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

Award Number: F31DK145216
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/08/2026
PERIOD OF PERFORMANCE END DATE: 12/07/2027

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Establishing the function of POU2F3 co-activator OCA-T2 in tuft cell development - PROJECT SUMMARY 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $34,114 )
2026	2026	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/8/2026	NEW	$34,114
														Subtotal = $34,114

Grand Total All Awards = $34,114

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

Award Number: F31DK145216

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/08/2026

PERIOD OF PERFORMANCE END DATE: 12/07/2027

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