# Sox Proteins Modulate Genomic Specificity of B-catenin Regulated Transcription in the Developing Gut

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $557,134

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal will test the hypothesis that SOX transcription factors (TFs) modulate the genomic
specificity of Wnt/Beta-catenin (BCAT) mediated transcription in early gut development and determine
the underlying molecular mechanisms. Wnt signaling regulates gene expression in digestive system
development, homeostasis and disease, where it is an important therapeutic target. While the core Wnt
transcriptional machinery is well studied, how cell-specific target genes are selected remains one of the most
important unresolved issues in the field. Current dogma is that canonical Wnt stabilizes cytoplasmic BCAT, which
translocates to the nucleus and interacts with one of four TCF/LEF HMG-box TFs to stimulate transcription.
However, all TCFs bind to nearly identical consensus sites indicating they alone cannot account for the diversity
of transcriptional responses. Using the complementary advantages of Xenopus embryos and differentiating
human pluripotent stem cells (hPSC), we have accumulated compelling evidence that SOX HMG-box TFs
modulate the genomic specificity of Wnt/BCAT-mediated transcription during early gut development. Our
preliminary ChIP-seq data and functional analyses suggests that different SOX TFs can recruit BCAT to distinct
enhancers in a tissue specific manner. On some enhancers SOX and BCAT synergistically activate transcription
independent of TCFs. Other enhancers appear to be co-occupied by SOX, BCAT and TCFs, suggesting tertiary
complexes where SOX and TCF might cooperate or compete to bind DNA and BCAT to activate or represses
transcription. These data suggest novel regulatory mechanisms and indicate that SOXs may be wide-spread
unappreciated factors regulating Wnt responses. We propose to test this hypothesis with the following aims:
Aim 1: Test the hypothesis that SOXs regulate the genomic recruitment of BCAT to lineage specific enhancers.
Aim 2: Determine how Sox17 and Bcat coregulate Wnt-responsive enhancers to control spatially restricted
 transcription in the embryo.
Aim 3: Determine the biochemical mechanisms by which SOX-BCAT-TCF complexes interact on DNA.
These studies will reveal the SOX-BCAT regulated GRN of gut development and provide a new paradigm
for how cell-specific Wnt-mediated transcription is regulated in development and disease.

## Key facts

- **NIH application ID:** 10328965
- **Project number:** 5R01DK123092-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Aaron M Zorn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $557,134
- **Award type:** 5
- **Project period:** 2021-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328965

## Citation

> US National Institutes of Health, RePORTER application 10328965, Sox Proteins Modulate Genomic Specificity of B-catenin Regulated Transcription in the Developing Gut (5R01DK123092-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328965. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*