Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

Abstract The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymph...

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Autores principales:	Kirill Batmanov, Wei Wang, Magnar Bjørås, Jan Delabie, Junbai Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a3a553a85191441ab02a874e256af4f6
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spelling	oai:doaj.org-article:a3a553a85191441ab02a874e256af4f62021-12-02T12:32:02ZIntegrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma10.1038/s41598-017-07226-42045-2322https://doaj.org/article/a3a553a85191441ab02a874e256af4f62017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07226-4https://doaj.org/toc/2045-2322Abstract The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymphoma (FL), a disease for which little is known about the contribution of regulatory gene mutations. Results from a test FL cohort revealed three novel highly recurrent regulatory mutation blocks near important genes implicated in FL, BCL6 and BCL2. Similar findings were detected in a validation FL cohort. We also found transcription factors (TF) whose binding may be disturbed by these mutations in FL: disruption of FOX TF family near the BCL6 promoter may result in reduced BCL6 expression, which then increases BCL2 expression over that caused by BCL2 gene translocation. Knockdown experiments of two TF hits (FOXD2 or FOXD3) were performed in human B lymphocytes verifying that they modulate BCL6/BCL2 according to the computationally predicted effects of the SNVs on TF binding. Overall, our proposed integrative analysis facilitates non-coding driver identification and the new findings may enhance the understanding of FL.Kirill BatmanovWei WangMagnar BjøråsJan DelabieJunbai WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kirill Batmanov Wei Wang Magnar Bjørås Jan Delabie Junbai Wang Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
description	Abstract The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymphoma (FL), a disease for which little is known about the contribution of regulatory gene mutations. Results from a test FL cohort revealed three novel highly recurrent regulatory mutation blocks near important genes implicated in FL, BCL6 and BCL2. Similar findings were detected in a validation FL cohort. We also found transcription factors (TF) whose binding may be disturbed by these mutations in FL: disruption of FOX TF family near the BCL6 promoter may result in reduced BCL6 expression, which then increases BCL2 expression over that caused by BCL2 gene translocation. Knockdown experiments of two TF hits (FOXD2 or FOXD3) were performed in human B lymphocytes verifying that they modulate BCL6/BCL2 according to the computationally predicted effects of the SNVs on TF binding. Overall, our proposed integrative analysis facilitates non-coding driver identification and the new findings may enhance the understanding of FL.
format	article
author	Kirill Batmanov Wei Wang Magnar Bjørås Jan Delabie Junbai Wang
author_facet	Kirill Batmanov Wei Wang Magnar Bjørås Jan Delabie Junbai Wang
author_sort	Kirill Batmanov
title	Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
title_short	Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
title_full	Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
title_fullStr	Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
title_full_unstemmed	Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma
title_sort	integrative whole-genome sequence analysis reveals roles of regulatory mutations in bcl6 and bcl2 in follicular lymphoma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a3a553a85191441ab02a874e256af4f6
work_keys_str_mv	AT kirillbatmanov integrativewholegenomesequenceanalysisrevealsrolesofregulatorymutationsinbcl6andbcl2infollicularlymphoma AT weiwang integrativewholegenomesequenceanalysisrevealsrolesofregulatorymutationsinbcl6andbcl2infollicularlymphoma AT magnarbjøras integrativewholegenomesequenceanalysisrevealsrolesofregulatorymutationsinbcl6andbcl2infollicularlymphoma AT jandelabie integrativewholegenomesequenceanalysisrevealsrolesofregulatorymutationsinbcl6andbcl2infollicularlymphoma AT junbaiwang integrativewholegenomesequenceanalysisrevealsrolesofregulatorymutationsinbcl6andbcl2infollicularlymphoma
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Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma

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