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Small genomic insertions form enhancers that misregulate oncogenes

Author(s)
Hnisz, Denes; Li, Zhaodong; Weichert-Leahey, Nina; Rahman, Sunniyat; Liu, Yu; Etchin, Julia; Li, Benshang; Shen, Shuhong; Zhang, Jinghui; Look, A. Thomas; Mansour, Marc R.; Abraham, Brian Joseph; Weintraub, Abraham Selby; Kwiatkowski, Nick; Li, Charles Han; Lee, Tong Ihn; Young, Richard A.; ... Show more Show less
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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.
Date issued
2017-06-20
URI
http://hdl.handle.net/1721.1/110068
Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Abraham, Brian J.; Hnisz, Denes; Weintraub, Abraham S.; Kwiatkowski, Nicholas; Li, Charles H.; Li, Zhaodong; Weichert-Leahey, Nina et al. “Small Genomic Insertions Form Enhancers That Misregulate Oncogenes.” Nature Communications 8 (February 2017): 14385 © The Author(s) 2017
Version: Final published version
ISSN
2041-1723

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