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

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收录情况： ◇ SCIE ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：梯队期刊

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机构： [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]Department of Geriatrics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China [3]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 [4]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 [5]Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China

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关键词： Epitranscriptomics N6-methyladenosine (m6A) Inherited retinal dystrophies YTHDC2 Retina function Photoreceptor degeneration

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 unexclusive. 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 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.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

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出版当年[2023]版：

大类 | 2 区生物学

小类 | 3 区生化与分子生物学 3 区遗传学

最新[2023]版：

大类 | 2 区生物学

小类 | 3 区生化与分子生物学 3 区遗传学

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出版当年[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 GENETICS & HEREDITY

最新[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 GENETICS & HEREDITY

影响因子： 6.6 最新[2023版] 5.8 最新五年平均 6.6 出版当年[2023版] 0 出版当年五年平均 6.6 出版前一年[2023版]

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第一作者机构： [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

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通讯作者：

通讯机构： [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]Department of Geriatrics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China [3]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 [4]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 [5]Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003, China

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

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