p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation

Abstract

p57^Kip2 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.

Keywords: Ascl2; CDKN1C; CP: Stem cell research; Hopx; Lgr5; intestinal stem cells; p57(Kip2); transcriptional regulation.