The m6A reader YTHDC2 maintains visual function and retinal photoreceptor survival through modulating translation of PPEF2 and PDE6B

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外文摘要：Inherited retinal dystrophies(IRDs)are major causes of visual Impairment and Irreversible blindness worldwide,while the precise molecular and genetic mechanisms are still elusive.N6-methyladenosine(m6A)modification is the most prevalent internal modification in eukaryotic mRNA.YTH domain containing 2(YTHDC2),an m6A reader protein,has recently been identified as a key player in germline development and human cancer.However,its contribution to retinal function remains unknown.Here,we explore the role of YTHDC2 in the visual function of retinal rod photoreceptors by generating rod-specific Ythdc2 knockout mice.Results show that Ythdc2 deficiency in rods causes diminished scotopic ERG responses and progressive retinal degeneration.Multi-omics analysis further identifies Ppef2 and Pde6b as the potential targets of YTHDC2 in the retina.Specifically,via its YTH domain,YTHDC2 recognizes and binds m6A-modified Ppef2 mRNA at the coding sequence and Pde6b mRNA at the 5'-UTR,resulting in enhanced translation efficiency without affecting mRNA levels.Compromised translation efficiency of Ppef2 and Pde6b after YTHDC2 depletion ultimately leads to decreased protein levels in the retina,impaired retinal function,and progressive rod death.Collectively,our finding highlights the importance of YTHDC2 in visual function and photoreceptor survival,which provides an unreported elucidation of IRD pathogenesis via epitranscriptomics.

外文关键词：

EpitranscriptomicsN6-methyladenosine(m6A)Inherited retinal dystrophiesYTHDC2Retina functionPhotoreceptor degeneration

作者：

Yeming Yang、Xiaoyan Jiang、Junyao Chen、Lu Liu、Guo Liu、Kuanxiang Sun、Wenjing Liu、Xianjun Zhu、Qiuyue Guan

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作者单位：

The Sichuan Provincial Key Laboratory for Human Disease Gene Study,Center for Medical Genetics,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China

Department of Geriatrics,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China

Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026),Sichuan Academy of Medical Sciences and Sichuan Provincia

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaDepartment of Science and Technology of Sichuan ProvinceDepartment of Science and Technology of Sichuan Provinceprogram of Science and Technology International Cooperation Project of Qinghai province(China)Sichuan Intellectual Property Office(China)CAMS Innovation Fund for Medical SciencesOpen Project of Henan Provincial Key Laboratory of Ophthalmology and Visual Science

项目编号：

8197084182101160821210032023ZYD01722023YFS01612022-HZ-8142022-ZS-00702019-12M-5-03220KFKT02

出版年：

2024

DOI：

10.1016/j.jgg.2023.12.007

遗传学报

中国遗传学会中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD

影响因子：0.821

ISSN：1673-8527

年,卷(期)：2024.51(2)

参考文献量51