Ribosome Homeostasis Regulated by SETD2 Preserves Intestinal Epithelial Barrier

ABSTRACT Strict regulation of epithelial cells is crucial for maintaining intestinal barrier integrity and preventing intestinal diseases. While transcriptional regulation is well recognized as vital in this process, translational regulation is equally important. SETD2, a methyltransferase, is involved in transcriptional regulation to maintain intestinal epithelial barrier function. However, its role in translation remains largely unexplored. Here, we found SETD2 deficiency leads to the downregulation of ribosome biogenesis progress coupled with transcriptome‐proteome discordance. Further ribosome profiling sequencing analyses showed reduced translational efficiency of cell adhesion and junction signatures in impaired intestinal epithelial barrier. Mechanistically, SETD2 ablation causes dysregulation and recruitment disorders of ribosome biogenesis factors, impairing the composition and distribution of ribosomal proteins. This disruption of ribosome biogenesis and homeostasis results in translational disorder of barrier maintenance genes, thereby compromising the intestinal barrier. Collectively, our findings unveil a previously unappreciated role of ribosome biogenesis and translational regulation in safeguarding intestinal epithelial barrier, and disclose a previously undiscovered role of SETD2 in modulating ribosome homeostasis.