Gastrointestinal transcription factors drive lineage-specific developmental programs in organ specification and cancer.

Abstract

Transcription factors (TFs) are spatially and temporally regulated during gut organ specification. Although accumulating evidence shows aberrant reactivation of developmental programs in cancer, little is known about how TFs drive lineage specification in development and cancer. We first defined gastrointestinal tissue-specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs. We revealed that <i>Sox2</i> is not only essential for gastric specification, by maintaining chromatin accessibility at forestomach lineage loci, but also sufficient to promote forestomach/esophageal transformation upon <i>Cdx2</i> deletion. By comparing our gastrointestinal lineage-specific transcriptome to human gastrointestinal cancer data, we found that stomach and intestinal lineage-specific programs are reactivated in <i>Sox2^high</i> /<i>Sox9^high</i> and <i>Cdx2^high</i> cancers, respectively. By analyzing mice deleted for both <i>Sox2</i> and <i>Sox9</i>, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.