Chronic Loss of STAG2 Leads to Altered Chromatin Structure Contributing to DE-Regulated Transcription in AML.

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.

Chromatin structure in cancer

“…We illustrate non-coding mutations affecting CTCF binding sites in the context of weakened TADs, neo-TADs, and TAD boundaries. CTCF HiChIP data visualized (from [85]) with annotations for how these structural elements may be altered in tumors. B Tissue-specific pioneer transcription factors at loop anchors.…”

“…B Tissue-specific pioneer transcription factors at loop anchors. We illustrate chromatin loop domains, visualized (from [85]) with CTCF HiChIP, and annotations for how transcription factors would occupy the termini of loop domains. C Structural variants can alter chromatin domains.…”

“…D Illustration of interchromosomal rearrangements revealed in in Hi-C experiments, with interactions spanning chromosome 10 and chromosome 16 from GM12878 cells, visualized from available Hi-C data [6]. E Intrachromosomal structural variation with rearrangements occurring within a chromosome, viewed from HiChIP experiments in AML cells, focused on chromosome 13 [85]. F Mammalian cohesin complexes are illustrated with the major subunits SMC1, SMC3, RAD21, STAG2 shown (left).…”

“…F Mammalian cohesin complexes are illustrated with the major subunits SMC1, SMC3, RAD21, STAG2 shown (left). Chromatin domains are shown in AML cells with wild-type cohesion complexes (right; chromosome 7), visualized from available data [85]. G Cohesin mutations affect chromatin interactions.…”

“…Cohesin loss can occur through alterations in the major subunits, as shown (left). The result of Cohesin mutations on chromatin interactions is the substantial loss of TAD-level interactions, as visualized from available data on AML cells with STAG2 loss (right; chromosome 7, [85]) binding of tissue-specific TFs or pioneer factors at loop anchors (Fig. 1B).…”