p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation
Justine Creff,
Ada Nowosad,
Anne Prel,
Anne Pizzoccaro,
Marion Aguirrebengoa,
Nicolas Duquesnes,
Caroline Callot,
Thomas Jungas,
Christine Dozier,
Arnaud Besson
Affiliations
Justine Creff
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Ada Nowosad
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Anne Prel
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Anne Pizzoccaro
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Marion Aguirrebengoa
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Nicolas Duquesnes
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Caroline Callot
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Thomas Jungas
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Christine Dozier
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
Arnaud Besson
Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France; Corresponding author
Summary: p57Kip2 is a cyclin/CDK inhibitor and a negative regulator of cell proliferation. Here, we report that p57 regulates intestinal stem cell (ISC) fate and proliferation in a CDK-independent manner during intestinal development. In the absence of p57, intestinal crypts exhibit an increased proliferation and an amplification of transit-amplifying cells and of Hopx+ ISCs, which are no longer quiescent, while Lgr5+ ISCs are unaffected. RNA sequencing (RNA-seq) analyses of Hopx+ ISCs show major gene expression changes in the absence of p57. We found that p57 binds to and inhibits the activity of Ascl2, a transcription factor critical for ISC specification and maintenance, by participating in the recruitment of a corepressor complex to Ascl2 target gene promoters. Thus, our data suggest that, during intestinal development, p57 plays a key role in maintaining Hopx+ ISC quiescence and repressing the ISC phenotype outside of the crypt bottom by inhibiting the transcription factor Ascl2 in a CDK-independent manner.
