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Small genomic insertions form enhancers that misregulate oncogenes

Author

Listed:
  • Brian J. Abraham

    (Whitehead Institute for Biomedical Research)

  • Denes Hnisz

    (Whitehead Institute for Biomedical Research)

  • Abraham S. Weintraub

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Nicholas Kwiatkowski

    (Whitehead Institute for Biomedical Research)

  • Charles H. Li

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Zhaodong Li

    (Dana-Farber Cancer Institute, Harvard Medical School
    Children’s Hospital)

  • Nina Weichert-Leahey

    (Dana-Farber Cancer Institute, Harvard Medical School
    Children’s Hospital)

  • Sunniyat Rahman

    (UCL Cancer Institute, University College London)

  • Yu Liu

    (St Jude Children’s Research Hospital)

  • Julia Etchin

    (Dana-Farber Cancer Institute, Harvard Medical School
    Children’s Hospital)

  • Benshang Li

    (Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine
    Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine)

  • Shuhong Shen

    (Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine
    Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine)

  • Tong Ihn Lee

    (Whitehead Institute for Biomedical Research)

  • Jinghui Zhang

    (St Jude Children’s Research Hospital)

  • A. Thomas Look

    (Dana-Farber Cancer Institute, Harvard Medical School
    Children’s Hospital)

  • Marc R. Mansour

    (UCL Cancer Institute, University College London)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

Abstract

The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers.

Suggested Citation

  • Brian J. Abraham & Denes Hnisz & Abraham S. Weintraub & Nicholas Kwiatkowski & Charles H. Li & Zhaodong Li & Nina Weichert-Leahey & Sunniyat Rahman & Yu Liu & Julia Etchin & Benshang Li & Shuhong Shen, 2017. "Small genomic insertions form enhancers that misregulate oncogenes," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14385
    DOI: 10.1038/ncomms14385
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