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mA 修饰突变型亨廷顿 RNA 促进致病性亨廷顿转录本的生物发生。

mA modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts.

机构信息

Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciències, Universitat de Barcelona, Barcelona, Spain.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

出版信息

EMBO Rep. 2024 Nov;25(11):5026-5052. doi: 10.1038/s44319-024-00283-7. Epub 2024 Oct 11.

DOI:10.1038/s44319-024-00283-7
PMID:39394467
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11549361/
Abstract

In Huntington's disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of mA in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that mA methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed mA's role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that mA methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for mA in aberrant splicing of Htt mRNA.

摘要

在亨廷顿病（HD）中，异常的亨廷顿（HTT）mRNA 加工产生编码致病 HTT 外显子 1 蛋白的 HTT1a 转录本。HTT1a 产生的机制尚未完全阐明。鉴于 mA 在 RNA 加工和剪接中的作用，我们研究了其在 HTT1a 产生中的参与。在这里，我们表明，在纹状体中的亨廷顿 RNA 内的隐匿性 poly(A) 位点（IpA1 和 IpA2）之前，mA 甲基化增加在 Hdh+/Q111 小鼠和人类 HD 样本中。我们还通过药理学抑制和 METTL3 敲低以及使用 dCas13-ALKBH5 系统在 HD 小鼠细胞中靶向 Htt 内含子 1 的去甲基化来评估 mA 在突变型 Htt mRNA 加工中的作用。我们的数据表明，Htt1a 转录本水平受 METTL3 和 Htt 内含子 1 的甲基化状态调节。它们还表明，内含子 1 中的 mA 甲基化取决于扩展的 CAG 重复。我们的发现强调了 mA 在 HTT mRNA 异常剪接中的潜在作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/ec4625b58fc5/44319_2024_283_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/a6a2b10559ff/44319_2024_283_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/91ccd2ad3ecf/44319_2024_283_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/ec4625b58fc5/44319_2024_283_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/c0adddb82fac/44319_2024_283_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/b5236c47a24a/44319_2024_283_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/65a7bad62b0c/44319_2024_283_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/d82ec961fb87/44319_2024_283_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/b9de7b4c4536/44319_2024_283_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/a6a2b10559ff/44319_2024_283_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/91ccd2ad3ecf/44319_2024_283_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abe3/11549361/ec4625b58fc5/44319_2024_283_Fig9_ESM.jpg

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Determinant of m6A regional preference by transcriptional dynamics.转录动力学对m6A区域偏好性的决定因素
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Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.人纹状体和小脑内细胞类型特异性 CAG 重复扩展及突变亨廷顿蛋白毒性。
Nat Genet. 2024 Mar;56(3):383-394. doi: 10.1038/s41588-024-01653-6. Epub 2024 Jan 30.
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METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL.METTL3 介导的 m6A 修饰控制剪接因子丰度并有助于侵袭性 CLL。
Blood Cancer Discov. 2023 May 1;4(3):228-245. doi: 10.1158/2643-3230.BCD-22-0156.
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