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

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

doi:10.1016/j.jgg.2023.12.007

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

J Genet Genomics. 2024 Feb;51(2):208-221. doi: 10.1016/j.jgg.2023.12.007. Epub 2023 Dec 28.

Authors

Yeming Yang¹, Xiaoyan Jiang¹, Junyao Chen¹, Lu Liu¹, Guo Liu¹, Kuanxiang Sun¹, Wenjing Liu¹, Xianjun Zhu², Qiuyue Guan³

Affiliations

¹ 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.
² 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 Provincial People's Hospital, Chengdu, Sichuan 610072, China; Qinghai Key Laboratory of Qinghai Tibet Plateau Biological Resources, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China; Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China. Electronic address: xjzhu@uestc.edu.cn.
³ 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. Electronic address: guanqiuyue@med.uestc.edu.cn.

PMID: 38157933
DOI: 10.1016/j.jgg.2023.12.007

Abstract

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.

Keywords: Epitranscriptomics; Inherited retinal dystrophies; N(6)-methyladenosine (m(6)A); Photoreceptor degeneration; Retina function; YTHDC2.

MeSH terms

Animals
Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics
Humans
Mice
Photoreceptor Cells, Vertebrate* / metabolism
Photoreceptor Cells, Vertebrate* / pathology
RNA Helicases / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Retinal Degeneration* / genetics
Retinal Degeneration* / metabolism
Retinal Degeneration* / pathology

Substances

Cyclic Nucleotide Phosphodiesterases, Type 6
PDE6B protein, human
RNA Helicases
RNA, Messenger
YTHDC2 protein, human
Pde6b protein, mouse
Ppef2 protein, mouse
Ythdc2 protein, mouse