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.

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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

Author notes

    • Cristina Gontan

    Present address: Department of Reproduction and Development, Erasmus MC, Rotterdam, The Netherlands.

    • Erik Engelen
    •  & Umut Akinci

    These authors contributed equally to this work


  1. Department of Cell Biology, Erasmus Medical Center (MC), Rotterdam, The Netherlands.

    • Erik Engelen
    • , Umut Akinci
    • , Jun Hou
    • , Maaike Moen
    • , Sjaak Philipsen
    • , Frank G Grosveld
    •  & Raymond A Poot
  2. Department of Biology, University of Bergen, Bergen, Norway.

    • Jan Christian Bryne
    •  & Boris Lenhard
  3. Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.

    • Cristina Gontan
    •  & Robbert J Rottier
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Dorota Szumska
    •  & Shoumo Bhattacharya
  5. Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.

    • Christel Kockx
    •  & Wilfred van IJcken
  6. Proteomics Center, Erasmus MC, Rotterdam, The Netherlands.

    • Dick H W Dekkers
    •  & Jeroen Demmers
  7. Department of Biochemistry, Erasmus MC, Rotterdam, The Netherlands.

    • Erik-Jan Rijkers
  8. Department of Genetics, University of North Carolina Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Larysa H Pevny


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Raymond A Poot.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Tables 1–3 and 11–13.

Excel files

  1. 1.

    Supplementary Table 4

    List of genes regulated by Sox2 and Chd7, identified by microarrays.

  2. 2.

    Supplementary Table 5

    Genome-wide Sox2 peaks, identified by ChIP-sequencing.

  3. 3.

    Supplementary Table 6

    Sox2 peaks within 10 kb of genes.

  4. 4.

    Supplementary Table 7

    List of genes that are activated and bound by Sox2.

  5. 5.

    Supplementary Table 8

    Genome-wide Chd7 peaks, identified by ChIP-sequencing.

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    Supplementary Table 9

    Chd7 peaks within 10 kb of genes.

  7. 7.

    Supplementary Table 10

    List of genes that are activated and bound by Sox2 and Chd7.

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