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

Nature Genetics volume 50, pages 329–332 (2018)Cite this article

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A Publisher Correction to this article was published on 03 June 2019

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

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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.

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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.

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  • 03 June 2019

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

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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.

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Author notes

  1. A list of members and affiliations appears in the Supplementary Note.

  2. Gabrielle Olley and Morad Ansari contributed equally to this work.

Authors and Affiliations

  1. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK

    Gabrielle Olley, Morad Ansari, Hemant Bengani, Ana Blatnik, Wendy A. Bickmore, Madapura M. Pradeepa & David R. FitzPatrick

  2. MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK

    Graeme R. Grimes & Alex von Kriegsheim

  3. Department of Biochemistry, Oxford University, Oxford, UK

    James Rhodes

  4. Cancer Genetics Clinic, Institute of Oncology, Ljubljana, Slovenia

    Ana Blatnik

  5. Department of Medical Genetics, Belfast City Hospital, Belfast, UK

    Fiona J. Stewart

  6. North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK

    Emma Wakeling

  7. South East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, UK

    Nicola Carroll

  8. Department of Medical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK

    Alison Ross

  9. East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke’s Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Soo-Mi Park

  10. School of Biological Sciences, University of Essex, Colchester, UK

    Madapura M. Pradeepa

Authors
  1. Gabrielle Olley
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Consortia

Deciphering Developmental Disorders Study

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, Madapura M. Pradeepa or David R. FitzPatrick.

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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

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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

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