Intestinal secretory differentiation reflects niche-driven phenotypic and epigenetic plasticity of a common signal-responsive terminal cell [RNA-Seq]

Enterocytes and four classic secretory cell types derive from intestinal epithelial stem cells. Based on morphology, location, and canonical markers, goblet and Paneth cells are considered distinct secretory types. Here, we report high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of their enteroendocrine or tuft cell siblings. Mouse and human goblet and Paneth cells express extraordinary fractions of few antimicrobial genes, which reflect specific responses to local niches. Wnt signaling retains some ATOH1+ secretory cells in crypt bottoms, where absence of BMP signaling potently induces Paneth features. Cells that migrate away from crypt bottoms encounter BMPs and thereby acquire goblet properties. These phenotypes and underlying accessible cis-elements interconvert in post-mitotic cells. Thus, goblet and Paneth properties represent alternative phenotypic manifestations of a common signal-responsive terminal cell type. These findings reveal exquisite niche-dependent cell plasticity and cis-regulatory dynamics in likely response to antimicrobial needs. Overall design: Duodenal villi TOM+ cells from Atoh1CreERT2/+; R26Tom mice were isolated by flow cytometry 36 h after tamoxifen injection IP to specifically enrich for goblet cells. Duodenal crypt TOM+ cells from Atoh1CreERT2/+; R26Tom mice were isolated by flow cytometry 12 days after tamoxifen injection IP to specifically enrich for Paneth cells. To investigate the regulation of secretory differentiation, we established Dox inducible ATOH1 primary human cell lines, and EPCAM+ cells were taken without Dox treatment or with Dox treatment for 48 h and with Dox + WnthiBMPlo treatment or with Dox +WntloBMPhi treatment for 48 h.