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Rapid immune activation requires tight control of mRNA stability in CD8⁺ T cells. Here, the authors show that a compositive RNA motif – m⁶A sites positioned next to AU-rich elements - marks mRNAs for rapid decay during activation, revealing a coordinated mechanism that shapes T-cell immunity.

Highly conserved recursive splice sites are identified in vertebrates, particularly within long genes encoding proteins that are involved in neuronal development; analysis of the splicing mechanism reveals that such recursive splicing sites can be used to dictate different mRNA isoforms.

A method, termed hiCLIP, has been developed to determine the RNA duplexes bound by RNA-binding proteins, revealing an unforeseen prevalence of long-range duplexes in 3′ untranslated regions (UTRs), and a decreased incidence of SNPs in duplex-forming regions; the results also show that RNA structure is able to regulate gene expression.

The authors discover a homeostatic process termed interstasis, in which an increased concentration of proteins within RNA–protein condensates induces the sequestration of their own mRNAs.

ATP-dependent helicases remodel the spliceosome and proofread splice site recognition. A new method – Purified Spliceosome iCLIP (psiCLIP) – probes protein-RNA interactions in defined spliceosome complexes to reveal how the helicases Prp16 and Prp22 promote correct mRNA synthesis through dynamic binding on their RNA substrates.

Here the authors show that, upon embryo implantation, signaling triggers a large-scale rearrangement of protein–RNA interactions. Phosphorylated LIN28A reassembles onto the 3′ untranslated region termini of pluripotency-associated mRNAs, where it converges with the binding of poly(A)-binding protein and drives selective mRNA decay.

Although non-coding RNAs have roles in transcription and chromatin function, nascent pre-mRNA is usually considered to be passive during these processes. Recently identified interactions between nascent pre-mRNAs and regulatory proteins suggest that both types of RNA regulate transcription and chromatin function.

Protein–RNA interactions are central to the regulation of gene expression. Emerging technologies for pinpointing these interactions, both in large complexes and between individual proteins and RNA, are discussed. Methods for analysing these data are also considered.

Mapping spliceosome engagement with pre-mRNAs using iCLIP reveals how the position and strength of branchpoints affect the crosslinking patterns of spliceosomal factors.

Advances in transcriptomics and analysis have identified thousands of previously unknown non-canonical splicing events. In this Review, the authors discuss the mechanisms and functions of these events and their roles in a variety of diseases. They explain how non-canonical splicing mechanisms can be targeted or exploited for therapeutic strategies.

TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

Here the authors describe that the human origin recognition complex subunit 1 (ORC1) binds to RNAs transcribed from genes with origins of replication at their TSS impacting origin activation.

Axonal transcriptomes have been characterized, but their regulation and role in neuronal circuits remain unclear. Here authors uncover activity-dependent RNA localization in axons important for memory consolidation.

CDK11 functions with histone pre-mRNA-processing factor FLASH to upregulate expression of replication-dependent histone genes in S phase and to couple transcription and processing of nascent histone transcripts in mammalian cells.

PKCε is known to exert a role in genome protection by directly phosphorylating and switching the specificity of Aurora B. Here the authors identify SERBP1 as a parallel mitotic PKCε substrate controlling translation and ensuring the integrity of chromosome segregation and successful cell division.

Recent studies have indicated that a cell's proteome is significantly larger than the number of protein-coding genes due to extensive alternative splicing. This study describes an unbiased, genome-wide method to characterize RNA-protein binding interactions in vivo. The binding sites of the neuron-specific splicing factor Nova are characterized with the unexpected result that Nova may have an additional function in regulating alternative polyadenylation as well.

Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.

The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

Ule and colleagues discuss cross-linking and immunoprecipitation (CLIP) methods for characterizing the RNA binding partners of RNA-binding proteins and explore the data analysis workflows, best practices and applications for these techniques. The Primer also considers methods for characterizing the protein binding partners of specific RNAs and discusses how data from these complementary methods can be integrated into CLIP workflows.

Comparative analysis of microexons across bilaterians identifies a new protein domain associated with the evolutionary origin of microexon inclusion in neural tissues.

CDK11 associates with SF3B1 and phosphorylates threonine residues at the N terminus of SF3B1 during spliceosome activation, and the inhibition of CDK11 blocks the activation and leads to widespread intron retention and the accumulation of non-functional spliceosomes on pre-mRNAs and chromatin.

Nanopore direct RNA Sequencing data contain information about the presence of RNA modifications, but their detection poses substantial challenges. Here the authors introduce Nanocompore, a new methodology for modification detection from Nanopore data.

This Review describes how increasingly sophisticated omics data and computational models of the splicing code are paving the way to more accurate, context-specific splicing predictions, while also providing insights into the regulatory mechanisms and therapeutic applications of alternative splicing.

MicroRNAs bind to the 3′-untranslated region of genes to regulate expression. In this study, an RNA-binding protein, RMB38, is shown to selectively regulate the access of some microRNAs to their targets, and control the expression of some p53 target genes.

TDP-43 is a RNA-binding protein that forms inclusion bodies in ALS. The authors show that TDP-43 preferentially binds long clusters of UG-rich sequences and that TDP-43 binding on pre-mRNAs influences alternative splicing. Many alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or are implicated in neurological diseases.

Myocardial hypoxia activates HIF1α, which activates the splicing factor SF3B1, which mediates a splice switch of the fructose-metabolising enzyme KHK, so that the C isoform that has superior affinity for fructose is expressed in the heart—pathological heart growth and contractile dysfunction can therefore be suppressed by depleting SF3B1 or deleting KHK.

The RNA-binding protein HuR post-transcriptionally regulates mRNA splicing. Turner and colleagues demonstrate that HuR serves a critical role in thymus-independent antigen responses by regulating the fate of genes related to B cell energy use.

TDP-43 regulates alternative splicing of the cystic fibrosis transmembrane regulator (CFTR) and is found in cytosolic granules associated with several neurodegenerative disorders. A new solution structure of the tandem RNA-recognition motifs (RRMs) that mediate interactions with its UG-rich RNA targets reveals a new RRM arrangement critical for TDP-43 function.

Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner.

Intron retention (IR) can increase protein diversity and function, and yet unregulated IR may be detrimental to cellular health. This study shows that aberrant IR occurs in ALS and finds nuclear loss of an RNA-binding protein called SFPQ as a new molecular hallmark in this devastating condition.

hiCLIP is an NGS-based method for identifying RNA duplexes that interact with an RNA-binding protein of interest. A unique feature is the inclusion of a linker that allows both parts of the duplex to be identified with certainty.

Even though heterogeneous nuclear ribonucleoprotein C (hnRNP C) is among the most abundant proteins in the nucleus, its role in splicing has remained unresolved. Data obtained using a newly developed individual-nucleotide UV crosslinking and immunoprecipitation (iCLIP) technique, integrated with alternative splicing profiles, indicate how the position of hnRNP particles determines their effect on inclusion of alternative exons.

The SMAD2 and SMAD3 protein interactome links TGFβ signalling to diverse effectors including m⁶A methyltransferase, which has a role in regulating differentiation of human pluripotent stem cells.

In addition to its known roles in nonsense-mediated mRNA decay, recent findings show that the exon junction complex (EJC) participates in diverse mRNA maturation processes, including splicing, transport and translation. This multi-functionality is reflected by an increasing number of EJC-related disorders being discovered.