# Epigenetic Modulation in Septic Immunosuppression

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $460,866

## Abstract

Project summary
A hallmark of septic immunosuppression is a reduced number of lymphocytes due to decreased lymphocyte
proliferation and increased cell death. A low lymphocyte count referred to as lymphopenia underscores a poor
prognosis for septic patients with lower bacterial clearance and second nosocomial infections and death.
Epigenetics modulates chromatin architecture to regulate immunity. Despite its importance, the role of
epigenetics in septic immunosuppression in terms of lymphopenia remains elusive. In this proposal, we identify
that bacteria-elevated Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine
Methyltransferase 1 (PRMT4/ CARM1) is critical for lymphopenia in sepsis; depletion of PRMT4 or inhibition of
PRMT4 may attenuate the bacteria-mediated lymphocyte death in cellular and mice models. Our preliminary
study shows that bacteria increase PRMT4 at protein level in murine and human lymphocytes. Bacteria reduce
an E3 ubiquitin ligase SCF-FBXO9 to promote PRMT4 protein stability and abundance in the cells that leads to
lymphocyte death. Depletion of PRMT4 or inhibition of PRMT4 with small molecule reduces bacteria mediated
lymphocyte death in cellular and mice septic models. These findings demonstrate an un-described role of a key
chromatin modulator PRMT4 in lymphocyte death that may shed lights on novel therapeutic avenue in septic
immunosuppression. Therefore, our central hypothesis is that bacteria elevates PRMT4 protein inhibiting its
SCF-Fbxo9 mediated proteasomal degradation that causes substantial lymphocyte death to lead
immunosuppression; thus inhibition of PRMT4 may attenuate bacteria-mediated lymphocyte death in septic
immuno-suppression. To explore this hypothesis we propose the following aims: (i) to determine if bacteria
derived endotoxin LPS elevates PRMT4 protein levels by reducing an E3 ubiquitin ligase SCF-Fbxo9; and (ii) to
study if elevated PRMT4 leads to substantial lymphocyte death thereby inhibition of PRMT4 may attenuate
bacteria-induced septic immunosuppression. These studies will establish the pathophysiological function of a
chromatin modulator, PRMT4, as a new effector in lymphocyte death in sepsis. These studies will expand the
conceptual groundwork for us to understand how epigenetic regulation plays a central role in the pathogenesis
of septic immunosuppression. These studies may serve as a springboard for translational approaches eventually
using small molecule therapeutics to target this immune modulator.

## Key facts

- **NIH application ID:** 10413821
- **Project number:** 5R01HL142997-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Chunbin Zou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $460,866
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413821

## Citation

> US National Institutes of Health, RePORTER application 10413821, Epigenetic Modulation in Septic Immunosuppression (5R01HL142997-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10413821. Licensed CC0.

---

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