دورية أكاديمية
أعرض في EDS

Alternative splicing coupled to nonsense-mediated decay coordinates downregulation of non-neuronal genes in developing mouse neurons.

التفاصيل البيبلوغرافية
العنوان: Alternative splicing coupled to nonsense-mediated decay coordinates downregulation of non-neuronal genes in developing mouse neurons.
المؤلفون: Zhuravskaya A; Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK., Yap K; Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK., Hamid F; Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK. fursham.hamid@kcl.ac.uk., Makeyev EV; Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK. eugene.makeyev@kcl.ac.uk.
المصدر: Genome biology [Genome Biol] 2024 Jun 20; Vol. 25 (1), pp. 162. Date of Electronic Publication: 2024 Jun 20.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100960660 Publication Model: Electronic Cited Medium: Internet ISSN: 1474-760X (Electronic) Linking ISSN: 14747596 NLM ISO Abbreviation: Genome Biol Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London : Genome Biology Ltd., c2000-
مواضيع طبية MeSH: Nonsense Mediated mRNA Decay* , Alternative Splicing* , Neurons*/metabolism , Polypyrimidine Tract-Binding Protein*/metabolism , Polypyrimidine Tract-Binding Protein*/genetics , Down-Regulation*, Animals ; Mice ; Exons ; Heterogeneous-Nuclear Ribonucleoproteins/metabolism ; Heterogeneous-Nuclear Ribonucleoproteins/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Gene Expression Regulation, Developmental ; Cell Differentiation/genetics ; Neurogenesis/genetics
مستخلص: Background: The functional coupling between alternative pre-mRNA splicing (AS) and the mRNA quality control mechanism called nonsense-mediated decay (NMD) can modulate transcript abundance. Previous studies have identified several examples of such a regulation in developing neurons. However, the systems-level effects of AS-NMD in this context are poorly understood.
Results: We developed an R package, factR2, which offers a comprehensive suite of AS-NMD analysis functions. Using this tool, we conducted a longitudinal analysis of gene expression in pluripotent stem cells undergoing induced neuronal differentiation. Our analysis uncovers hundreds of AS-NMD events with significant potential to regulate gene expression. Notably, this regulation is significantly overrepresented in specific functional groups of developmentally downregulated genes. Particularly strong association with gene downregulation is detected for alternative cassette exons stimulating NMD upon their inclusion into mature mRNA. By combining bioinformatic analyses with CRISPR/Cas9 genome editing and other experimental approaches we show that NMD-stimulating cassette exons regulated by the RNA-binding protein PTBP1 dampen the expression of their genes in developing neurons. We also provided evidence that the inclusion of NMD-stimulating cassette exons into mature mRNAs is temporally coordinated with NMD-independent gene repression mechanisms.
Conclusions: Our study provides an accessible workflow for the discovery and prioritization of AS-NMD targets. It further argues that the AS-NMD pathway plays a widespread role in developing neurons by facilitating the downregulation of functionally related non-neuronal genes.
(© 2024. The Author(s).)
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معلومات مُعتمدة: BB/M001199/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/M007103/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/V006258/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
فهرسة مساهمة: Keywords: Alternative splicing; Custom transcriptome annotation; Downregulation of non-neuronal genes; Neuronal development; Nonsense-mediated decay; R package
المشرفين على المادة: 139076-35-0 (Polypyrimidine Tract-Binding Protein)
0 (Ptbp1 protein, mouse)
0 (Heterogeneous-Nuclear Ribonucleoproteins)
0 (RNA, Messenger)
تواريخ الأحداث: Date Created: 20240620 Date Completed: 20240621 Latest Revision: 20240703
رمز التحديث: 20240703
مُعرف محوري في PubMed: PMC11188260
DOI: 10.1186/s13059-024-03305-8
PMID: 38902825
قاعدة البيانات: MEDLINE
الوصف
تدمد:1474-760X
DOI:10.1186/s13059-024-03305-8