ETV1 is a key regulator of enteroendocrine PYY production.

Abstract

Background The intestine constitutes the largest endocrine organ and is a rich source of hormones that regulate metabolism. Enteroendocrine cells (EECs) can be subtyped based on their secretion of specific hormones with L-cells being characterised by expression of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Collectively, these hormones play important roles in appetite regulation, however, it is not known, how they are regulated transcriptionally. The ETS Variant Transcription Factor 1 (ETV1) is expressed by L-cells, but its function remains unknown. Methods 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 in EECs, ETV1 loss-of-function and overexpression experiments were performed in murine small intestinal organoids. Gene expression was subsequently assessed with qPCR and scRNA-seq. Results We confirmed that Etv1 is enriched in the L-cell lineage both in vivo and in organoid cultures. Furthermore, we find that mutations of ETV1 in organoids 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. Conclusions We identify ETV1 as a regulator of Pyy expression illustrating for the first time how specific hormone levels in the L-cell lineage are transcriptionally regulated.