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Small genomic insertions form enhancers that misregulate oncogenes

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 challeng...

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Autores principales: Abraham, Brian J., Hnisz, Denes, Weintraub, Abraham S., Kwiatkowski, Nicholas, Li, Charles H., Li, Zhaodong, Weichert-Leahey, Nina, Rahman, Sunniyat, Liu, Yu, Etchin, Julia, Li, Benshang, Shen, Shuhong, Lee, Tong Ihn, Zhang, Jinghui, Look, A. Thomas, Mansour, Marc R., Young, Richard A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309821/
https://www.ncbi.nlm.nih.gov/pubmed/28181482
http://dx.doi.org/10.1038/ncomms14385
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author Abraham, Brian J.
Hnisz, Denes
Weintraub, Abraham S.
Kwiatkowski, Nicholas
Li, Charles H.
Li, Zhaodong
Weichert-Leahey, Nina
Rahman, Sunniyat
Liu, Yu
Etchin, Julia
Li, Benshang
Shen, Shuhong
Lee, Tong Ihn
Zhang, Jinghui
Look, A. Thomas
Mansour, Marc R.
Young, Richard A.
author_facet Abraham, Brian J.
Hnisz, Denes
Weintraub, Abraham S.
Kwiatkowski, Nicholas
Li, Charles H.
Li, Zhaodong
Weichert-Leahey, Nina
Rahman, Sunniyat
Liu, Yu
Etchin, Julia
Li, Benshang
Shen, Shuhong
Lee, Tong Ihn
Zhang, Jinghui
Look, A. Thomas
Mansour, Marc R.
Young, Richard A.
author_sort Abraham, Brian J.
collection PubMed
description 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.
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spelling pubmed-53098212017-02-27 Small genomic insertions form enhancers that misregulate oncogenes Abraham, Brian J. Hnisz, Denes Weintraub, Abraham S. Kwiatkowski, Nicholas Li, Charles H. Li, Zhaodong Weichert-Leahey, Nina Rahman, Sunniyat Liu, Yu Etchin, Julia Li, Benshang Shen, Shuhong Lee, Tong Ihn Zhang, Jinghui Look, A. Thomas Mansour, Marc R. Young, Richard A. Nat Commun Article 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. Nature Publishing Group 2017-02-09 /pmc/articles/PMC5309821/ /pubmed/28181482 http://dx.doi.org/10.1038/ncomms14385 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Abraham, Brian J.
Hnisz, Denes
Weintraub, Abraham S.
Kwiatkowski, Nicholas
Li, Charles H.
Li, Zhaodong
Weichert-Leahey, Nina
Rahman, Sunniyat
Liu, Yu
Etchin, Julia
Li, Benshang
Shen, Shuhong
Lee, Tong Ihn
Zhang, Jinghui
Look, A. Thomas
Mansour, Marc R.
Young, Richard A.
Small genomic insertions form enhancers that misregulate oncogenes
title Small genomic insertions form enhancers that misregulate oncogenes
title_full Small genomic insertions form enhancers that misregulate oncogenes
title_fullStr Small genomic insertions form enhancers that misregulate oncogenes
title_full_unstemmed Small genomic insertions form enhancers that misregulate oncogenes
title_short Small genomic insertions form enhancers that misregulate oncogenes
title_sort small genomic insertions form enhancers that misregulate oncogenes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309821/
https://www.ncbi.nlm.nih.gov/pubmed/28181482
http://dx.doi.org/10.1038/ncomms14385
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