APPRIS: annotation of principal and alternative splice isoforms

The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins’ alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease.

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Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer

Molecules ◽

10.3390/molecules24040763 ◽

2019 ◽

Vol 24 (4) ◽

pp. 763 ◽

Cited By ~ 10

Author(s):

Lavinia Carabet ◽

Eric Leblanc ◽

Nada Lallous ◽

Helene Morin ◽

Fariba Ghaidi ◽

...

Keyword(s):

Prostate Cancer ◽

Alternative Splice ◽

Small Molecule ◽

Rna Binding ◽

Critical Role ◽

Hnrnp A1 ◽

Castration Resistant Prostate Cancer ◽

Splice Isoforms ◽

Castration Resistant ◽

Computer Aided

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1–RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.

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Faculty Opinions recommendation of Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.716997868.792302873 ◽

2012 ◽

Author(s):

Juan Valcárcel ◽

Sophie Bonnal

Keyword(s):

Cancer Cells ◽

Alternative Splice ◽

Splice Sites ◽

Mature Mrna

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IsoDetect: Detection of splice isoforms from third generation long reads based on short feature sequences

Current Bioinformatics ◽

10.2174/1574893615666200316101205 ◽

2020 ◽

Vol 15 ◽

Author(s):

Hongdong Li ◽

Wenjing Zhang ◽

Yuwen Luo ◽

Jianxin Wang

Keyword(s):

Sequence Similarity ◽

Detection Methods ◽

Sequence Information ◽

Third Generation ◽

Sequencing Data ◽

Splice Isoforms ◽

Third Generation Sequencing ◽

Long Reads ◽

Feature Sequence ◽

Generation Sequencing

Aims: Accurately detect isoforms from third generation sequencing data. Background: Transcriptome annotation is the basis for the analysis of gene expression and regulation. The transcriptome annotation of many organisms such as humans is far from incomplete, due partly to the challenge in the identification of isoforms that are produced from the same gene through alternative splicing. Third generation sequencing (TGS) reads provide unprecedented opportunity for detecting isoforms due to their long length that exceeds the length of most isoforms. One limitation of current TGS reads-based isoform detection methods is that they are exclusively based on sequence reads, without incorporating the sequence information of known isoforms. Objective: Develop an efficient method for isoform detection. Method: Based on annotated isoforms, we propose a splice isoform detection method called IsoDetect. First, the sequence at exon-exon junction is extracted from annotated isoforms as the “short feature sequence”, which is used to distinguish different splice isoforms. Second, we aligned these feature sequences to long reads and divided long reads into groups that contain the same set of feature sequences, thereby avoiding the pair-wise comparison among the large number of long reads. Third, clustering and consensus generation are carried out based on sequence similarity. For the long reads that do not contain any short feature sequence, clustering analysis based on sequence similarity is performed to identify isoforms. Result: Tested on two datasets from Calypte Anna and Zebra Finch, IsoDetect showed higher speed and compelling accuracy compared with four existing methods. Conclusion: IsoDetect is a promising method for isoform detection. Other: This paper was accepted by the CBC2019 conference.

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Differential Expression of BARD1 Isoforms in Melanoma

Genes ◽

10.3390/genes12020320 ◽

2021 ◽

Vol 12 (2) ◽

pp. 320

Author(s):

Lorissa I. McDougall ◽

Ryan M. Powell ◽

Magdalena Ratajska ◽

Chi F. Lynch-Sutherland ◽

Sultana Mehbuba Hossain ◽

...

Keyword(s):

Long Range ◽

Patient Outcomes ◽

Splice Variants ◽

Significant Proportion ◽

Nanopore Sequencing ◽

Rna Seq ◽

Splice Isoforms ◽

Tissue Samples ◽

Multiple Transcripts ◽

Mrna Variants

Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore sequencing, RT-qPCR, and RNA sequencing analyses, we examined the transcription of BARD1 splice isoforms in melanoma cell lines and patient tissue samples. Seventy-six BARD1 mRNA variants were identified in total, with several previously characterised isoforms (γ, φ, δ, ε, and η) contributing to a large proportion of the expressed transcripts. In addition, we identified four novel splice events, namely, Δ(E3_E9), ▼(i8), IVS10+131▼46, and IVS10▼176, occurring in various combinations in multiple transcripts. We found that short-read RNA-Seq analyses were limited in their ability to predict isoforms containing multiple non-contiguous splicing events, as compared to long-range nanopore sequencing. These studies suggest that further investigations into the functional significance of the identified BARD1 splice variants in melanoma are warranted.

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Conservation of human alternative splice events in mouse

Nucleic Acids Research ◽

10.1093/nar/gkg355 ◽

2003 ◽

Vol 31 (10) ◽

pp. 2544-2552 ◽

Cited By ~ 70

Author(s):

T. A. Thanaraj

Keyword(s):

Alternative Splice

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