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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

<a href="/cs/project/GA18-21466S" target="_blank" >GA18-21466S: Ligandy Wnt a buňky produkující tyto ligandy při obnově střevního epitelu, jeho regeneraci a v nádorech tlustého střeva mimo mutaci indukující nádor</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Svazek periodika

12

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

16

Strana od-do

1368

Kód UT WoS článku

000626168500024

EID výsledku v databázi Scopus

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