Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes

Abstract

The HMG-box transcription factor Sox2 plays a role throughout neurogenesis1 and also acts at other stages of development2, as illustrated by the multiple organs affected in the anophthalmia syndrome caused by SOX2 mutations3,4,5. Here we combined proteomic and genomic approaches to characterize gene regulation by Sox2 in neural stem cells. Chd7, a chromatin remodeling ATPase associated with CHARGE syndrome6,7, was identified as a Sox2 transcriptional cofactor. Sox2 and Chd7 physically interact, have overlapping genome-wide binding sites and regulate a set of common target genes including Jag1, Gli3 and Mycn, genes mutated in Alagille, Pallister-Hall and Feingold syndromes, which show malformations also associated with SOX2 anophthalmia syndrome or CHARGE syndrome8,9,10. Regulation of disease-associated genes by a Sox2-Chd7 complex provides a plausible explanation for several malformations associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Indeed, we found that Chd7-haploinsufficient embryos showed severely reduced expression of Jag1 in the developing inner ear.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Interaction partners of Sox2 and Chd7 in neural stem cells.
Figure 2: Target genes of Sox2 and Chd7 in neural stem cells.
Figure 3: Sox2 and Chd7 regulate genes of the Notch and Sonic Hedgehog signaling pathways.
Figure 4: Expression of Jag1 is strongly reduced in otocysts of Chd7 heterozygous embryos.

Similar content being viewed by others

Accession codes

Accessions

ArrayExpress

References

  1. Pevny, L.H. & Nicolis, S.K. Sox2 roles in neural stem cells. Int. J. Biochem. Cell Biol. 42, 421–424 (2010).

    Article  CAS  Google Scholar 

  2. Guth, S.I. & Wegner, M. Having it both ways: Sox protein function between conservation and innovation. Cell. Mol. Life Sci. 65, 3000–3018 (2008).

    Article  CAS  Google Scholar 

  3. Williamson, K.A. et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum. Mol. Genet. 15, 1413–1422 (2006).

    Article  CAS  Google Scholar 

  4. Fantes, J. et al. Mutations in SOX2 cause anophthalmia. Nat. Genet. 33, 461–463 (2003).

    Article  CAS  Google Scholar 

  5. Kelberman, D. et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J. Clin. Invest. 116, 2442–2455 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Vissers, L.E. et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet. 36, 955–957 (2004).

    Article  CAS  Google Scholar 

  7. Zentner, G.E., Layman, W.S., Martin, D.M. & Scacheri, P.C. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am. J. Med. Genet. A. 152A, 674–686 (2010).

    Article  CAS  Google Scholar 

  8. Okuno, T., Takahashi, H., Shibahara, Y., Hashida, Y. & Sando, I. Temporal bone histopathologic findings in Alagille's syndrome. Arch. Otolaryngol. Head Neck Surg. 116, 217–220 (1990).

    Article  CAS  Google Scholar 

  9. van Bokhoven, H. et al. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat. Genet. 37, 465–467 (2005).

    Article  CAS  Google Scholar 

  10. Kang, S., Graham, J.M. Jr., Olney, A.H. & Biesecker, L.G. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat. Genet. 15, 266–268 (1997).

    Article  CAS  Google Scholar 

  11. Gontan, C. et al. Exportin 4 mediates a novel nuclear import pathway for Sox family transcription factors. J. Cell Biol. 185, 27–34 (2009).

    Article  CAS  Google Scholar 

  12. van den Berg, D.L. et al. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6, 369–381 (2010).

    Article  CAS  Google Scholar 

  13. Hurd, E.A. et al. Loss of Chd7 function in gene-trapped reporter mice is embryonic lethal and associated with severe defects in multiple developing tissues. Mamm. Genome 18, 94–104 (2007).

    Article  CAS  Google Scholar 

  14. Alavizadeh, A. et al. The Wheels mutation in the mouse causes vascular, hindbrain, and inner ear defects. Dev. Biol. 234, 244–260 (2001).

    Article  CAS  Google Scholar 

  15. Visel, A., Thaller, C. & Eichele, G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 32, D552–D556 (2004).

    Article  CAS  Google Scholar 

  16. Hu, Q. et al. The EGF receptor-sox2-EGF receptor feedback loop positively regulates the self-renewal of neural precursor cells. Stem Cells 28, 279–286 (2010).

    Article  CAS  Google Scholar 

  17. Bani-Yaghoub, M. et al. Role of Sox2 in the development of the mouse neocortex. Dev. Biol. 295, 52–66 (2006).

    Article  CAS  Google Scholar 

  18. Favaro, R. et al. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat. Neurosci. 12, 1248–1256 (2009).

    Article  CAS  Google Scholar 

  19. Taranova, O.V. et al. SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev. 20, 1187–1202 (2006).

    Article  CAS  Google Scholar 

  20. Howard, T.D. et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet. 15, 36–41 (1997).

    Article  Google Scholar 

  21. Bajpai, R. et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 463, 958–962 (2010).

    Article  CAS  Google Scholar 

  22. Schnetz, M.P. et al. Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res. 19, 590–601 (2009).

    Article  CAS  Google Scholar 

  23. Schnetz, M.P. et al. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression. PLoS Genet. 6, e1001023 (2010).

    Article  Google Scholar 

  24. Roessler, E. et al. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc. Natl. Acad. Sci. USA 100, 13424–13429 (2003).

