Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.

Overview

1. Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, SC711 Sparks Center 1720 7th Avenue South, Birmingham, AL 35294 USA

Abstract

Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein–protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13041-026-01304-3.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32494623, at figshare; found in DataCite
• figshare:32494626, at figshare; found in DataCite
• figshare:32494629, at figshare; found in DataCite
• figshare:32494632, at figshare; found in DataCite
• figshare:32494635, at figshare; found in DataCite
• figshare:32494638, at figshare; found in DataCite
• figshare:32494641, at figshare; found in DataCite
• figshare:32494644, at figshare; found in DataCite
• figshare:32494647, at figshare; found in DataCite

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 keywords, 14 MeSH terms, 1 funder, 87 references.

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This paper

Verma, A. K., Roy, B., Prall, K., Hulwi, E., & Dwivedi, Y. (2026). Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats. Molecular brain, 19(1), 43. https://doi.org/10.1186/s13041-026-01304-3

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