Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML
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Journal of Translational Medicine Open Access
RESEARCH
Chronic loss of STAG2 leads to altered chromatin structure contributing to de‑regulated transcription in AML James S. Smith1, Katrina M. Lappin1, Stephanie G. Craig1, Fabio G. Liberante1,2, Clare M. Crean1, Simon S. McDade1, Alexander Thompson1,3, Ken I. Mills1*† and Kienan I. Savage1*†
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. Keywords: STAG2, Cohesion, Acute myeloid leukaemia, RNA-seq, ChIP-seq, HiChIP, HOX, MAPK pathway Background Acute Myeloid Leukaemia (AML) is a highly clonal disease characterised by the rapid expansion of differentiation-blocked myeloid precursor cells, resulting in defective haematopoiesis and eventually, bone marrow failure [1]. In recent years, large-scale sequencing studies have identified a plethora of mutations within patient derived AML cells, expanding our understanding of the genomic landscape and highlighting the complexity of the varying subtypes of this disease [2]. One of the emerging *Correspondence: [email protected]; [email protected] † Ken I. Mills and Kienan I. Savage are joint senior authors 1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, Northern Ireland, UK Full list of author information is available at the end of the article
genomic disease subgroups involves mutations within chromatin remodelling and splicing related genes, including members of the cohesin complex. Approximately 11% of patients diagnosed with a myeloid malignancy, including AML, Myelodysplastic syndrome, (MDS) and Myeloproliferative neoplasm (MPN), have been shown to harbour a mutation within a member of the cohesin complex, with many more showing significantly reduced expression of complex members [3–5]. Mutations within cohesin complex genes have also been identified in clinically normal and aging individuals following sequencing analysis of large populations, indicating that these mutations are early events in leukaemogenesis, leadin
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