    Article  CAS  Google Scholar 

  25. Bosman, E.A. et al. Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum. Mol. Genet. 14, 3463–3476 (2005).

    Article  CAS  Google Scholar 

  26. Avilion, A.A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).

    Article  CAS  Google Scholar 

  27. Kiernan, A.E. et al. The Notch ligand Jagged1 is required for inner ear sensory development. Proc. Natl. Acad. Sci. USA 98, 3873–3878 (2001).

    Article  CAS  Google Scholar 

  28. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16, 243–251 (1997).

    Article  CAS  Google Scholar 

  29. Brooker, R., Hozumi, K. & Lewis, J. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133, 1277–1286 (2006).

    Article  CAS  Google Scholar 

  30. Kiernan, A.E. et al. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434, 1031–1035 (2005).

    Article  CAS  Google Scholar 

  31. Shaw-Smith, C. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J. Med. Genet. 43, 545–554 (2006).

    Article  CAS  Google Scholar 

  32. Conti, L. et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol. 3, e283 (2005).

    Article  Google Scholar 

  33. Sun, Y. et al. Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture. Mol. Cell. Neurosci. 38, 245–258 (2008).

    Article  CAS  Google Scholar 

  34. Ivanova, N. et al. Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533–538 (2006).

    Article  CAS  Google Scholar 

  35. Soler, E. et al. The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. Genes Dev. 24, 277–289 (2010).

    Article  CAS  Google Scholar 

  36. Hou, J. et al. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS ONE 5, e10312 (2010).

    Article  Google Scholar 

  37. Kiernan, A.E. et al. ENU mutagenesis reveals a highly mutable locus on mouse chromosome 4 that affects ear morphogenesis. Mamm. Genome 13, 142–148 (2002).

    Article  CAS  Google Scholar 

  38. Sakai, K. & Miyazaki, J. A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem. Biophys. Res. Commun. 237, 318–324 (1997).

    Article  CAS  Google Scholar 

  39. Nowak, D.E., Tian, B. & Brasier, A.R. Two-step cross-linking method for identification of NF-κB gene network by chromatin immunoprecipitation. Biotechniques 39, 715–725 (2005).

    Article  CAS  Google Scholar 

  40. Jothi, R., Cuddapah, S., Barski, A., Cui, K. & Zhao, K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res. 36, 5221–5231 (2008).

    Article  CAS  Google Scholar 

  41. Bailey, T.L. & Elkan, C. The value of prior knowledge in discovering motifs with MEME. Proc. Int. Conf. Intell. Syst. Mol. Biol. 3, 21–29 (1995).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Abelo for advice on the otocyst stainings, A. Smith for 46C ES cells, S. Pollard for advice on deriving neural stem cells, Z. Ozgür for micro-array hybridizations, M. van den Hout-van Vroonhoven for Illumina GAP analyses and P. Wade for Mi2-β antibody. R.A.P., E.E. and U.A. were supported by a Vidi grant, ALW-open program grant and a Chemical Sciences ECHO grant, respectively, all from the Netherlands Organisation for Scientific Research (NWO). J.C.B. was supported by EuTRACC, B.L. was supported by grants from the Norwegian Research Council (YFF) and the Bergen Research Foundation. C.G. and R.J.R. were supported in part by the Sophia Foundation for Medical Research. S.B. was supported by a British Heart Foundation Chair Award (CH/09/003) and Project Grant award (PG/08/045/25069).

Author information

Authors and Affiliations

Authors

Contributions

E.E. and U.A. performed nearly all experiments and analyzed the data. J.C.B. and B.L. normalized the ChIP-Seq data and performed all bioinformatic analyses. J.H. and S.P. normalized and formatted the microarray gene expression data. C.G., R.A.P. and R.J.R. created the F-Sox2 embryonic stem cells. D.S. and S.B. assisted in the mouse work, M.M. performed the GST pull down experiment, C.K. and W.v.IJ. performed the microarray analyses and Illumina sequencing of the ChIP material. D.H.W.D. and J.D. performed the mass spectrometry analyses. E.-J.R. provided bioinformatic assistance in the early stages of this work. L.H.P. provided Sox2 COND mice. F.G.G. set up the ChIP sequencing facility and the bioinformatics infrastructure. R.J.R. created Sox2+/− mice from Sox2 COND mice. R.A.P. designed the study, analyzed the data and wrote the manuscript with support from coauthors.

Corresponding author

Correspondence to Raymond A Poot.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 and 11–13. (PDF 10090 kb)

Supplementary Table 4

List of genes regulated by Sox2 and Chd7, identified by microarrays. (XLS 64 kb)

Supplementary Table 5

Genome-wide Sox2 peaks, identified by ChIP-sequencing. (XLS 848 kb)

Supplementary Table 6

Sox2 peaks within 10 kb of genes. (XLS 1359 kb)

Supplementary Table 7

List of genes that are activated and bound by Sox2. (XLS 119 kb)

Supplementary Table 8

Genome-wide Chd7 peaks, identified by ChIP-sequencing. (XLS 2599 kb)

Supplementary Table 9

Chd7 peaks within 10 kb of genes. (XLS 3279 kb)

Supplementary Table 10

List of genes that are activated and bound by Sox2 and Chd7. (XLS 39 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Engelen, E., Akinci, U., Bryne, J. et al. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet 43, 607–611 (2011). https://doi.org/10.1038/ng.825

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.825

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing