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

0544585 - ÚMG 2022 RIV GB eng J - Článek v odborném periodiku
Borrelli, C. - Valenta, Tomáš - Handler, K. - Velez, K. - Gurtner, A. - Moro, G. - Lafzi, A. - Roditi, L.V. - Hausmann, G. - Arnold, I.C. - Moor, A.E. - Basler, K.
Differential regulation of beta-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells.
Nature Communications. Roč. 12, č. 1 (2021), č. článku 1368. E-ISSN 2041-1723
Grant CEP: GA ČR(CZ) GA18-21466S
Institucionální podpora: RVO:68378050
Klíčová slova: gene * colon
Obor OECD: Cell biology
Impakt faktor: 17.694, rok: 2021
Způsob publikování: Open access
https://www.nature.com/articles/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/betacatenin 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 betacatenin 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 betacatenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with betacatenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune betacatenin'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/betacatenin output requires selective modulation of gene expression by transcriptional co-factors. How downstream regulators of Wnt/betacatenin 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 betacatenin differentially regulate Wnt target gene activation, in turn differentially affecting the murine IESC proliferation and differentiation.
Trvalý link: http://hdl.handle.net/11104/0321427