Background: Long non-coding RNA taurine-upregulated gene 1 (TUG1) is involved in various cellular processes, but its role in cerebral ischemia–reperfusion injury remains unclear. This study investigated TUG1’s role in regulating the nucleocytoplasmic shuttling of human antigen R (HuR), a key apoptosis regulator under ischemic conditions. Methods: CRISPR-Cas9 technology was used to generate TUG1 knockout Sprague Dawley rats to assess TUG1’s impact on ischemic injury. The infarct area and neuronal apoptosis were evaluated using TUNEL, hematoxylin and eosin (HE), and TTC staining, while behavioral functions were assessed. Immunofluorescence staining with confocal microscopy was employed to examine TUG1-mediated HuR translocation and expression changes in the apoptosis-related proteins COX-2 and Bax. Results: TUG1 knockout rats showed significantly reduced cerebral infarct areas, decreased neuronal apoptosis, and improved neurological functions compared to controls. Immunofluorescence staining revealed that HuR translocation from the nucleus to the cytoplasm was inhibited, leading to decreased COX-2 and Bax expression levels. Conclusions: TUG1 knockout reduces ischemic damage and neuronal apoptosis by inhibiting HuR nucleocytoplasmic shuttling, making TUG1 a potential therapeutic target for ischemic stroke.

The inhibitor of growth (ING) family of proteins is emerging as a pivotal regulator of epigenetic modifications within the nervous system. These proteins are involved in various cellular processes, including apoptosis, cell cycle control, and DNA repair, through interactions with chromatin-modifying complexes. Recent studies underscore the dual role of ING proteins in both tumor suppression and neuronal differentiation, development, and neuroprotection. This review summarizes the epigenetic functions of ING proteins in neurobiology, with a focus on their involvement in neural development and their relevance to neuro-oncological diseases. We explore the mechanisms by which ING proteins influence chromatin state and gene expression, highlighting their interactions with histone acetyltransferases, deacetylases, histone methyltransferases, DNA modification enzymes, and non-coding RNAs. A deeper understanding of the role of ING proteins in epigenetic regulation in the nervous system may pave the way for novel therapeutic strategies targeting neurological disorders.

Circular RNAs (circRNAs) are novel class of stable regulatory RNAs abundantly expressed in the brain. However, their role in fear extinction (EXT) memory remains largely unexplored. To investigate the mechanisms of Circular Special AT-rich Sequence Binding Protein 2 (circSatb2) in EXT memory, we constructed a lentivirus overexpressing circSatb2 and injected it into the infralimbic prefrontal cortex (ILPFC) of the mouse brain. Following extinction training and subsequent testing, we observed an essential role of circSatb2 in this dynamic process. RNA sequencing (RNA-seq) and bioinformatics analyses revealed that circSatb2 enhances the transcription of Roundabout Guidance Receptor 3 (Robo3), a key gene implicated in axon guidance and synaptic plasticity, which was validated by RT-qPCR. Neuronal morphology was assessed using confocal microscopy to determine changes in dendritic spine density. Our results demonstrated that circSatb2 significantly enhances Robo3 transcription, leading to increased dendritic spine formation and improved synaptic plasticity. In conclusion, circSatb2 promotes the formation of EXT memory by upregulating Robo3 transcription and enhancing synaptic plasticity. These findings position circSatb2 as a potential therapeutic target for disorders associated with memory impairment.

Background: The precise role of RNA modification in post-traumatic stress disorder (PTSD) remains incompletely understood. This study aims to elucidate the effects of five common RNA modifications in PTSD, specifically m⁶A, m⁵C, m¹A, m⁷G, and ψ. Methods: We extracted data from the GEO repository to conduct a series of bioinformatics analyses. These included differential analysis to identify key regulators of five common RNA modifications, model construction using random forest (RF), least absolute shrinkage and selection operator (LASSO), and nomogram techniques, as well as consensus clustering of RNA modification subtypes. Furthermore, GO enrichment analysis was performed on DEGs associated with various RNA modification patterns. Immune cell infiltration was assessed using PCA and ssGSEA. RT-qPCR was performed to validate RNA modification-related genes (RMGs). Results: Twenty-one differentially expressed RMGs were identified. LASSO and RF intersection yielded eight signature genes (YTHDC1, IGFBP1, IGF2BP1, ALKBH5, NSUN4, TET2, TET3, WDR4) that robustly diagnosed PTSD (AUC = 0.804). Furthermore, these feature genes were validated using RT-qPCR, which was basically consistent with the results of bioinformatics analysis. Consensus clustering analysis may reveal two distinguishable subtypes: clusterA marked by high immunoinflammation, and clusterB characterized by high-neuroendocrine dysregulation. Conclusions: RMGs may play a crucial role in the pathogenesis of PTSD. Analyzing RNA modification patterns could offer potential diagnostic markers and help to guide immunotherapeutic approaches or neurotransmitter system interventions for PTSD in the future.

