Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Taylor, Katarzyna; Sobczak, Krzysztof

doi:10.3390/ijms21145161

Cited by 22 publications

(17 citation statements)

References 338 publications

(434 reference statements)

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“…t is estimated that about 15-30% of the variants causing inherited diseases affect splicing [1][2][3][4][5] . The underlying mechanisms include skipping, truncation, and elongation of exons as well as intron retention 6,7 .…”

mentioning

confidence: 99%

Detection of aberrant splicing events in RNA-seq data using FRASER

et al. 2021

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Aberrant splicing is a major cause of rare diseases. However, its prediction from genome sequence alone remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we develop FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1 causing mucolipidosis. FRASER automatically controls for latent confounders, which are widespread and affect sensitivity substantially. Moreover, FRASER is based on a count distribution and multiple testing correction, thus reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor loss of sensitivity. Applying FRASER to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available.

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confidence: 99%

Detection of aberrant splicing events in RNA-seq data using FRASER

et al. 2021

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“…Aberrant splicing is a major cause of rare disease. It is estimated that splicing mutations are responsible for 15–60% of human disease mutations [ 97 , 98 , 99 ]. By proposing FRASER [ 100 ], Mertes et al responded to the lack of statistical significance assessments for splicing events in the field of RD.…”

Section: Ae Applications In Biological and Medical Contexts Beyond Rdmentioning

confidence: 99%

A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases

Pratella

Saadi

Bannwarth

et al. 2021

IJMS

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Rare diseases (RDs) concern a broad range of disorders and can result from various origins. For a long time, the scientific community was unaware of RDs. Impressive progress has already been made for certain RDs; however, due to the lack of sufficient knowledge, many patients are not diagnosed. Nowadays, the advances in high-throughput sequencing technologies such as whole genome sequencing, single-cell and others, have boosted the understanding of RDs. To extract biological meaning using the data generated by these methods, different analysis techniques have been proposed, including machine learning algorithms. These methods have recently proven to be valuable in the medical field. Among such approaches, unsupervised learning methods via neural networks including autoencoders (AEs) or variational autoencoders (VAEs) have shown promising performances with applications on various type of data and in different contexts, from cancer to healthy patient tissues. In this review, we discuss how AEs and VAEs have been used in biomedical settings. Specifically, we discuss their current applications and the improvements achieved in diagnostic and survival of patients. We focus on the applications in the field of RDs, and we discuss how the employment of AEs and VAEs would enhance RD understanding and diagnosis.

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“…Recent advances in this field have provided new information on DNA and RNA, complementing ensemble techniques in exploring topics ranging from structure (e.g., the intermediate and non-native structures) to mechanics (e.g., how structures are formed and the roles of competing pathways), dynamics (e.g., the intra-molecular interactions in folding and misfolding), and function (e.g., the relationship between dynamics and function) [15]. This is particularly important for RNA, whose regulatory and stimulatory role is greatly dependent on conformational changes, which might be both large-scale rearrangements and subtle fluctuations [16,17]. Additionally, because RNA is prone to degradation at high temperatures (especially in the presence of magnesium ions), optical tweezers experiments that can be carried out at physiological temperatures offer a technical advantage over thermal denaturation experiments (e.g., UV melting) in studying the impact of ions on RNA folding.…”

Section: Introductionmentioning

confidence: 99%

Complex Conformational Dynamics of the Heart Failure-Associated Pre-miRNA-377 Hairpin Revealed by Single-Molecule Optical Tweezers

Nogal

Rajan

Westerlund

et al. 2021

IJMS

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Pre-miRNA-377 is a hairpin-shaped regulatory RNA associated with heart failure. Here, we use single-molecule optical tweezers to unzip pre-miRNA-377 and study its stability and dynamics. We show that magnesium ions have a strong stabilizing effect, and that sodium ions stabilize the hairpin more than potassium ions. The hairpin unfolds in a single step, regardless of buffer composition. Interestingly, hairpin folding occurs either in a single step (type 1) or through the formation of intermediates, in multiple steps (type 2) or gradually (type 3). Type 3 occurs only in the presence of both sodium and magnesium, while type 1 and 2 take place in all buffers, with type 1 being the most prevalent. By reducing the size of the native hairpin loop from fourteen to four nucleotides, we demonstrate that the folding heterogeneity originates from the large size of the hairpin loop. Further, while efficient pre-miRNA-377 binders are lacking, we demonstrate that the recently developed C2 ligand displays bimodal activity: it enhances the mechanical stability of the pre-miRNA-377 hairpin and perturbs its folding. The knowledge regarding pre-miRNA stability and dynamics that we provide is important in understanding its regulatory function and how it can be modulated to achieve a therapeutic effect, e.g., in heart failure treatment.

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Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Cited by 22 publications

References 338 publications

Detection of aberrant splicing events in RNA-seq data using FRASER

Detection of aberrant splicing events in RNA-seq data using FRASER

A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases

Complex Conformational Dynamics of the Heart Failure-Associated Pre-miRNA-377 Hairpin Revealed by Single-Molecule Optical Tweezers

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