8.2
CiteScore
6.6
Impact Factor
Volume 51 Issue 2
Feb.  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Genetics and Genomics  > 2024  >  51(2): 208-221

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

doi: 10.1016/j.jgg.2023.12.007
  •  

    a. 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;

  •  

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

  •  

    c. 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;

  •  

    d. 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;

  •  

    e. Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China

Funds:

This study was supported by the National Natural Science Foundation of China (81970841, 82101160, 82121003), the Department of Science and Technology of Sichuan Province (2023ZYD0172, 2023YFS0161), the program of Science and Technology International Cooperation Project of Qinghai province (China) (No. 2022-HZ-814), Sichuan Intellectual Property Office (China) (No. 2022-ZS-0070), the CAMS Innovation Fund for Medical Sciences (2019-12M-5-032), and Open Project of Henan Provincial Key Laboratory of Ophthalmology and Visual Science (20KFKT02). The funders had no role in the study design, data collection and analysis, or preparation of the manuscript.

  • Received Date: 2023-08-30
  • Accepted Date: 2023-12-22
  • Rev Recd Date: 2023-12-22
    • Available Online: 2025-06-07
  • Publish Date: 2023-12-28
    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. N-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.
    • FullText(HTML)
  • loading
    • References(51)
  • Bailey, A.S., Batista, P.J., Gold, R.S., Chen, Y.G., de Rooij, D.G., Chang, H.Y., Fuller, M.T., 2017. The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. Elife 6, e26116.
    Berger, W., Kloeckener-Gruissem, B., Neidhardt, J., 2010. The molecular basis of human retinal and vitreoretinal diseases. Prog. Retin. Eye Res. 29, 335-375.
    Chang, B., Hawes, N., Pardue, M., German, A., Hurd, R., Davisson, M., Nusinowitz, S., Rengarajan, K., Boyd, A., Sidney, S., et al., 2007. Two mouse retinal degenerations caused by missense mutations in the β-subunit of rod cGMP phosphodiesterase gene. Vision Res. 47, 624-633.
    Chen, C.Y.A., Ezzeddine, N., Shyu, A.B., 2008. Messenger RNA half-life measurements in mammalian cells. Methods Enzymol. 448, 335-357.
    Fadl, B.R., Brodie, S.A., Malasky, M., Boland, J.F., Kelly, M.C., Kelley, M.W., Boger, E., Fariss, R., Swaroop, A., Campello, L., et al., 2020. An optimized protocol for retina single-cell RNA sequencing. Mol. Vision 26, 705.
    Goswami-Sewell, D., Bagnetto, C., Gomez, C.C., Anderson, J.T., Maheshwari, A., Zuniga-Sanchez, E., 2023. βII-spectrin is required for synaptic positioning during retinal development. J. Neurosci. 43, 5277-5289.
    Hsu, P.J., Zhu, Y., Ma, H., Guo, Y., Shi, X., Liu, Y., Qi, M., Lu, Z., Shi, H., Wang, J., 2017. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 27, 1115-1127.
    Huang, H., Weng, H., Sun, W., Qin, X., Shi, H., Wu, H., Zhao, B.S., Mesquita, A., Liu, C., Yuan, C.L., et al., 2018. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 20, 285-295.
    Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., Yang, Y., Yi, C., Lindahl, T., Pan, T., Yang, Y.G., et al., 2011. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885-887.
    Kakakhel, M., Tebbe, L., Makia, M.S., Conley, S.M., Sherry, D.M., Al-Ubaidi, M.R., Naash, M.I., 2020. Syntaxin 3 is essential for photoreceptor outer segment protein trafficking and survival. Proc. Natl. Acad. Sci. U. S. A. 117, 20615-20624.
    Kretschmer, J., Rao, H., Hackert, P., Sloan, K.E., Hobartner, C., Bohnsack, M.T., 2018. The m6A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1. RNA 24, 1339-1350.
    Li, J., Yang, X., Qi, Z., Sang, Y., Liu, Y., Xu, B., Liu, W., Xu, Z., Deng, Y., 2019. The role of mRNA m6A methylation in the nervous system. Cell Biosci. 9, 66.
