# Homeostatic control of intestinal stem cell renewal by two transcriptional coactivators

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Mechanisms that integrate local and systemic cues to precisely regulate stem-cell based tissue renewal remain
unclear, particularly in the rapidly cycling gastrointestinal (GI) epithelium. A pair of transcriptional coactivator
proteins that promote growth and intestinal stem cell renewal – the Hippo pathway protein YAP1 and the nuclear
receptor (NR) interactor NCOA3 – are each implicated in the progression of colorectal cancers. Both of these
factors have orthologs in the common fruit fly, D. melanogaster, which combines robust fertility, rapid generation
time, a relatively simple genome, and an extensive genetic toolbox to make this system a powerful model to
investigate gut renewal mechanisms. Components of the mammalian Hippo and NR pathways have homologs
in D. melanogaster, including the nuclear coactivator proteins Yorkie (Yki; YAP1 in humans) and Taiman (Tai;
nuclear receptor coactivator-3, NCOA3 in humans). Prior studies established that (i) Yki and Tai physically
interact through respective WW (tryptophan-tryptophan) domains and PPxY (proline-proline-x-tyrosine) motifs,
(ii) Tai modulates Yki-driven overgrowth of fly larval epithelia, and (iii) Tai and Yki each play a role in intestinal
stem cell (ISC) proliferation. Based on this and other evidence, we hypothesize that the cooperativity of the
Tai/NR and Yki/Hippo complex regulates ISC renewal by activating a unique set of target genes distinct from
canonical Tai/NR or Yki/Hippo targets. We generated a critical tool to test this hypothesis: a CRISPR mutant fly
stock in which the PPxY motifs of endogenous Tai are converted to PPxA, blocking Tai’s binding to Yki. These
viable homozygous mutants (taiPPxA/taiPPxA) allow precise and selective decoupling of the Tai/NR and Yki/Hippo
pathways in vivo. This proposal will investigate how Hippo and NR signaling converge on the Yki-Tai interaction
to activate transcription of genes required for gut renewal using D. melanogaster midgut as a model via the
following specific aims: Aim 1 will define the distribution of intestinal cell types and mitotic activity in taiPPxA/taiPPxA
mutant and control flies following acute intestinal injury; Aim 2 will define effects of taiPPxA on gene expression
and chromatin accessibility during intestinal renewal to identify Yki-Tai target genes that are activated during
injury induced ISC renewal. The findings of this study will provide insight into how two systemic signaling
pathways, Hippo and NR, converge on their downstream transcriptional targets, Yki/YAP1 and Tai/NCOA3, to
regulate local ISC-dependent tissue renewal.

## Key facts

- **NIH application ID:** 10997769
- **Project number:** 1F31DK139740-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Victoria Placentra
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997769

## Citation

> US National Institutes of Health, RePORTER application 10997769, Homeostatic control of intestinal stem cell renewal by two transcriptional coactivators (1F31DK139740-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997769. Licensed CC0.

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