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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F21%3A00544585" target="_blank" >RIV/68378050:_____/21:00544585 - isvavai.cz</a>

Result on the web

<a href="https://www.nature.com/articles/s41467-021-21591-9" target="_blank" >https://www.nature.com/articles/s41467-021-21591-9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-021-21591-9" target="_blank" >10.1038/s41467-021-21591-9</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10601 - Cell biology

Project

<a href="/en/project/GA18-21466S" target="_blank" >GA18-21466S: Wnt ligands and Wnt-secreting cells for intestinal homeostasis, regeneration and colon cancer: a complex world beyond the cancer-activating mutation</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Volume of the periodical

12

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

16

Pages from-to

1368

UT code for WoS article

000626168500024

EID of the result in the Scopus database

—