Noncoding RNA circBtnl1 suppresses self‐renewal of intestinal stem cells via disruption of Atf4 mRNA stability

Abstract

Intestinal stem cells (ISCs) at the crypt base are responsible for the regeneration of the intestinal epithelium. However, how ISC self‐renewal is regulated still remains unclear. Here we identified a circular RNA, circBtnl1, that is highly expressed in ISCs. Loss of circBtnl1 in mice enhanced ISC self‐renewal capacity and epithelial regeneration, without changes in mRNA and protein levels of its parental gene Btnl1. Mechanistically, circBtnl1 and Atf4 mRNA competitively bound the ATP‐dependent RNA helicase Ddx3y to impair the stability of Atf4 mRNA in wild‐type ISCs. Furthermore, ATF4 activated Sox9 transcription by binding to its promoter via a unique motif, to enhance the self‐renewal capacity and epithelial regeneration of ISCs. In contrast, circBtnl1 knockout promoted Atf4 mRNA stability and enhanced ATF4 expression, which caused Sox9 transcription to potentiate ISC stemness. These data indicate that circBtnl1‐mediated Atf4 mRNA decay suppresses Sox9 transcription that negatively modulates self‐renewal maintenance of ISCs. image Intestinal stem cells (ISCs) at the crypt base are responsible for the regeneration of intestinal epithelium. This study shows that a circular RNA, circBtnl1, negatively regulates the self‐renewal maintenance of ISCs in vivo . CircBtnl1 knockout enhances self‐renewal capacity of intestinal stem cells and epithelial regeneration in mice. CircBtnl1 and Atf4 mRNA competitively bind Ddx3y RNA helicase to modulate Atf4 mRNA stability. ATF4 activates Sox9 transcription by binding onto its promoter, which enhances self‐renewal maintenance of intestinal stem cells.