Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
Chen Zhao
Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
Junbao Wang
Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
Xiaoping Miao
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
Gen Zheng
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Min Wu
Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China; College of Life Sciences, Wuhan University, Wuhan, China
Mei Ye
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
Ying Liu
Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
The β-catenin-dependent canonical Wnt signaling is pivotal in organ development, tissue homeostasis, and cancer. Here, we identified an upstream enhancer of Ctnnb1 – the coding gene for β-catenin, named ieCtnnb1 (intestinal enhancer of Ctnnb1), which is crucial for intestinal homeostasis. ieCtnnb1 is predominantly active in the base of small intestinal crypts and throughout the epithelia of large intestine. Knockout of ieCtnnb1 led to a reduction in Ctnnb1 transcription, compromising the canonical Wnt signaling in intestinal crypts. Single-cell sequencing revealed that ieCtnnb1 knockout altered epithelial compositions and potentially compromised functions of small intestinal crypts. While deletion of ieCtnnb1 hampered epithelial turnovers in physiologic conditions, it prevented occurrence and progression of Wnt/β-catenin-driven colorectal cancers. Human ieCTNNB1 drove reporter gene expression in a pattern highly similar to mouse ieCtnnb1. ieCTNNB1 contains a single-nucleotide polymorphism associated with CTNNB1 expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues was stronger than that in adjacent normal tissues. HNF4α and phosphorylated CREB1 were identified as key trans-factors binding to ieCTNNB1 and regulating CTNNB1 transcription. Together, these findings unveil an enhancer-dependent mechanism controlling the dosage of Wnt signaling and homeostasis in intestinal epithelia.
