# Protein Arginine Methyltransferases in γ-Globin Regulation and Sickle Cell Disease: Emerging Connections to Oxidative Stress

## TL;DR

This paper explores how protein arginine methyltransferases (PRMTs) influence γ-globin expression and fetal hemoglobin in sickle cell disease, linking oxidative stress to potential new therapies.

## Contribution

The paper introduces a novel framework connecting oxidative stress signaling to PRMT activity in regulating fetal hemoglobin expression in sickle cell disease.

## Key findings

- PRMTs regulate γ-globin expression through transcriptional repression and post-transcriptional control.
- Oxidative stress signaling may modulate PRMT activity, linking cellular stress to fetal hemoglobin induction.
- PRMT-dependent pathways are proposed as a therapeutic target for sickle cell disease and β-hemoglobinopathies.

## Abstract

Reactive oxygen species (ROS) are unavoidable byproducts of cellular metabolism and are normally controlled by tightly regulated antioxidant systems. Red blood cells (RBCs) are particularly susceptible to oxidative stress due to their high oxygen exposure and iron content. In sickle cell disease (SCD), this vulnerability is exacerbated, as sickled RBCs generate chronically elevated ROS that contribute directly to disease pathophysiology. This review examines emerging evidence linking oxidative stress responses to regulation of fetal hemoglobin (HbF) expression through protein arginine methyltransferases (PRMTs). PRMTs catalyze arginine methylation of histone and non-histone substrates, thereby shaping chromatin structure, transcriptional programs, and translational control. We highlight recent findings demonstrating that specific PRMTs regulate γ-globin expression through distinct mechanisms, including transcriptional repression at the β-globin locus and post-transcriptional control of γ-globin mRNA translation. We propose that oxidative stress signaling may modulate PRMT activity, creating a mechanistic link between cellular stress responses and HbF induction. Because HbF inhibits pathological hemoglobin S polymerization, PRMT-dependent pathways represent an attractive therapeutic axis for SCD and related β-hemoglobinopathies. By integrating oxidative stress biology with PRMT-mediated epigenetic and translational regulation, this review outlines a unifying framework for HbF control, identifies critical knowledge gaps, and highlights future directions for the development of targeted epigenetic therapies.