    Li, L., Krasnykov, K., Homolka, D., Gos, P., Mendel, M., Fish, R.J., Pandey, R.R., Pillai, R.S., 2022. The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition. Mol. Cell 82, 1678-1690.
    Li, S., Chen, D., Sauve, Y., McCandless, J., Chen, Y.J., Chen, C.K., 2005. Rhodopsin-iCre transgenic mouse line for Cre-mediated rod-specific gene targeting. Genesis 41, 73-80.
    Liao, S., Sun, H., Xu, C., 2018. YTH domain: a family of N6-methyladenosine (m6A) readers. Genomics Proteomics Bioinformatics 16, 99-107.
    Lin, J.B., Apte, R.S., 2018. NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies. Prog Retin Eye Res. 67, 118-129.
    Liu, J., Yue, Y., Han, D., Wang, X., Fu, Y., Zhang, L., Jia, G., Yu, M., Lu, Z., Deng, X., et al., 2014. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93-95.
    Liu, S., Li, G., Li, Q., Zhang, Q., Zhuo, L., Chen, X., Zhai, B., Sui, X., Chen, K., Xie, T., et al., 2020. The roles and mechanisms of YTH domain-containing proteins in cancer development and progression. Am. J. Cancer Res. 10, 1068.
    Liu, T., Wei, Q., Jin, J., Luo, Q., Liu, Y., Yang, Y., Cheng, C., Li, L., Pi, J., Si, Y., et al., 2020. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 48, 3816-3831.
    Ma, L., Chen, T., Zhang, X., Miao, Y., Tian, X., Yu, K., Xu, X., Niu, Y., Guo, S., Zhang, C., et al., 2021. The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 38. 101801.
    Madeira, M.H., Boia, R., Santos, P.F., Ambrosio, A.F., Santiago, A.R., 2015. Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases. Mediators Inflamm. 2015, 673090.
    Menon, M., Mohammadi, S., Davila-Velderrain, J., Goods, B.A., Cadwell, T.D., Xing, Y., Stemmer-Rachamimov, A., Shalek, A.K., Love, J.C., Kellis M., et al., 2019. Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration. Nat. Commun. 10, 4902.
    Meyer, K.D., Patil, D.P., Zhou, J., Zinoviev, A., Skabkin, M.A., Elemento, O., Pestova, T.V., Qian, S.B., Jaffrey, S.R., 2015. 5' UTR m6A promotes cap-independent translation. Cell 163, 999-1010.
    Molday, R., Hicks, D., Molday, L., 1987. Peripherin. A rim-specific membrane protein of rod outer segment discs. Invest. Ophthalmol. Vis. Sci. 28, 50-61.
    Niu, F., Che, P., Yang, Z., Zhang, J., Yang, L., Zhuang, M., Ou, X., Ji, S.-J., 2022. m6A regulation of cortical and retinal neurogenesis is mediated by the redundant m6A readers YTHDFs. iScience 25, 104908.
    Papermaster, D.S., Dreyer,W.J., 1974. Rhodopsin content in the outer segment membranes of bovine and frog retinal rods. Biochemistry 13, 2438-2444.
    Ramulu, P., Kennedy, M., Xiong, W.-H., Williams, J., Cowan, M., Blesh, D., Yau, K.W., Hurley, J.B., Nathans, J., 2001. Normal light response, photoreceptor integrity, and rhodopsin dephosphorylation in mice lacking both protein phosphatases with EF hands (PPEF-1 and PPEF-2). Mol. Cell Biol. 21, 8605-8614.
    Reed, M., Takemaru, K.I., Ying, G., Frederick, J.M., Baehr, W., 2022. Deletion of CEP164 in mouse photoreceptors post-ciliogenesis interrupts ciliary intraflagellar transport (IFT). PLos Genet. 18, e1010154.
    Rose, K., Walston, S.T., Chen, J., 2017. Separation of photoreceptor cell compartments in mouse retina for protein analysis. Mol. Neurodegener. 12, 28.
    Sarria, I., Orlandi, C., McCall, M.A., Gregg, R.G., Martemyanov, K.A., 2016. Intermolecular interaction between anchoring subunits specify subcellular targeting and function of RGS proteins in retina ON-bipolar neurons. J. Neurosci. 36, 2915-2925.
    Sasaki, Y., Kakita, H., Kubota, S., Sene, A., Lee, T.J., Ban, N., Dong, Z., Lin, J.B., Boye, S.L., DiAntonio, A., et al., 2020. SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration. Elife 9, e62027.
    Shi, H., Chai, P., Jia, R., Fan, X., 2020. Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation. Mol. Cancer 19, 78.
