# Multifaceted Regulation of Mineralocorticoid Receptor Transcriptional Activities

> **NIH NIH R35** · EMORY UNIVERSITY · 2024 · $388,228

## Abstract

Project Summary
Transcription factors (TFs) recognize specific DNA sequences and recruit coregulators including chromatin
modification enzymes to direct gene expression. The human nuclear receptor (NR) family includes 48 TFs that
play crucial roles in a number of biological processes including metabolism, reproduction, and inflammation.
The NRs share a highly disordered N-terminal domain (NTD), and two folded domains: a DNA-binding domain
(DBD) and a C-terminal ligand binding domain (LBD), connected by a small unstructured hinge region. Despite
numerous studies focusing on the individual LBD and DBD, how ligands elicit full-length NR activities remains
elusive with massive knowledge gaps in the roles of NTD and allostery between DBD and LBD. The long-term
goal of the laboratory is to develop the molecular-level understanding of the mechanism underlying the NR
transcriptional activity. We will use mineralocorticoid receptor (MR) as an exemplary member in this proposal.
MR is highly expressed in the renal distal nephron epithelial cells and plays critical roles in fluid and electrolyte
homeostasis. It is also expressed in non-epithelial tissues such as heart, vasculature, brain, adipose and liver
tissues. Overactivation of MR in these tissues leads to increased inflammation, fibrosis and oxidative stress.
MR antagonist have shown great promise as therapies for cardiovascular and renal disease. However, their
development is severely lagging compared to others targeting MR homologs such as glucocorticoid, androgen
and estrogen receptors. Detailed studies of each domain, including the least understood, intrinsically
disordered NTD, and how these domains cooperate with each other in the full-length MR is highly required for
the deeper understanding of MR activity regulation. The focus of this proposal will be on: 1) determine how
NTD and hinge region regulate MR transcription by forming biomolecular condensates and 2) determine how
the interdomain and intradomain allostery tune the MR-mediated transcription. An integration of biophysical
approaches with structural biology and phase separation studies, as proposed here, is essential to decipher
this highly dynamic and disordered system. While being fundamentally important to our understanding of MR
activity controlling gene transcription, our results can guide the future development of MR antagonist targeting
various diseases caused by dysfunctional MR activities.

## Key facts

- **NIH application ID:** 10941132
- **Project number:** 1R35GM155032-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Xu Liu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,228
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941132

## Citation

> US National Institutes of Health, RePORTER application 10941132, Multifaceted Regulation of Mineralocorticoid Receptor Transcriptional Activities (1R35GM155032-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10941132. Licensed CC0.

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