Chronic loss of STAG2 leads to altered chromatin structure contributiong to de-regulated transcription in AML

James Smith, Katrina Lappin, Stephanie Craig, Fabio Liberante, Simon McDade, Alexander Thompson, Ken Mills*, Kienan Savage

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Background:
The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member.

Methods:
Here we use functional genomics (RNA-seq, ChIP-seq and HiChIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss.

Results:
The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains that, in turn, led to altered genome compartmentalisation. These changes in genome structure resulted in altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway, resulting in increased sensitivity to MEK inhibition.

Conclusions:
The altered genomic architecture driven by the chronic loss of STAG2 results in altered gene expression that may contribute to leukaemogenesis and may be therapeutically targeted.
Original languageEnglish
Pages (from-to)339-357
Number of pages18
JournalJOURNAL OF TRANSLATIONAL MEDICINE
Volume18
DOIs
Publication statusPublished - 03 Sep 2020

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