJ Foster JW Kwok C Weller PA Guioli S Goodfellow PN 1996 Campomelic dysplasia with XY sex reversal: diverse phenotypes resulting from mutations in a single gene Ann N Y Acad Sci 785 137 149 8702120
  55. Sekido R Lovell-Badge R 2008 Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer Nature 453 930 934 18454134
  56. Sock E Pagon RA Keymolen K Lissens W Wegner M Scherer G 2003 Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia Hum Mol Genet 12 1439 1447 12783851
  57. Tang Q Chen Y Meyer C Geistlinger T Lupien M Wang Q Liu T Zhang Y Brown M Liu XS 2011 A comprehensive view of nuclear receptor cancer cistromes Cancer Res 71 6940 6947 21940749 PMC3610570
  58. Tsuda M Takahashi S Takahashi Y Asahara H 2003 Transcriptional co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9 J Biol Chem 278 27224 27229 12732631
  59. Visel A Blow MJ Li Z Zhang T Akiyama JA Holt A Plajzer-Frick I Shoukry M Wright C Chen F 2009 ChIP-seq accurately predicts tissue-specific activity of enhancers Nature 457 854 858 19212405 PMC2745234
  60. Vokes SA Ji HK McCuine S Tenzen T Giles S Zhong S Longabaugh WJR Davidson EH Wong WH McMahon AP 2007 Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning Development 134 1977 1989 17442700
  61. Wagner T Wirth J Meyer J Zabel B Held M Zimmer J Pasantes J Bricarelli FD Keutel J Hustert E 1994 Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9 Cell 79 1111 1120 8001137
  62. Wainwright EN Jorgensen JS Kim Y Truong V Bagheri-Fam S Davidson T Svingen T Fernandez-Valverde SL McClelland KS Taft RJ 2013 SOX9 regulates microRNA miR-202-5p/3p expression during mouse testis differentiation Biol Reprod 89 34 23843232
  63. Wang J Gardner BM Lu Q Rodova M Woodbury BG Yost JG Roby KF Pinson DM Tawfik O Anderson HC 2009 Transcription factor Nfat1 deficiency causes osteoarthritis through dysfunction of adult articular chondrocytes J Pathol 219 163 172 19526482 PMC2975457
  64. Whyte WA Orlando DA Hnisz D Abraham BJ Lin CY Kagey MH Rahl PB Lee TI Young RA 2013 Master transcription factors and mediator establish super-enhancers at key cell identity genes Cell 153 307 319 23582322 PMC3653129
  65. Wright E Hargrave MR Christiansen J Cooper L Kun J Evans T Gangadharan U Greenfield A Koopman P 1995 The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos Nat Genet 9 15 20 7704017
  66. Yoshida CA Yamamoto H Fujita T Furuichi T Ito K Inoue K Yamana K Zanma A Takada K Ito Y 2004 Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog Genes Dev 18 952 963 15107406 PMC395853
  67. Yueh YG Gardner DP Kappen C 1998 Evidence for regulation of cartilage differentiation by the homeobox gene Hoxc-8 Proc Natl Acad Sci U S A 95 9956 9961 9707582 PMC21443
  68. Zentner GE Tesar PJ Scacheri PC 2011 Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions Genome Res 21 1273 1283 21632746 PMC3149494
  69. Zhang P Jimenez SA Stokes DG 2003 Regulation of human COL9A1 gene expression. Activation of the proximal promoter region by SOX9 J Biol Chem 278 117 123 12399468
  70. Zhou G Lefebvre V Zhang Z Eberspaecher H de Crombrugghe B 1998 Three high mobility group-like sequences within a 48-base pair enhancer of the Col2a1 gene are required for cartilage-specific expression in vivo J Biol Chem 273 14989 14997 9614106
  71. Zhou VW Goren A Bernstein BE 2011 Charting histone modifications and the functional organization of mammalian genomes Nature reviews Genetics 12 7 18 21116306

Cited by

Sorted by citations

Authors
Ohba, S., He, X., Hojo, H., & McMahon, A. P.
Affiliations
  • The University of Tokyo (JP)
  • University of Southern California (US)
Corresponding author
  • Ohba, Shinsuke
  • McMahon, Andrew P.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2015-07
Volume
12
Issue
2
Pages
229-243
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2015.06.013
PMC
PMC4504750
OpenAlex
W1849784044
Cited by
179
References
6
Citations by year
2026: 5 · 2025: 13 · 2024: 11 · 2023: 16 · 2022: 20 · 2021: 18 · 2020: 26 · 2019: 20 · 2018: 17 · 2017: 17 · 2016: 12 · 2015: 2 · 2014: 1
FWCI
6.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Takeda Science Foundation
  • Japan Society for the Promotion of Science (15K15732, 26221311, 26713054)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK056246, P01DK056246)
  • Core Research for Evolutional Science and Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
SOX9, chondrocytes, transcriptional regulation, enhancers, super-enhancers, chromatin organization, transcription start sites, chondrogenic differentiation, skeletal development, gene regulatory networks
MeSH terms
Animals, Cells, Cultured, Gene Expression Regulation, Humans, Mice, Inbred ICR, Transcriptional Activation, Sequence Analysis, DNA, Chondrocytes, Chromatin Immunoprecipitation, Core Binding Factor Alpha 1 Subunit, Mice, SOX9 Transcription Factor

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