Single-cell sequencing analysis reveals the essential role of the m6A reader YTHDF1 in retinal visual function by regulating TULP1 and DHX38 translation

被引：0

作者：

Zhu, Xian-Jun ^{[1
,2
,3
,4
,5
]}

Jiang, Xiao-Yan ^{[2
]}

Liu, Wen-Jing ^{[2
]}

Fan, Yu-Di ^{[2
]}

Liu, Guo ^{[2
,3
]}

Yao, Shun ^{[1
,6
]}

Sun, Kuan-Xiang ^{[2
]}

Chen, Jun-Yao ^{[2
]}

Lei, Bo ^{[1
,6
]}

Yang, Ye-Ming ^{[2
,4
,5
]}

机构：

[1] Zhengzhou Univ, Henan Eye Hosp, Henan Prov Peoples Hosp, Peoples Hosp,Henan Branch,Natl Clin Res Ctr Ocular, Zhengzhou 450003, Henan, Peoples R China

[2] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Ctr Med Genet, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 610072, Sichuan, Peoples R China

[3] Jinfeng Lab, Sichuan Chongqing Joint Key Lab Pathol & Lab Med, Chongqing 400039, Peoples R China

[4] Chinese Acad Sci, Qinghai Key Lab Qinghai Tibet Plateau Biol Resourc, Xining 810008, Qinghai, Peoples R China

[5] Northwest Inst Plateau Biol, Qinghai Prov Key Lab Tibetan Med Res, Xining 810008, Qinghai, Peoples R China

[6] Henan Acad Innovat Med Sci, Eye Inst, Zhengzhou 451162, Henan, Peoples R China

来源：

ZOOLOGICAL RESEARCH | 2025年 / 46卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Epitranscriptomics; N6-methyladenosine (m6A); Inherited retinal dystrophies (IRDs); YTHDF1; Single-cell RNA sequencing; Photoreceptor degeneration; TUBBY-LIKE PROTEIN-1; RETINITIS-PIGMENTOSA; NUCLEAR-RNA; MUTATION; N6-METHYLADENOSINE;

D O I：

10.24272/j.issn.2095-8137.2024.399

中图分类号：

Q95 [动物学];

学科分类号：

071002 ;

摘要：

N6-methyladenosine (m6A) modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function. The m6A reader YTHDF1 has been shown to enhance the translational efficiency of m6A-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 m6A-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 m6A reader proteins in retinal degeneration, identifying potential therapeutic targets for severe retinopathies.

引用

页码：429 / 445

页数：17