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内含子 RNA 元件调节因子 VIII 外显子 16 的剪接。

An intronic RNA element modulates Factor VIII exon-16 splicing.

机构信息

Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.

Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.

出版信息

Nucleic Acids Res. 2024 Jan 11;52(1):300-315. doi: 10.1093/nar/gkad1034.

DOI:10.1093/nar/gkad1034
PMID:37962303
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10783525/
Abstract

Pathogenic variants in the human Factor VIII (F8) gene cause Hemophilia A (HA). Here, we investigated the impact of 97 HA-causing single-nucleotide variants on the splicing of 11 exons from F8. For the majority of F8 exons, splicing was insensitive to the presence of HA-causing variants. However, splicing of several exons, including exon-16, was impacted by variants predicted to alter exonic splicing regulatory sequences. Using exon-16 as a model, we investigated the structure-function relationship of HA-causing variants on splicing. Intriguingly, RNA chemical probing analyses revealed a three-way junction structure at the 3'-end of intron-15 (TWJ-3-15) capable of sequestering the polypyrimidine tract. We discovered antisense oligonucleotides (ASOs) targeting TWJ-3-15 partially rescue splicing-deficient exon-16 variants by increasing accessibility of the polypyrimidine tract. The apical stem loop region of TWJ-3-15 also contains two hnRNPA1-dependent intronic splicing silencers (ISSs). ASOs blocking these ISSs also partially rescued splicing. When used in combination, ASOs targeting both the ISSs and the region sequestering the polypyrimidine tract, fully rescue pre-mRNA splicing of multiple HA-linked variants of exon-16. Together, our data reveal a putative RNA structure that sensitizes F8 exon-16 to aberrant splicing.

摘要

人类凝血因子 VIII (F8) 基因中的致病变异导致血友病 A (HA)。在这里，我们研究了 97 种导致 HA 的单核苷酸变异对 F8 的 11 个外显子剪接的影响。对于大多数 F8 外显子，剪接对外显子中导致 HA 的变异不敏感。然而，包括外显子 16 在内的几个外显子的剪接受到预测改变外显子剪接调控序列的变异的影响。我们使用外显子 16 作为模型，研究了导致 HA 的变异对剪接的结构-功能关系。有趣的是，RNA 化学探测分析揭示了在内含子 15 的 3' 端存在一个能够隔离多嘧啶 tract 的三链 junction 结构 (TWJ-3-15)。我们发现靶向 TWJ-3-15 的反义寡核苷酸 (ASO) 通过增加多嘧啶 tract 的可及性，部分挽救了剪接缺陷的外显子 16 变异体。TWJ-3-15 的顶端茎环区域还包含两个 hnRNPA1 依赖性内含子剪接沉默子 (ISS)。阻断这些 ISS 的 ASO 也部分挽救了剪接。当联合使用时，靶向 ISS 和隔离多嘧啶 tract 的区域的 ASO 完全挽救了外显子 16 的多个与 HA 相关的变异体的前体 mRNA 剪接。总之，我们的数据揭示了一种可能的 RNA 结构，使 F8 外显子 16 对外显子剪接异常敏感。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/9768f698f96f/gkad1034fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/a35c142e5b73/gkad1034figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/ad15b253ec9a/gkad1034fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/7d524a5c55c2/gkad1034fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/b9699ad48882/gkad1034fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/d5e30488dfcc/gkad1034fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/79c5b00902ab/gkad1034fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/8b5ece3d8bfd/gkad1034fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/9768f698f96f/gkad1034fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/a35c142e5b73/gkad1034figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/ad15b253ec9a/gkad1034fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/7d524a5c55c2/gkad1034fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/b9699ad48882/gkad1034fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/d5e30488dfcc/gkad1034fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/79c5b00902ab/gkad1034fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/8b5ece3d8bfd/gkad1034fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/550d/10783525/9768f698f96f/gkad1034fig7.jpg

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All exons are not created equal-exon vulnerability determines the effect of exonic mutations on splicing.并非所有外显子都是平等的——外显子的脆弱性决定了外显子突变对剪接的影响。
Nucleic Acids Res. 2024 May 8;52(8):4588-4603. doi: 10.1093/nar/gkae077.
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Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics.核酸治疗药物临床前开发中使用的实验模型系统。
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Vulnerable exons, like ACADM exon 5, are highly dependent on maintaining a correct balance between splicing enhancers and silencers.易损外显子，如 ACADM 外显子 5，高度依赖于维持剪接增强子和沉默子之间的正确平衡。
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