ARID5A RNA-binding coordinates microglial defense and ferroptosis in iPSC-derived models.
Danielle M Schafer, Steven M Blue, Shuhao Xu, Orel Mizrahi, Maya L Gosztyla, Lena Street, Katherine L Rothamel, Hema Kopalle, Samuel B Landry, Elijah Khalil F Rosales, Rebecca H Tien, Sara Elmsaouri, Nicole G Coufal, Marko Jovanovic, Gene W Yeo
Nature communications · 2026 · Vol. 17 (1)
Abstract
RNA-binding proteins (RBPs) are key regulators of gene expression that shape cellular function in health and disease. However, the roles of RBPs in immune cells within the central nervous system (CNS) remain poorly understood. Here, we identify ARID5A as an RBP highly expressed in microglia and uncover its RNA-mediated regulatory functions using integrated multi-omics analyses of its RNA, DNA, and protein interactions. ARID5A regulates the splicing and translation of its RNA targets, many of which are integral to lysosomal, immune, and iron metabolism pathways. We confirm the functional relevance of this ARID5A-dependent RNA regulatory network by demonstrating that ARID5A modulates lysosomal activity, cytokine secretion, iron accumulation, and ferroptosis in iPSC-derived microglia. We further demonstrate that knockdown of microglial ARID5A reduces neuronal ferroptosis in co-cultures, underscoring the interconnected nature of these pathways. Moreover, in microglia harboring the TREM2-T66M mutation, ARID5A depletion restores dysregulated lysosomal and metabolic functions. Our results highlight the importance of protein-RNA interactions in regulating microglial cell biology.
Potentially related datasets 6
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| GSE328331 | GSE · GEO GEO ↗ | Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [RIP-Seq] |
| GSE290625 | GSE · GEO GEO ↗ | Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [eclip] |
| GSE73721 | GSE · GEO GEO ↗ | RNA-Seq of human astrocytes |
| GSE290755 | GSE · GEO GEO ↗ | Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [rna-seq] |
| GSE290765 | GSE · GEO GEO ↗ | Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [cutnrun] |
| MSV000097123 | MASSIVE · MassIVE | No title in the index |
Funding 7 grants
| Grant | Funder |
|---|---|
| U24 HG009889 | NHGRI NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| RF1 MH126719 | NIMH NIH HHS (United States) |
| R01 HG011864 | NHGRI NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| HG011864 | U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
| MH126719 | U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) |