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Mutational synergy during leukemia induction remodels chromatin accessibility, modification and genome topology to alter gene expression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE146669 | GEO | 2021/06/01

REPOSITORIES: GEO

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Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression.

Project description:Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional 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 mutations in Npm1c to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a previously unknown superenhancer 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.

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (pCHiC)

Project description:Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergise to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. We have utilized an allelic series of mice carrying the most common mutations in AML, namely Flt3-ITD and Npm1c. These model different “transition states” (normal: wild-type (WT); pre-malignant: single mutant (SM) with either Flt3-ITD or Npm1c; malignant: double mutant (DM)) during AML induction. We have analyzed hematopoietic stem and progenitor cells (HSPCs) from WT and mutant mice for gene expression (RNA-seq), chromatin activation states (ChIP-seq for H3K4me1, H3K4me3, H3K27ac), chromatin accessibility (ATAC-seq), and promoter-anchored 3-D chromatin interaction (promoter capture HiC, pCHiC) and have integrated these analyses to determine the transcriptional, epigenetic and DNA-topological evolution of AML. These findings allow the identification of long-range cis-regulatory circuits, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (ATAC-seq)

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (RNA-seq)

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (ChIP-seq)

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Mutational synergy during leukemia induction remodels chromatin accessibility, modification and genome topology to alter gene expression

Project description:Mutational synergy during leukemia induction remodels chromatin accessibility, modification and genome topology to alter gene expression

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (pCHiC)

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (ChIP-seq)

Project description:Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (ChIP-seq)

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (ATAC-seq)

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction (RNA-seq)

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