# PPARgamma as an architectural regulator of gene expression in endocrine signaling

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

PROJECT SUMMARY
The canonical view of Nuclear Hormone Receptors (NHRs) is that these are ligand-activated transcription
factors acting as DNA-bound, lipid-controlled genomic switches. A group of NHRs are acting as heterodimers
with the obligate heterodimeric partner Retinoid X Receptor (RXR). One of the key partners of RXR is the
Peroxisome Proliferator-Activated Receptor gamma (PPAR). PPAR is viewed as a modified fatty acid and
prostanoid regulated transcription factor essential for fat cell differentiation and contributing to lipid metabolite
induced transcriptional regulation in many cell types including macrophages. Using traditional ligand centric
approaches, we and others were able to identify PPAR target genes and ligand regulated processes including
cholesterol uptake and efflux, inhibition of inflammatory responses, regulating insulin sensitivity and promoting
tissue repair in macrophages cells. These findings make this receptor a key endocrine regulator of metabolism
and inflammation in this cell type. A major weakness of prior research was that it focused solely on ligand-
dependent activities of the receptors and did not consider ligand-independent ones. Therefore, there is a
substantial gap in our understanding of receptor biology and action. Recent genome-wide determinations of
binding sites identified at least two orders of magnitude more genomic binding sites in fat cells and
macrophages as regulated genes would necessitate. This prompted us to explore PPAR:RXR cistromes in
alternatively polarized macrophages. We have gathered preliminary evidence to suggest that (1) The
macrophage PPARγ:RXR cistrome is greatly extended upon IL-4 polarization directed by STAT6; (2)
Chromatin-bound PPARγ is predominantly ligand-insensitive in alternatively polarized macrophages; (3)
PPARγ:RXR heterodimers are architectural elements of the genome, and (4) the heterodimer confers
transcriptional memory via retained gene-enhancer looping. This allows us to formulate new hypotheses as
follows: A large fraction of PPAR:RXR heterodimers is ligand-insensitive; (a) Contributing to the epigenome of
IL-4 polarized macrophages and provides links between enhancers and promoters via looping utilizing the
cohesin complex and/or CTCF; (b) Establishes transcriptional cellular memory and (C) Contributes to
macrophage tissue-specification and transcriptional adaptation. We are proposing to test these at three levels.
At the chromatin and genome folding level we will determine the epigenomic roles for PPAR. At the cellular
level we will determine the role PPAR plays in opening of chromatin and transcriptional memory. Finally at the
in vivo level, contribution of PPAR to lung macrophage function and response to viral infection will be explored.
The results will likely open up new avenues of research into the epigenomic programming of macrophages with
translational potential in chronic inflammatory and metabolic disease and tissue regeneration.

## Key facts

- **NIH application ID:** 9978820
- **Project number:** 5R01DK115924-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laszlo Nagy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978820

## Citation

> US National Institutes of Health, RePORTER application 9978820, PPARgamma as an architectural regulator of gene expression in endocrine signaling (5R01DK115924-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978820. Licensed CC0.

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