Background: Aging is recognized as the key risk for intracerebral hemorrhage (ICH). The detailed mechanisms of aging in ICH warrant exploration. This study aimed to identify potential aging-related genes associated with ICH. Methods: ICH-specific aging-related genes were determined by the intersection of differentially expressed genes (DEGs) between perihematomal tissues and corresponding contralateral parts of four patients with ICH (GSE24265) and 349 aging-related genes obtained from the Aging Atlas database. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses were performed to identify the potential biological functions and pathways in which these ICH-specific aging-related genes may be involved. Then, PPI network was established to identify the hub genes of ICH-specific aging-related genes. Meanwhile, miRNA-mRNA and transcription factor (TF)-mRNA regulatory networks were constructed to further explore the ICH-specific aging-related genes regulation. The relationship between these hub genes and immune infiltration was also further explored. Additional single-cell RNA-seq analysis (scRNA-seq, GSE167593) was used to locate the hub genes in different cell types. Besides, expression levels of the hub genes were validated using clinical samples from our institute and another GEO dataset (GSE206971). Results: This study identified 24 ICH-specific aging-related genes, including 22 up-regulated and 2 down-regulated genes. The results of GO and KEGG suggested that the ICH-specific aging-related genes mainly enriched in immunity and inflammation-related pathways, suggesting that aging may affect the ich pathogenesis by regulating inflammatory and immune-related pathways. Conclusion: Our study revealed 24 ICH-specific aging-related genes and their functions highly pertinent to ICH pathogenesis, providing new insights into the impact of aging on ICH.

Purpose: Anxiety disorders are highly heritable, but their underlying genetic mechanisms remain poorly understood. This study aimed to identify and functionally characterize genes whose expression is causally linked to anxiety disorder risk by integrating the parallel single-tissue genetic data. Methods: We applied a parallel single-tissue summary-data-based Mendelian randomization (SMR) approach. This integrated large-scale anxiety disorder GWAS statistics with expression quantitative trait loci (eQTL) data from peripheral blood and 13 brain regions. The functional impact of a prioritized SNP (rs4494021) was tested via dual-luciferase reporter assay. The behavioral consequences were investigated by performing stereotaxic, lentivirus-mediated overexpression of ARRDC1 specifically in the mouse cerebellar hemisphere, followed by comprehensive behavioral testing. Results: The SMR analysis identified thirteen potential causal genes (ITIH3, ZKSCAN4, GNL3, SLC35C1, FNBP4, COPZ1, ATP5MC1, ITIH4, EHMT1, PTPMT1, ARRDC1, NEK4, and BTN3A2). Among them, ARRDC1 emerged as a significant gene, showing associations with anxiety disorders in blood, cerebellar hemisphere, and cerebellum. The risk allele of the promoter SNP rs4494021 significantly enhanced ARRDC1 transcriptional activity. Crucially, cerebellar overexpression of ARRDC1 in mice robustly induced anxiety-like behaviors, including reduced exploration in the open field test, decreased open-arm activity in the elevated plus maze, and increased avoidance in the light-dark box test. Conclusion: By bridging genetic epidemiology with molecular and behavioral validation, this study identifies ARRDC1 promoter SNP rs4494021 as a genetically associated marker for anxiety disorders and functionally validates that elevated cerebellar ARRDC1 expression contributes to anxiety pathogenesis. These findings establish ARRDC1 as a functionally supported risk gene and highlight a novel component of anxiety-related neurocircuitry.