Establishing the function of POU2F3 CO-activator OCA-T2 in tuft cell development

Active Project Grant Awarded Last action

Award ID
F31DK145216
Recipient
Awarding agency
Obligated
$34,114

Award facts

Assistance listing
93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
Completion date 0% complete
Place of performance
Cold Spring Harbor, NY 11724, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Tuft cells are chemosensory cells, responsible for modulating type 2 inflammatory responses within the mucosal linings of vertebrates. These cells are critical for the maintenance of a healthy GUT microbiome, and their functions are implicated in chronic inflammatory conditions, such as ulcerative colitis. The function of development of tuft cell subtypes is a major question in the field. Tuft cell identity is invariably dependent upon expression of the lineage master regulator POU2F3. My lab recently published two novel, specific CO-activators of POU2F3, named OCA-T1 and OCA-T2. OCA-T1-/- mice lack small intestinal tuft cells, demonstrate a quantifiable reduction in colonic tuft cells, and maintain tuft cells within the stomach. This phenotype incompletely pheno-copies POU2F3 deficiency; thus, my project seeks to close this GAP by investigating the role of OCA-T2 in tuft cell development in vivo. Specifically, i hypothesize that expression of OCA-T2 is required for the early development of tuft cells, due to its unique ability to establish a tuft cell-specific epigenome, which is maintained by OCA-T1 or OCA-T2 in a context-specific manner. We have generated two distinct OCA-T2-/- mouse models, which harbor germline knockout of either exon 1 or exon 2 of the gene encoding OCA-T2. Much like in OCA-T1 knockout, tuft cell staining of OCA-T2-/- mice shows a surprising loss of small intestinal and colonic tuft cells. These findings suggest distinct, essential functions of both OCA-T1 and OCA-T2 in the differentiation of intestinal tuft cells. Interestingly, RNA-fish staining revealed crypt-biased expression within the murine small intestine. I will characterize the physiology of intestinal and colonic inflammation in these mice (aim 1). The goal of this aim is to establish the distinct function of OCA-T2 in the gastrointestinal epithelium. Tuft cell-enriched single cell RNA-SEQ (scrnaseq) of the murine small intestinal epithelium has identified enriched OCA-T2 expression within a tuft cell progenitor population. In a POU2F3-naïve cell line context, lentiviral overexpression of OCA-T2 demonstrates a remarkable ability to drive transcription of a greater number of genes, and to a greater extent, than OCA-T1. Of note, OCA-T2 upregulates both POU2F3 and OCA-T1, whereas OCA-T1 fails to upregulate OCA-T2. To investigate this regulatory logic further, i will employ both EX vivo and in vitro transcriptomics and epigenomics (aim 2). The goal of this aim is to determine the functional specificity of the OCA-TS and evaluate changes in gene expression and chromatin state established and maintained by each CO-activator. This project will define the distinct role of the novel POU2F3 CO-activator OCA-T2 in the transcriptional regulation of tuft cell development, closing the GAP between OCA-T1-/- phenotypes and POU2F3-/- phenotypes. This understanding will open novel avenues for therapeutic intervention in chronic intestinal inflammation.

Quick answers

Who received award F31DK145216?

F31DK145216 was awarded to Cold Spring Harbor Laboratory by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on December 8, 2026.

How much is award F31DK145216 worth?

$34,114 has been obligated on F31DK145216.

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