ETV1 is a key regulator of enteroendocrine PYY production.

The intestine is a rich source of hormones that regulate metabolism. Among these are glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both expressed by L-cells. These hormones play important roles in promoting satiety; however, how they are regulated transcriptionally is not known. ETS variant transcription factor 1 (ETV1) is expressed by L-cells, but its function remains unknown. Here, we examined Etv1 expression in single-cell RNA-sequencing (scRNA-seq) datasets from the mouse small intestine and from organoid cultures. To assess the functional role of ETV1, loss-of-function and overexpression experiments were performed in organoids. Gene expression was subsequently assessed with quantitative PCR and scRNA-seq. Our results confirmed Etv1 enrichment in the L-cell lineage both in vivo and in organoids. Furthermore, mutations in ETV1 led to a decrease in Pyy expression levels with no effect on Gcg levels or on overall cell composition and organoid morphology. Moreover, overexpression of ETV1 led to a modest, but specific, increase in Pyy levels. We thus identified ETV1 as a regulator of Pyy expression, illustrating, for the first time, how specific hormones in the L-cell lineage are transcriptionally regulated.