RNA Biology最新文献

Co-translational mRNA decay occurs when 5'to3' exonucleases follow the last translating ribosome, generating in vivo ribosome protected fragments. Degradome sequencing (5PSeq)therefore offers unique insights into ribosome dynamics. Despite its potential, resources for systematic analysis of 5'P mRNA decay intermediates and associated features, such as ribosome stalls and collisions, are scarce. We introduce 5PSeq Explorer, a web-based platform built from 773 uniformly processed 5PSeq datasets across 23 species in bacteria and Ascomycota suitable for exploring ribosome dynamics in vivo at codon, amino acid, and transcript levels. By integrating normalized counts, structured metadata, and scalable visualization tools, 5PSeq Explorer provides a framework for studying the crosstalk between mRNA decay and ribosome dynamics. To ensure reproducibility and accessibility, we offer both a public web interface and a Docker-based plug-and-play local version. URL: https://fivepseq-explorer.serve.scilifelab.se/app/fivepseq-explorer.

microRNAs (miRNAs) are endogenous ~22 nucleotide long, non-coding RNAs that post-transcriptionally regulate gene expression. During miRNA biogenesis, stem-loop-containing miRNA precursors are enzymatically cleaved to form a small RNA duplex. Cleavage positions are determined based on the position of structural motifs and junctions on the stem-loop precursor. The duplex end containing a favourable 5' nucleotide and lower thermodynamic stability is subsequently loading into an Argonaute protein. Typically, one duplex (guide) strand is retained in Argonaute and becomes functional whereas the other (passenger) strand is degraded. Therefore, accurate structural predictions of miRNA intermediates and quantification of duplex end stabilities are important towards understanding miRNA biogenesis. Here, we compiled predicted secondary structures for all Caenorhabditis elegans miRNA hairpins and duplexes at physiologically relevant temperatures. We developed a new approach to calculate the thermodynamic stability of miRNA duplex ends, which resulted in improved predictions of miRNA strand selection. Our approach introduces hard constraints to folding algorithms to restrict base-pairing of terminal nucleotides, which improves modelling of in vivo duplex end unwinding. We propose that constrained RNA folding can be used to evaluate local stabilities within an RNA secondary structure.

RNA biology is undergoing a transformative revolution driven by AI foundation models. These models learn the intricate relationships between RNA sequence, structure, and function by training on vast, diverse datasets spanning millions of RNA molecules across various species. Through self-supervised learning on these sequences, these models acquire a generalizable understanding of RNA, which can then be fine-tuned for various downstream tasks, thereby enabling the decoding of functional rules embedded in RNA sequences. In this review, we provide a comprehensive guide to RNA foundation models. Using concrete examples of RNA biology, we begin with the concept of foundation models and review the importance of pre-training datasets, architectural innovations, self-supervised strategies, and fine-tuning approaches that allow general RNA representations to be translated into task-specific models. Crucially, we highlight how explainable AI (XAI) methods transform these models from black-box predictors into valuable discovery tools that reveal candidate cis-regulatory elements and structural motifs. As RNA foundation models keep advancing and integrating more multimodal biological data, they aim to uncover additional regulatory rules and functions encoded in RNA.

SINEs (Short Interspersed Nuclear Elements) are a class of retrotransposons, among the most prolific and transcriptionally active groups of repetitive elements. Rodent B1/B2-SINEs and primate Alu RNAs are upregulated in stress responses such as cellular heat shock or upon viral infection. Here we review recent findings demonstrating that SINE RNAs have also integrated as adaptive regulators of gene expression in different biological contexts, particularly in nervous system lesion, degeneration and remodelling. These integral roles in physiological processes reinforce the concept that SINEs provide 'cheap genes' for evolutionary adaptation of non-coding RNA to biological function.

In the rat pheochromocytoma cell line PC12, which resembles sympathetic neurons, miRNA activity decreases during differentiation, and inactivation of the let-7a miRNP is essential for differentiation. We sought to examine how let-7a activity is affected during differentiation. Extracellular vesicle-mediated miRNA export is a common strategy used by mammalian cells to regulate miRNA activity. HuR, a protein that influences miRNA stability and activity by exporting Ago2-unbound miRNAs via extracellular vesicles, decreases in differentiating PC12 cells, whereas another ELAVL protein, HuD, increases. We found that HuD expression increases to assume HuR's role in miRNA export regulation, thereby aiding differentiation by modulating specific miRNAs, such as let-7a and miR-125b. HuD binds these miRNAs, reducing their activity and promoting their export, thereby supporting PC12 differentiation. This switch in miRNA export responsibility from HuR to HuD may be both necessary and sufficient for neuronal differentiation.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder whose pathophysiological mechanisms remain incompletely understood. Alternative splicing of transcription factors (TFs) may lead to significant functional consequences in the pathogenesis of PCOS. This study investigated genome-wide AS patterns and the expression of key TFs in PCOS to identify functionally relevant splicing events in a human dataset and validate them in a mouse model. Bioinformatics analysis of a PCOS RNA-seq dataset revealed 42 differentially spliced TFs, with enrichment in transcriptional regulation and metabolic pathways. Subsequent validation in a PCOS mouse model highlighted significant upregulation of Nfkb1 and Nfkb2, along with a specific exon-skipping event in Nfkb1 ;(Nfkb1-ES1496). Our findings demonstrate altered AS of critical TFs in PCOS, implicating dysregulated NF-κB signalling through splicing modulation as a potential contributor to the disorder, which may offer novel biomarker or therapeutic avenues.

