6533b861fe1ef96bd12c44a7
RESEARCH PRODUCT
Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction
George GiotopoulosShabana VohraCarsten Müller-tidowFaisal BasheerAnnalisa MupoAnnalisa MupoDaniel SascaDaniel SascaPaolo GallipoliPaolo GallipoliEshwar MeduriSarah J. HortonLudovica MarandoMalgorzata GozdeckaMalgorzata GozdeckaOliver M. DoveyOliver M. DoveyXiaonan WangGeorge S. VassiliouGeorge S. VassiliouShuchi Agrawal-singhCameron S. OsborneAracely Castillo-venzorBrian J. P. HuntlyHaiyang YunHaiyang Yunsubject
Transcription (biology)hemic and lymphatic diseasesMyeloid leukemiaLocus (genetics)EpigeneticsAlleleBiologyEnhancerTopologyChromatinGenomic organizationdescription
AbstractAltered 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-20 |