Multi-omics profiling uncovers LINC00486-associated lncRNA regulation in human traumatic brain injury.

Abstract

Background: Traumatic brain injury (TBI) induces broad molecular changes in the human brain, altering gene expression in diverse neural and glial cells. While the transcriptional effects of TBI on protein-coding genes are well characterized, the roles of long noncoding RNAs (lncRNAs), key regulators of gene expression and chromatin, remain largely unknown.

Objective: Our objective was to identify lncRNAs altered in TBI and explore their potential regulatory functions.

Methods: We applied an integrative multi-omics approach combining single-nucleus RNA sequencing (snRNA-seq), isoform-level transcriptomics, transposable element (TE) annotation, and RNA-binding protein (RBP) interaction analyses. Public snRNA-seq datasets from cortical tissues of 12 TBI patients and 5 controls were analyzed to resolve injury-driven transcriptional signatures. We have performed differential expression analysis on 12,801 human lncRNAs, examined isoform-specific expression with TE content, and explored RBP-lncRNA interactions using CLIP-seq data.

Results: Cell-type diversity decreased in TBI, and reactive and progenitor-like states were expanded. We identified 190 upregulated lncRNAs, mainly in glial cells. Among these, LINC00486 emerged as a brain-enriched lncRNA consistently increased after TBI. Isoform analysis showed its dominant brain isoform contains LINEs and LTRs, linking it to regulatory networks associated with endogenous retroelement activation. Functional enrichment connected LINC00486 to neurodevelopment, serotonin metabolism, and neuroinflammatory pathways. CLIP-seq data confirmed its interactions with stress-responsive RBPs such as AGO2 and TARDBP.

Conclusions: Our multi-omics analysis identifies LINC00486 as a potential regulator of transcriptional plasticity in TBI. Its TE content and RBP interactions suggest a role in lncRNA-mediated regulatory networks during injury, highlighting possible therapeutic targets in neurotrauma.