I want to give a big shoutout to my mentor Ramesh Shivdasani, my fellow lab members, and all the fantastic collaborators. It was an excellent team effort.
Here is a link to the full text: authors.elsevier.com/c/1kusf6tu0C...
#PanethCell #GobletCell #Epigenetics #IntestinalBiology

A minority of enhancers are uniquely activated in Paneth cells under Wnt-favored conditions, shedding light on how epigenetic priming directs cell function along the crypt–villus axis.

Beyond phenotypic plasticity, our study maps cis-regulatory dynamics of intestinal secretory differentiation: Tuft and EE cells display thousands of unique enhancers, while many goblet and Paneth enhancers are shared with intestinal stem cells.

These insights redefine how we think about cell fate in the intestinal epithelium. Instead of being fixed identities, goblet and Paneth cells may be viewed as flexible, context-dependent states—a paradigm shift with potential implications for understanding intestinal diseases.

A striking aspect of our findings is the reversible nature of this phenotypic switch. Even post-mitotic cells can rapidly convert their secretory identity in response to local niche signals—a process underpinned by dynamic chromatin changes.

Under forced Wnt and especially low BMP conditions, goblet cells gain Paneth features; conversely, BMP exposure potently suppresses Paneth markers and enhances goblet gene expression both in mouse and primary human 2D culture cells.

Experimentally, we demonstrated this plasticity by altering Wnt/BMP levels in vivo (e.g., via Apc deletion and RSPO modulation) and in organoid cultures.

Niche signals play a pivotal role! High Wnt and low BMP signaling, characteristic of the crypt base, push ATOH1+ cells to adopt a Paneth profile, while increased BMP (and lower Wnt) as cells move up the crypt drive a goblet cell phenotype.

Our data show that both cell types originate from a common ATOH1+ secretory progenitor. Rather than being independently specified, goblet and Paneth cells share most mRNAs and many regulatory elements—only a few key antimicrobial genes differentiate them.

Using lineage tracing with Atoh1Cre-ER mice, along with single-cell RNA and chromatin accessibility (snATAC-seq) analyses, we found an unexpectedly high overlap in the transcriptomes and epigenetic landscapes of goblet and Paneth cells.

The intestinal epithelium renews rapidly from stem cells, generating absorptive enterocytes and secretory cells. While enteroendocrine and tuft cells follow distinct trajectories, goblet and Paneth cells have long been thought of as separate terminal fates—until now.