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.

BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome

A Publisher Correction to this article was published on 12 February 2018

This article has been updated

Abstract

We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: BRD4 mutations in CdLS and CdLS-like disorders.
Fig. 2: Binding of wild-type BRD4 and the BRD4 Tyr430Cys variant to histone and non-histone proteins.

Change history

  • 03 June 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. 1.

    Hnisz, D. et al. Cell 155, 934–947 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Rao, S. S. P. et al. Cell 171, 305–320 (2017).

    CAS  Article  Google Scholar 

  3. 3.

    Watrin, E., Kaiser, F. J. & Wendt, K. S. Curr. Opin. Genet. Dev. 37, 59–66 (2016).

    CAS  Article  Google Scholar 

  4. 4.

    Yuan, B. et al. J. Clin. Invest. 125, 636–651 (2015).

    Article  Google Scholar 

  5. 5.

    Bot, C. et al. J. Cell Sci. 130, 1134–1146 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Zuin, J. et al. PLoS Genet. 10, e1004153 (2014).

    Article  Google Scholar 

  7. 7.

    Haarhuis, J. H. I. et al. Cell 169, 693–707 (2017).

    CAS  Article  Google Scholar 

  8. 8.

    Ciosk, R. et al. Mol. Cell 5, 243–254 (2000).

    CAS  Article  Google Scholar 

  9. 9.

    Schwarzer, W. et al. Nature 551, 51–56 (2017).

    Article  Google Scholar 

  10. 10.

    Deardorff, M. A. et al. Am. J. Hum. Genet. 90, 1014–1027 (2012).

    CAS  Article  Google Scholar 

  11. 11.

    Gil-Rodríguez, M. C. et al. Hum. Mutat. 36, 454–462 (2015).

    Article  Google Scholar 

  12. 12.

    Musio, A. et al. Nat. Genet. 38, 528–530 (2006).

    CAS  Article  Google Scholar 

  13. 13.

    Deardorff, M. A. et al. Nature 489, 313–317 (2012).

    CAS  Article  Google Scholar 

  14. 14.

    Ansari, M. et al. J. Med. Genet. 51, 659–668 (2014).

    CAS  Article  Google Scholar 

  15. 15.

    Parenti, I. et al. Clin. Genet. 89, 74–81 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Izumi, K. et al. Nat. Genet. 47, 338–344 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Deciphering Developmental Disorders Study. Nature 542, 433–438 (2017).

    Article  Google Scholar 

  18. 18.

    Kline, A. D. et al. Am. J. Med. Genet. A. 143A, 1287–1296 (2007).

    Article  Google Scholar 

  19. 19.

    Houzelstein, D. et al. Mol. Cell. Biol. 22, 3794–3802 (2002).

    CAS  Article  Google Scholar 

  20. 20.

    Kawauchi, S. et al. PLoS Genet. 5, e1000650 (2009).

    Article  Google Scholar 

  21. 21.

    Zhang, J. et al. Cancer Discov. 7, 322–337 (2017).

    Article  Google Scholar 

  22. 22.

    Kanno, T. et al. Nat. Struct. Mol. Biol. 21, 1047–1057 (2014).

    CAS  Article  Google Scholar 

  23. 23.

    Vollmuth, F., Blankenfeldt, W. & Geyer, M. J. Biol. Chem. 284, 36547–36556 (2009).

    CAS  Article  Google Scholar 

  24. 24.

    Gerth-Kahlert, C. et al. Mol. Genet. Genomic Med. 1, 15–31 (2013).

    CAS  Article  Google Scholar 

  25. 25.

    Filippakopoulos, P. et al. Nature 468, 1067–1073 (2010).

    CAS  Article  Google Scholar 

  26. 26.

    Pradeepa, M. M., Sutherland, H. G., Ule, J., Grimes, G. R. & Bickmore, W. A. PLoS Genet. 8, e1002717 (2012).

    CAS  Article  Google Scholar 

  27. 27.

    Turriziani, B. et al. Biology 3, 320–332 (2014).

    CAS  Article  Google Scholar 

  28. 28.

    Cox, J. et al. Mol. Cell. Proteomics 13, 2513–2526 (2014).

    CAS  Article  Google Scholar 

  29. 29.

    Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Science 316, 1497–1502 (2007).

    CAS  Article  Google Scholar 

  30. 30.

    Pradeepa, M. M. et al. Nat. Genet. 48, 681–686 (2016).

    CAS  Article  Google Scholar 

  31. 31.

    Illingworth, R. S. et al. Genes Dev. 29, 1897–1902 (2015).

    CAS  Article  Google Scholar 

  32. 32.

    Ritchie, M. E. et al. Nucleic Acids Res. 43, e47 (2015).

    Article  Google Scholar 

  33. 33.

    Langmead, B. & Salzberg, S. L. Nat. Methods 9, 357–359 (2012).

    CAS  Article  Google Scholar 

  34. 34.

    Ramírez, F. et al. Nucleic Acids Res. 44 (W1), W160–W165 (2016).

    Article  Google Scholar 

  35. 35.

    ENCODE Project Consortium. Nature 489, 57–74 (2012).

    Article  Google Scholar 

  36. 36.

    Quinlan, A. R. & Hall, I. M. Bioinformatics 26, 841–842 (2010).

    CAS  Article  Google Scholar 

  37. 37.

    Wei, Y. et al. Nucleic Acids Res. 44 (D1), D172–D179 (2016).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the CdLS Foundation of the UK and Ireland and particularly the families of the affected children for their time and support for the research. G.O., M.A., H.B., W.A.B., M.M.P. and D.R.F. were funded by the MRC University Unit award to the University of Edinburgh for the MRC Human Genetics Unit. The work of A.v.K. was supported by Carnegie Trust Research Incentive Grant 70382. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network.

Author information

Affiliations

Authors

Consortia

Contributions

W.A.B., M.M.P. and D.R.F. conceived the study. D.R.F., W.A.B. and M.M.P. wrote the manuscript. All of the authors read and commented on the manuscript. G.O., M.A., H.B., N.C., M.M.P. and the DDD study generated the molecular biology and animal model data. A.v.K. generated and analyzed the mass spectrometry data. F.J.S., E.W., A.R. and S.M.P. provided expert clinical interpretation and details of the phenotype for each affected individual. A.B. performed the meta-analysis of the reported deletion cases. J.R. provided expert technical advice and cell reagents. G.R.G. performed the genomic and transcriptomic informatic analysis.

Corresponding authors

Correspondence to Wendy A. Bickmore or Madapura M. Pradeepa or David R. FitzPatrick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–20, Supplementary Tables 1–3 and Supplementary Note

Life Sciences Reporting Summary

Supplementary Table 4

BRD4 immunoprecipitation data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Olley, G., Ansari, M., Bengani, H. et al. BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome. Nat Genet 50, 329–332 (2018). https://doi.org/10.1038/s41588-018-0042-y

Download citation

Further reading

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