BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.

Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium. Synopsis: Both Wnt and BMP signaling regulate maintenance of Lgr5+ intestinal stem cells, but their interplay remains incompletely understood. This study shows that the BMP-suppressed chromatin regulator Bcl11b promotes Lgr5+ intestinal stem cell maintenance and epithelial regeneration by enhancing Wnt signaling. BMP signaling suppresses Bcl11b expression. Bcl11b ensures Lgr5+ intestinal stem cell maintenance and epithelial regeneration upon injury. Bcl11b activates Wnt signaling by facilitating the β-catenin-TCF4 interaction and inhibiting the chromatin remodeling complex NuRD. Bcl11b promotes colon cancer formation. The chromatin regulator Bcl11b promotes intestinal epithelium regeneration and the onset of colon cancer by activating Wnt signaling and inhibiting NuRD complex activity. [ABSTRACT FROM AUTHOR]