# Uncovering the Regulatory Mechanisms of the Fork Head Transcription Factor

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $49,774

## Abstract

PROJECT SUMMARY/ABSTRACT
The winged-helix DNA-binding FoxA transcription factors (TFs) play major roles in the development and
homeostasis of many organs. Importantly, FoxA proteins are expressed early and continuously in many tissues
and are essential both during development and postnatally for morphogenesis, glucose metabolism, and
expression of multiple organ-specific genes. Mutations in FoxA proteins are linked to cancer in multiple tissue
types (including the salivary gland), developmental defects that result in Parkinson-like phenotypes, and glucose
dysregulation, causing hypoglycemia. However, the identity of the downstream effectors and the extent of
coordination of FoxA proteins with other TFs to accomplish morphogenesis and regulate metabolic function are
largely unknown. Identifying these downstream effectors and their mechanistic nuances becomes possible by
studying the single Drosophila orthologue Fork head (Fkh) that represents all three FoxA members: FOXA1,
FOXA2, and FOXA3. Like FoxA proteins in vertebrates, Fkh is required for morphogenesis and maintenance of
organs in Drosophila, including the embryonic salivary gland (SG). In addition to its role in organ formation, Fkh
is known to coordinate with two other TFs, Sage and Senseless (Sens), to maintain SG viability and to regulate
the “secretome” – the collection of secreted products made by the SG. By performing ChIP-sequencing in parallel
with scRNA-sequencing followed by computational analysis, we will uncover the mechanistic details of how Fkh
coordinates with Sage and Sens to regulate the secretome (Aim 1). Furthermore, I will use our computational
analysis to identify candidate partner TFs of Fkh to then perform a mutational screen and look for morphological
phenotypes to characterize possible co-regulators of Fkh for morphogenesis (Aim 2). Through these proposed
experiments in Aims 1 and 2, the mechanistic details of how Fkh coordinates with Sage and Sens to regulate
the secretome can be elucidated while uncovering and characterizing co-regulators of Fkh for morphogenesis.
In addition to controlling organ form and function, FoxA family proteins also play a role in metabolism. Currently,
the SG is not known to have any metabolic roles but recent findings from our lab and others indicate that the SG
secretome may have additional endocrine functions related to systemic growth. In Drosophila, salivary gland
secreted factor (Sgsf) has been discovered as a SG secreted peptide that acts upon the AKT-MTOR pathway to
ultimately affect systemic growth. By studying Fkhs role in regulating secreted factors from the SG, the novel
function of the SG acting as endocrine organ can be further understood. To study this, I will utilize the biotinylating
enzyme BirA*G3 in conjunction with mass spectrometry and confocal imagery to explore the potential secretion
of metabolites from the SG. Candidate metabolites identified through these will then be tested for metabolic
consequences within both...

## Key facts

- **NIH application ID:** 10996811
- **Project number:** 1F31DE034305-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Nathaniel Laughner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,774
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996811

## Citation

> US National Institutes of Health, RePORTER application 10996811, Uncovering the Regulatory Mechanisms of the Fork Head Transcription Factor (1F31DE034305-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996811. Licensed CC0.

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