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Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression
Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611829/ https://www.ncbi.nlm.nih.gov/pubmed/34556857 http://dx.doi.org/10.1038/s41588-021-00925-9 |
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author | Yun, Haiyang Narayan, Nisha Vohra, Shabana Giotopoulos, George Mupo, Annalisa Madrigal, Pedro Sasca, Daniel Lara-Astiaso, David Horton, Sarah J. Agrawal-Singh, Shuchi Meduri, Eshwar Basheer, Faisal Marando, Ludovica Gozdecka, Malgorzata Dovey, Oliver M. Castillo-Venzor, Aracely Wang, Xiaonan Gallipoli, Paolo Müller-Tidow, Carsten Osborne, Cameron S. Vassiliou, George S. Huntly, Brian J. P. |
author_facet | Yun, Haiyang Narayan, Nisha Vohra, Shabana Giotopoulos, George Mupo, Annalisa Madrigal, Pedro Sasca, Daniel Lara-Astiaso, David Horton, Sarah J. Agrawal-Singh, Shuchi Meduri, Eshwar Basheer, Faisal Marando, Ludovica Gozdecka, Malgorzata Dovey, Oliver M. Castillo-Venzor, Aracely Wang, Xiaonan Gallipoli, Paolo Müller-Tidow, Carsten Osborne, Cameron S. Vassiliou, George S. Huntly, Brian J. P. |
author_sort | Yun, Haiyang |
collection | PubMed |
description | Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with Npm1c mutation to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members. |
format | Online Article Text |
id | pubmed-7611829 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-76118292022-03-23 Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression Yun, Haiyang Narayan, Nisha Vohra, Shabana Giotopoulos, George Mupo, Annalisa Madrigal, Pedro Sasca, Daniel Lara-Astiaso, David Horton, Sarah J. Agrawal-Singh, Shuchi Meduri, Eshwar Basheer, Faisal Marando, Ludovica Gozdecka, Malgorzata Dovey, Oliver M. Castillo-Venzor, Aracely Wang, Xiaonan Gallipoli, Paolo Müller-Tidow, Carsten Osborne, Cameron S. Vassiliou, George S. Huntly, Brian J. P. Nat Genet Article Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with Npm1c mutation to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members. 2021-10-01 2021-09-23 /pmc/articles/PMC7611829/ /pubmed/34556857 http://dx.doi.org/10.1038/s41588-021-00925-9 Text en https://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms |
spellingShingle | Article Yun, Haiyang Narayan, Nisha Vohra, Shabana Giotopoulos, George Mupo, Annalisa Madrigal, Pedro Sasca, Daniel Lara-Astiaso, David Horton, Sarah J. Agrawal-Singh, Shuchi Meduri, Eshwar Basheer, Faisal Marando, Ludovica Gozdecka, Malgorzata Dovey, Oliver M. Castillo-Venzor, Aracely Wang, Xiaonan Gallipoli, Paolo Müller-Tidow, Carsten Osborne, Cameron S. Vassiliou, George S. Huntly, Brian J. P. Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title | Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title_full | Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title_fullStr | Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title_full_unstemmed | Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title_short | Mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-Dimensional DNA topology to alter gene expression |
title_sort | mutational synergy during leukemia induction remodels chromatin accessibility, modification and 3-dimensional dna topology to alter gene expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611829/ https://www.ncbi.nlm.nih.gov/pubmed/34556857 http://dx.doi.org/10.1038/s41588-021-00925-9 |
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