RNA trafficking and subcellular localization—a review of mechanisms, experimental and predictive methodologies

Wang, Jun; Horlacher, Marc; Cheng, Lixin; Winther, Ole

doi:10.1093/bib/bbad249

Cited by 10 publications

(10 citation statements)

References 144 publications

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“…TYK2i treatment was associated with changes in the subcellular localization of key ISGs. Most notably, cytoplasmic CD274 mRNA was increased in TYK2i-treated RIP-LCMV-GP mice at day 14 and in NOD mice, suggesting that changes in subcellular localization of mRNAs may be influenced by reducing inflammation (74). Of note, changes in mRNA localization have been linked with changes in mRNA translation in several disease models (75,76).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Syed,

Ballew,

Lee

et al. 2024

Preprint

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SUMMARYTyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treatedin vitrowith IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin.In vivoadministration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GPmice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Syed,

Ballew,

Lee

et al. 2024

Preprint

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“…Transcript localization is largely governed by an intricate interplay of RNA-binding proteins (RBPs) 4 . Consequently, RBP-binding information is expected to boost the accuracy of localization predictions.…”

Section: Methodsmentioning

confidence: 99%

“…RNA localisation is the process of transporting and anchoring RNA molecules to specific subcellular regions, where they can perform their functions in gene expression, cell differentiation, and development [1][2][3][4] . The misregulation and perturbation of RNA localization are relevant to various disease phenotypes, including cancer [5][6][7][8] , development disorders [9][10][11][12] , and disorders involving neuromuscular or neuronal dysfunction [13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

“…Image-based models leverage manually curated features to characterize RNA distributions 22,23 or employ cutting-edge computer vision methods to learn hidden feature representation 24 . Sequence-based models 22,23,25 (see review 4 ) predict the localization derived from the primary sequence. The inherent features of cis- regulatory elements and the secondary structure are biologically relevant for determining where transcripts should be transported through binding with RNA-binding proteins (RBPs).…”

Section: Introductionmentioning

confidence: 99%

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DeepLocRNA: An Interpretable Deep Learning Model for Predicting RNA Subcellular Localization with domain-specific transfer-learning

Wang,

Horlacher,

Cheng

et al. 2023

Preprint

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Accurate prediction of RNA subcellular localization plays an important role in understanding cellular processes and functions. Although post-transcriptional processes are governed by trans-acting RNA-binding proteins (RBPs) through interaction with cis-regulatory RNA motifs, current methods do not incorporate RBP-binding information. In this paper, we propose DeepLocRNA, an interpretable deep-learning model that leverages a pre-trained multi-task RBP-binding prediction model to predict the subcellular localisation of RNA molecules via fine-tuning. We constructed DeepLocRNA using a comprehensive dataset with variant RNA types and evaluated it on held-out RNA species. Our model achieved state-of-the-art performance in predicting RNA subcellular localization in mRNA and miRNA. It has demonstrated great generalization capabilities, not only for human RNA but also for mice. Moreover, the interpretability of the model is enhanced through the motif analysis, enabling the understanding of the signal factors that contribute to the predictions. The proposed model provides general and powerful prediction abilities for different RNA and species, offering valuable insights into the localisation patterns of RNA molecules and contributing to advancing our understanding of cellular processes at the molecular level.

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“…These methods, however, are low throughput, and can monitor simultaneously only up to hundreds of transcripts. Furthermore, efforts have been made to develop computational methods for predicting RNA subcellular localization (see J Wang et al 2023, for a review). Nevertheless, most of these models base their predictions in sequence features, and are limited by the data they have been trained on.…”

Section: Introductionmentioning

confidence: 99%

Studying relative RNA localization From nucleus to the cytosol

Ntasis,

Guigó

2024

Preprint

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The precise coordination of important biological processes, such as differentiation and development, is highly dependent on the regulation of expression of the genetic information. The flow of the genetic information is tightly regulated on multiple levels. Among them, RNA export to cytosol is an essential step for the production of proteins in eukaryotic cells. Hence, estimating the relative concentration of RNA molecules of a given transcript species in the nucleus and in the cytosol is of major significance as it contributes to the understanding of the dynamics of RNA trafficking between the nucleus and the cytosol. The most efficient way to estimate the levels of RNA species genome-wide is through RNA sequencing (RNAseq). While RNAseq can be performed separately in the nucleus and in the cytosol, because measured transcript levels are relative to the total volume of RNA in these compartments, and because this volume is usually unknown, the transcript levels in the nucleus and in the cytosol cannot be directly compared. Here we show theoretically that if, in addition to nuclear and cytosolic RNA-seq, whole cell RNA-seq is also performed, then accurate estimations of the localization of transcripts can be obtained. Based on this, we designed a method that estimates, first the fraction of the total RNA volume in the cytosol (nucleus), and then, this fraction for every transcript. We evaluate our methodology on simulated data and nuclear and cytosolic single cell data available. Finally, we use our method to investigate the cellular localization of transcripts using bulk RNAseq data from the ENCODE project.

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RNA trafficking and subcellular localization—a review of mechanisms, experimental and predictive methodologies

Cited by 10 publications

References 144 publications

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

DeepLocRNA: An Interpretable Deep Learning Model for Predicting RNA Subcellular Localization with domain-specific transfer-learning

Studying relative RNA localization From nucleus to the cytosol

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