대장줄기세포의 항상성 유지 및 대장암 억제에서의 FOXD2 의 역할

Abstract

The gastrointestinal tract of most animals has a compartmentalized epithelium that exhibits digestive, absorption, secretion, and immune functions. Somatic stem cells contribute to the homeostasis of normal tissue, and their epigenomic features play an important role in regulating tissue identities or pathological progression. Enhancers are one of the key players controlling chromatin context-specific gene expressions in a spatial and temporal manner while maintaining tissue homeostasis, and their dysregulation leads to tumorigenesis. Here, epigenomic and transcriptomic analyses revealed that forkhead box protein D2 (FOXD2) is a hub for the gene regulatory network distinct to large intestinal stem cells, and its overexpression plays a decisive role in colon cancer regression. FOXD2 approaches the closed chromatin and facilitates mixed-lineage leukemia protein-4 (MLL4/KMT2D) binding to deposit H3K4 monomethylation. De novo FOXD2-mediated chromatin interaction reprogrammed enhancers and rewired the regulation of p53-responsive genes, eventually leading to cancer cell apoptosis. Taken together, our findings illustrated the novel mechanistic details of FOXD2 in suppressing colorectal cancer growth and suggested its function as a chromatin-tuning factor and a potential therapeutic target for colorectal cancer.