Single-cell sequencing analysis reveals the essential role of the m 6A reader YTHDF1 in retinal visual function by regulating TULP1 and DHX38 translation.

IF 4 1区 生物学 Q1 ZOOLOGY
Xian-Jun Zhu, Xiao-Yan Jiang, Wen-Jing Liu, Yu-Di Fan, Guo Liu, Shun Yao, Kuan-Xiang Sun, Jun-Yao Chen, Bo Lei, Ye-Ming Yang
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引用次数: 0

Abstract

N6-methyladenosine (m 6A) modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function. The m 6A reader YTHDF1 has been shown to enhance the translational efficiency of m 6A-modified mRNAs in the brain and is essential for learning and memory. However, its role in the mature retina remains unclear. Herein, we report a novel role of Ythdf1 in the maintenance of retinal function using a genetic knockout model. Loss of Ythdf1 resulted in impaired scotopic electroretinogram (ERG) responses and progressive retinal degeneration. Detailed analyses of rod photoreceptors confirmed substantial degenerative changes in the absence of ciliary defects. Single-cell RNA sequencing revealed comprehensive molecular alterations across all retinal cell types in Ythdf1-deficient retinas. Integrative analysis of methylated RNA immunoprecipitation (MeRIP) sequencing and RIP sequencing identified Tulp1 and Dhx38, two inheritable retinal degeneration disease-associated gene homologs, as direct targets of YTHDF1 in the retina. Specifically, YTHDF1 recognized and bound m 6A-modified Tulp1 and Dhx38 mRNA at the coding sequence (CDS), enhancing their translational efficiency without altering mRNA levels. Collectively, these findings highlight the essential role of YTHDF1 in preserving visual function and reveal a novel regulatory mechanism of m 6A reader proteins in retinal degeneration, identifying potential therapeutic targets for severe retinopathies.

单细胞测序分析揭示了m6a读取器YTHDF1通过调节TULP1和DHX38翻译在视网膜视觉功能中的重要作用。
mRNA的n6 -甲基腺苷(m6a)修饰是调节mRNA代谢和神经元功能的关键转录后调控机制。研究表明,m6a读卡器YTHDF1可以提高大脑中m6a修饰mrna的翻译效率,对学习和记忆至关重要。然而,它在成熟视网膜中的作用尚不清楚。在这里,我们报告了Ythdf1在维持视网膜功能中使用基因敲除模型的新作用。Ythdf1的缺失导致暗位视网膜电图(ERG)反应受损和进行性视网膜变性。杆状光感受器的详细分析证实,在没有纤毛缺陷的情况下,存在实质性的退行性改变。单细胞RNA测序揭示了ythdf1缺陷视网膜中所有视网膜细胞类型的全面分子改变。甲基化RNA免疫沉淀(MeRIP)测序和RIP测序的综合分析发现,两个遗传性视网膜变性疾病相关基因同源物Tulp1和Dhx38是视网膜中YTHDF1的直接靶点。具体来说,YTHDF1在编码序列(CDS)上识别并结合了m 6a修饰的Tulp1和Dhx38 mRNA,在不改变mRNA水平的情况下提高了它们的翻译效率。总之,这些发现突出了YTHDF1在维持视觉功能中的重要作用,揭示了m6a解读蛋白在视网膜变性中的一种新的调节机制,确定了严重视网膜病变的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Zoological Research
Zoological Research Medicine-General Medicine
CiteScore
7.60
自引率
10.20%
发文量
1937
审稿时长
8 weeks
期刊介绍: Established in 1980, Zoological Research (ZR) is a bimonthly publication produced by Kunming Institute of Zoology, the Chinese Academy of Sciences, and the China Zoological Society. It publishes peer-reviewed original research article/review/report/note/letter to the editor/editorial in English on Primates and Animal Models, Conservation and Utilization of Animal Resources, and Animal Diversity and Evolution.
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