Differential regulation of β-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells

• Published in: Nature communications Vol. 12; no. 1; pp. 1368 - 16
• Main Authors: Borrelli, Costanza, Valenta, Tomas, Handler, Kristina, Vélez, Karelia, Gurtner, Alessandra, Moro, Giulia, Lafzi, Atefeh, Roditi, Laura de Vargas, Hausmann, George, Arnold, Isabelle C., Moor, Andreas E., Basler, Konrad
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 38/32; 38/39; 45/100; 45/91; 631/532/2437; 631/80/86/2368; 64/60; 96/1; 96/100; 96/63; 96/95; Algorithms; Animals; Base Sequence; beta Catenin - chemistry; beta Catenin - metabolism; Cell Differentiation; Cell Proliferation; Cell self-renewal; Chromatin - metabolism; Chromatin Assembly and Disassembly; Crypts; Epithelium; Gene expression; Gene regulation; Homeostasis; Humanities and Social Sciences; Hyperplasia; Intestinal Mucosa - cytology; Intestine; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Mice; multidisciplinary; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Organoids - metabolism; Phenotype; Protein folding; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Transgenic mice; Wnt protein; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21591-9

The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we took advantage of knock-in mice harboring transgenic β-catenin alleles with mutations that specifically impair the recruitment of N- or C-terminal transcriptional co-factors. We show that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin’s transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by unfolded protein response stress and immune infiltration, results in a process resembling aberrant “villisation” of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires selective modulation of gene expression by transcriptional co-factors. How downstream regulators of Wnt/β-catenin signalling control the fate of intestinal epithelial stem cells (IESCs) is unclear. Here, the authors show that the transcriptional co-factors interacting with the N- and C-terminal domains of β-catenin differentially regulate Wnt target gene activation, in turn differentially affecting the murine IESC proliferation and differentiation.