Cervical cancer is a leading cause of cancer-related deaths, with cervical squamous cell carcinoma (CSCC) accounting for a majority of cases. Circular RNAs (circRNAs) have been repeatedly suggested as crucial effectors in modulating the development of multiple malignancies. The expression of circ_0002762 was predicted to be high in CSCC tissues in GEO dataset, but the functional role and underlying regulatory mechanism of circ_0002762 in CSCC was unclear. By series of functional assays and mechanism assays, supported by bioinformatics analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis and western blot assays, we identified that circ_0002762 aberrantly up-regulated in CSCC, promoting CSCC cell migration and invasion. Mechanically, circ_0002762 was transcriptionally activated by Fork head box A1 (FOXA1). Moreover, the involvement of nuclear factor kappa B (NF-kB) signalling in circ_0002762 regulation mechanism in CSCC cells was ascertained. Additionally, circ_0002762, predominantly accumulated in cell cytoplasm, was proved to recruit Mov10 RISC complex RNA helicase (MOV10) to enhance RelA mRNA stability, thus affecting CSCC cell migration and invasion. In summary, FOXA1-mediated circ_0002762 up-regulation could enhance the migratory and invasive abilities of CSCC cells via the MOV10/RelA/NF-kB pathway.

Complete nerve regeneration is limited in current therapeutic approaches for spinal cord injuries (SCIs) and peripheral nerve injuries (PNIs). Extracellular vesicles (EVs) and microRNAs (miRNAs) play a pivotal role in intercellular communication by transporting various biomolecules, including miRNAs, to the recipient cells. Thus, they are promising targets for novel neural regeneration drugs. This comprehensive study examined the roles of EV-derived miRNAs in facilitating neural rejuvenation after SCI and PNI. It also explored the mechanisms by which they augment neuroprotection and promote cell viability. It also discusses their translational potential for treating nerve injury and evaluates their potential impact on advancements in nerve resurrection and prospective research in regenerative medicine. The findings may provide effective treatments and improve outcomes, as well as contribute to addressing the direction for the next studies, for the pathologies of SCI and PNI.

Over the past decade, non-coding RNAs (ncRNAs) have gained prominence in research due to their widespread presence in cells, yet their functions remain increasingly complex and less understood. Despite being initially deemed 'junk', many lncRNAs are now recognized as key regulators in cells and are often affected in disease contexts. Notably, numerous mRNAs have annotated antisense RNAs (asRNAs). Because asRNAs resemble the largest group of lncRNAs and were identified to serve a general function in Saccharomyces cerevisiae, they are the focus of this review. In S. cerevisiae, the absence of RNA interference (RNAi) enables unbiased study and allowed researchers to investigate their roles in gene regulation more directly with intriguing results, summarized here. Expression of asRNA leads to the formation of double-stranded RNAs (dsRNAs) with the regarding sense counterpart, resulting in enhanced gene expression through preferential nuclear export. Thus, these hidden leaders can boost gene expression and require future attention pivotal for elucidating their influence on biological processes and revealing disease mechanisms.

There is no life without RNA or lipids. But could there be life with only RNA and lipids? The discovery that RNA can catalyse reactions in addition to encoding information opened new directions for engineering life and the possibility of life emerging from an RNA World. But a key missing ingredient for RNA-based biochemical systems is a mechanism to organize RNAs and regulate their activity. Lipids, which are essential for life and one of the most ancient biomolecules, can spontaneously self-assemble to form membranous bilayers, theoretically providing a surface that can serve to concentrate, protect, and regulate RNAs. This review explores the interactions between RNA and lipids, including the chemical basis for their interactions, and the implications for synthetic biology, RNA World, and modern cell biology. We discuss observations that RNA can selectively bind to lipid membranes in a sequence-dependent manner, and entertain how these interactions might be employed to engineer RNA-based sensors and regulatory elements in synthetic systems. The emerging field of RNA-lipid interactions opens new possibilities for engineering orthogonal biochemistries for synthetic cells, innovations in RNA therapeutics, and discovering potentially new facets of cellular regulation.