This review systematically examines the architectural and functional landscape of transposable element (TE)-derived chimeric RNAs, classifying them into three major categories: TE–coding gene chimeras, TE–lncRNA chimeras and TE–TE chimeras. We delineate four potential molecular mechanisms contributing to their biogenesis: transcriptional read-through coupled with cis-splicing, promoter hijacking by TE-derived regulatory elements, trans-splicing of independent transcripts and epigenetic regulation of TE genomic loci. Functionally, TE and their chimeric RNAs can coordinately participate in genomic regulation at different levels: they remodel native gene expression patterns via alternative promoters, introduce novel functional domains into proteins and lncRNAs, and form integrated transcriptional regulatory networks. These chimeric transcripts exert critical roles in early embryonic development, stem cell potency, differentiation or pathogenic condition. Looking forward, long-read sequencing and genomic targeting technologies hold great promise to unravel the functionality and therapeutic application of TE-derived chimeric RNAs. Collectively, this review establishes TE-derived chimeric RNAs as fundamental drivers of transcriptomic innovation, evolutionary adaptation and disease aetiology, bridging basic genome biology with physiology and clinical translation.
Chemical modifications of RNA bases and adenosine-to-inosine (A-to-I) editing are regulatory layers essentially unexplored in the retinal pigment epithelium (RPE), whose oxidative dysfunction underlies age-related macular degeneration. We mapped both layers in ARPE-19 cells exposed to tert-butyl hydroperoxide under two non-pharmacological interventions, Quantum Molecular Resonance (QMR) electrotherapy and a patient blood-derived secretome, across 56 libraries spanning four arms, three time points and matched stressed and stress-free conditions (GEO: GSE328981). Base modifications were called with HARMLNC and A-to-I editing screened with a transition-signal caller, then re-analysed with REDItools3, JACUSA2 and LoDEI. The high-confidence set comprised 241 calls at 15 sites, all of classes canonical to tRNA and rRNA. The most prevalent was an adenosine modification at chrM:2617 in mitochondrial 16S rRNA (MT-RNR2), detected in 51 of 56 libraries and in every arm. Two positions 1 bp apart lie in an EZR/SYTL3 overlap region, whereas a third chromosome 6 site maps to HLA-C, 127.5 Mb away. No position of either layer differed between treatment arms: 7 testable modification sites (minimum p = 0.19) and, at single-nucleotide resolution under dedicated callers agreeing to r = 0.975–0.992, 15 curated editing positions (minimum q = 0.169). Two one-sided tests bound any change in substitution composition within 1.4% and in mean editing frequency within 10% for secretome and combination and 20% for QMR. Against a stress-free baseline internal to the cohort, only chrM:13710 (MT-ND5) changed detectably (q = 0.03). These layers are therefore small, largely constitutive and quantifiably undisturbed by either intervention at the resolution available.
SARS-CoV-2 infection causes diverse clinical outcomes, with men facing higher risks of severe disease. Adenosine-to-inosine (A-to-I) RNA editing mediated by ADAR enzymes governs innate antiviral immunity, yet its contribution to COVID-19 severity and sex-biased disease remains unclear. We performed epitranscriptomic profiling on 126 blood samples from non-COVID controls and COVID-19 patients spanning different disease severities. We detected 1,466 differentially RNA-edited sites in 514 genes linked to clinical outcomes. Although ADAR expression increased in COVID-19 patients overall, it was strongly reduced in ICU patients compared with non-ICU patients, and this shift was far more prominent in males. This severity-associated and sex-biased ADAR/ADARB1 downregulation coincided with decreased global RNA editing and perturbed expression of immune-related edited transcripts. Cathepsin S (CTSS) was identified as a central regulatory node: elevated A-to-I editing within its 3’ UTR in ICU patients stabilizes CTSS mRNA. Without stratifying by disease severity, ADAR expression and global editing showed no significant sex differences; the large sex divergence only appeared among ICU patients. This indicates severity-dependent, not infection-innate, disruption of A-to-I editing, disproportionately amplified in critically ill males. CTSS 3’UTR editing may serve as a biomarker for patient stratification, revealing a mechanistic connection between epitranscriptomic changes and male-biased severe COVID-19.
The proteostasis network maintains cell function by safeguarding the proteome through the coordinated actions of protein synthesis, quality control, and degradation machinery including chaperones and the ubiquitin-proteasome system. Proteostasis collapse and activation of the integrated stress response (ISR) occur in ageing and neurodegeneration. Upon proteotoxic stress, translation suppression during the ISR drives the assembly of non-translating mRNAs into biomolecular condensates called stress granules. Stress granules act as a double-edged sword in the proteostasis network, serving beneficial or detrimental roles through their effects on translation, protein quality control, and protein aggregation. In this review, we discuss how protein synthesis, quality control, and degradation factors regulate stress granule dynamics, and conversely how stress granules impact proteostasis. While stress granules may initially protect cells by sequestering misfolded, aggregation-prone proteins and regulating translation, they may evolve into sites of pathological aggregation. Clarifying these intersections may reveal therapeutic strategies for neurodegeneration and other disease processes.
Circular RNAs (circRNAs) are covalently closed RNA molecules with increasingly recognized roles in post-transcriptional gene regulation, immune signalling, and host–pathogen interactions. Although circRNAs have been characterized across diverse biological contexts, their roles in viral infection, particularly HIV-1, remain an underexplored area of RNA biology. Here, we review current knowledge of circRNA function in HIV-1 infection, organized into three major themes. First, we examine host-derived circRNAs, which are broadly dysregulated during infection and correlate with viral load, immune status, and antiretroviral therapy response. Second, we discuss viral-derived circRNAs, highlighting emerging evidence that HIV-1 encodes functional circRNA isoforms capable of modulating viral replication and transcription. Finally, we review synthetic circRNA-based approaches that exploit key viral RNA–protein interactions as potential antiviral tools. Collectively, these findings underscore the expanding functional roles of circRNAs in HIV-1 infection and highlight their potential as both therapeutic targets and molecular tools for future research.
