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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.

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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 (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 (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)

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