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

Abstract

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. Here we use functional genomics 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. The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains which in turn led to altered genome compartmentalisation. These changes in genome structure were linked with altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway, which may contribute to disease development and response to therapy. AUTHOR SUMMARYAcute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) are clonal malignant diseases that affect the myeloid blood cell lineage. Around 40 different mutations have been identified as being associated with MDS and AML; several mutations effect genes in the cohesin complex particularly STAG2. STAG2 is an X-linked gene that is pivotal to the cohesin complex and the mutations result in a truncated gene and loss of function. We have introduced a clinically relevant truncating mutation into an isogeneic AML model. This has shown that changes in the sizes of loop and domains formed in the genome resulting in appropriate gene compartmentalisations. The associated changes in gene transcription has resulted in deregulation of HOX genes, essential for development and differentiation, and in the MAPK signalling pathway that could a therapeutic target.