# Role of Foxa2 in ligand-dependent activation of nuclear receptors

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $387,600

## Abstract

Project Summary/Abstract
 Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used
extensively in pharmacology to develop drug targets for diverse medical conditions, including
metabolic disease and cancer. While synthetic agonists and antagonists of nuclear receptors
ameliorate symptoms of many diseases, clinical use of these compounds leads to frequent side
effects that range in their severity. Type II receptors, such as FXR, LXR, and PPAR, which
function in fatty acid, bile acid, cholesterol, and glucose metabolism, are permanently positioned
in the nucleus regardless of the ligand status. The accepted paradigm regarding ligand activation
of type II receptors is a two-step process: 1) the receptor is bound to DNA in complex with a co-
repressor in absence of the ligand; 2) binding of the ligand induces a conformational change, co-
repressor/co-activator exchange, and initiation of transcription. However, we observe that
distribution of open chromatin sites changes upon ligand activation of nuclear receptors. In this
project, I hypothesize that pioneer factor Foxa2 modulates chromatin accessibility by evicting
nucleosomes to enable LXRα binding upon ligand activation, which challenges the accepted
paradigm.
 Considering current limitations to develop highly selective synthetic ligands for nuclear
receptors without significant side effects we propose that a genomic approach that separates LXR
targets into distinct regulatory modes characterized by chromatin state and presence/absence of
Foxa2 and LXRα binding sites will allow for genes with different physiological function to be
targeted separately. We will test whether Foxa2 and LXRα binding is interdependent during ligand
activation in Aim 1. We will ascertain the mechanism of Foxa2/LXRα interaction, discriminating
between three possibilities in Aim 2. LXR could play the role of a co-activator without binding
DNA, or both Foxa2 and LXRα need to be bound either in a proximal interaction or distal
interaction. Successful completion of our project will change current thinking regarding activation
of ligand-dependent gene expression and change the pharmacological approach to target nuclear
receptors essential to metabolism.

## Key facts

- **NIH application ID:** 11047348
- **Project number:** 7R01DK121059-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Irina Bochkis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,600
- **Award type:** 7
- **Project period:** 2020-01-10 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11047348

## Citation

> US National Institutes of Health, RePORTER application 11047348, Role of Foxa2 in ligand-dependent activation of nuclear receptors (7R01DK121059-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11047348. Licensed CC0.

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