Loss of ARID3A perturbs intestinal epithelial proliferation-differentiation ratio and regeneration
More about Open Access at the CrickAuthors list
Nikolaos Angelis Anna Baulies Domenech Florian Hubl Ania Kucharska Gavin Kelly Miriam Llorian Sopena Stefan Boeing Vivian LiAbstract
Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.
Journal details
Journal
Journal of Experimental Medicine
Volume
221
Issue number
10
Pages
e20232279
Available online
Publication date
Full text links
Publisher website (DOI)
10.1084/jem.20232279
Europe PubMed Central
39150450
Pubmed
39150450
Data and code
Keywords
Related topics
Type of publication
Publishing history
The publication was previously a preprint.
View preprint
