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Showing papers by "Cameron S. Osborne published in 2020"

Posted Content•DOI•
Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

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Haiyang Yun1, Haiyang Yun2, Shabana Vohra2, Annalisa Mupo3, Annalisa Mupo2, George Giotopoulos2, Daniel Sasca2, Daniel Sasca4, Sarah J. Horton2, Shuchi Agrawal-Singh2, Eshwar Meduri2, Faisal Basheer2, Ludovica Marando2, Malgorzata Gozdecka2, Malgorzata Gozdecka3, Oliver M. Dovey2, Oliver M. Dovey3, Aracely Castillo-Venzor, Xiaonan Wang2, Paolo Gallipoli5, Paolo Gallipoli2, Carsten Müller-Tidow1, Cameron S. Osborne6, George S. Vassiliou3, George S. Vassiliou2, Brian J. P. Huntly2 •
Heidelberg University1, University of Cambridge2, Wellcome Trust Sanger Institute3, University of Mainz4, Queen Mary University of London5, King's College London6
20 Mar 2020-bioRxiv
TL;DR: An integrated genomic approach is applied to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c, and 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.
Abstract: 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 (3-D) 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. These analyses allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of the Hoxa locus, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

1 citations