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Chronic loss of STAG2 leads to altered chromatin structure contributing to deregulated transcription in AML

ABSTRACT: In this study, we use functional genomics to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming. We show that STAG1 partially functionally compensates for loss of STAG2 but that this leads to a shift in chromatin domain size with loss of smaller domain structure and the maintenance and formation of large domain interactions, leading to altered genome compartmentalization. Taken together this suggests differing functions for STAG1 and STAG2 containing cohesion complexes. Additionally, the changes in genome structure driven by the chronic loss of STAG2 are linked with altered epigenetic marker deposition and changes in gene expression, including deregulation of the disease-relevant HOXA locus, which may contribute to disease development. Additionally, the altered genomic architecture driven by the chronic loss of STAG2 lead to altered MAPK signaling, resulting in increased sensitivity to MEK inhibition. This suggests that the altered genomic architecture induced by the chronic loss of STAG2 not only results in altered gene expression that may contribute to leukemogenesis but that this altered gene expression functionally affects cellular processes that may be therapeutically targeted in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111537 | GEO | 2020/03/31

REPOSITORIES: GEO

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