FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [ChIP-seq]
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ABSTRACT: The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.
ORGANISM(S): Mus musculus
PROVIDER: GSE247851 | GEO | 2024/09/11
REPOSITORIES: GEO
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