    Shi, R., Ying, S., Li, Y., Zhu, L., Wang, X., Jin, H., 2021. Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics. Cell Death Dis. 12, 346.
    Steele, F., O'Tousa, J.E., 1990. Rhodopsin activation causes retinal degeneration in drosophila rdgC mutant. Neuron 4, 883-890.
    Subramanian, R., Sahoo, D., 2022. Boolean implication analysis of single-cell data predicts retinal cell type markers. BMC Bioinformatics 23, 1-18.
    Sun, R.X., Zhu, H.J., Zhang, Y.R., Wang, J.N., Wang, Y., Cao, Q.C., Ji, J.D., Jiang, C., Yuan, S.T., Chen, X., et al., 2023. ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway. Cell Rep. 42, 112779.
    Tsang, S.H., Woodruff, M.L., Jun, L., Mahajan, V., Yamashita, C.K., Pedersen, R., Lin, C.S., Goff, S.P., Rosenberg, T., Larsen, M., et al., 2007. Transgenic mice carrying the H258N mutation in the gene encoding the β-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness. Hum. Mutat. 28, 243-254.
    Uhlen, M., Fagerberg, L., Hallstrom, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., Asplund, A., et al., 2015. Tissue-based map of the human proteome. Science 347, 1260419.
    Wang, X., Lu, Z., Gomez, A., Hon, G.C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al., 2014. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117-120.
    Wang, X., Zhao, B.S., Roundtree, I.A., Lu, Z., Han, D., Ma, H., Weng, X., Chen, K., Shi, H., He, C., 2015. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388-1399.
    Winkler, R., Gillis, E., Lasman, L., Safra, M., Geula, S., Soyris, C., Nachshon, A., Tai-Schmiedel, J., Friedman, N., Le-Trilling, V.T.K., et al., 2019. m6A modification controls the innate immune response to infection by targeting type I interferons. Nat. Immunol. 20, 173-182.
    Wu, S., Zhang, Y., Yao, L., Wang, J., Lu, F., Liu, Y., 2023. m6A-modified RNAs possess distinct poly (A) tails. J. Genet. Genomics 50, 208-211.
    Xu, C., Liu, K., Ahmed, H., Loppnau, P., Schapira, M., Min, J., 2015. Structural basis for the discriminative recognition of N6-methyladenosine RNA by the human YT521-B homology domain family of proteins. J. Biol. Chem. 290, 24902-24913.
    Yang, X., Lin, Y., Chen, T., Hu, W., Li, P., Qiu, X., Yang, B., Liang, A., Gao, W., 2023. YTHDF1 enhances chondrogenic differentiation by activating the Wnt/β-Catenin signaling pathway. Stem Cells Dev. 32, 115-130.
    Yang, Y., Cai, J., Yang, X., Wang, K., Sun, K., Yang, Z., Zhang, L., Yang, L., Gu, C., Huang, X., et al., 2022. Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma. Mol. Ther. 30, 2342-2353.
    Yang, Y., Shuai, P., Li, X., Sun, K., Jiang, X., Liu, W., Le, W., Jiang, H., Liu, Y., Zhu, X., 2022. Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival. BMC Biol. 20, 140.
    Yuan, W., Chen, S., Li, B., Han, X., Meng, B., Zou, Y., Chang, S., 2022. The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation. Transl. Oncol. 16, 101308.
    Zhang, H., Li, S., Doan, T., Rieke, F., Detwiler, P., Frederick, J., Baehr, W., 2007. Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments. Proc. Natl. Acad. Sci. U. S. A. 104, 8857-8862.
    Zhang, Y., Chen, W., Zheng, X., Guo, Y., Cao, J., Zhang, Y., Wen, S., Gao, W., Wu, Y., 2021. Regulatory role and mechanism of m6A RNA modification in human metabolic diseases. Mol. Ther. Oncolytics 22, 52-63.
    Zheng, G., Dahl, J.A., Niu, Y., Fedorcsak, P., Huang, C.-M., Li, C.J., Vagboe, C.B.,,Y., Wang, W.L., Song, S.H., 2013. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18-29.
    Zhou, B., Liu, C., Xu, L., Yuan, Y., Ma, X., 2021. N6-Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes. Hepatology 73 (1), 91–103.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索
    Get Citation
    PDF

    Article Metrics

    Article views (0) PDF downloads (0) Cited by ()
    Proportional views
    Related

    Editorial Office

    Journal of Genetics and Genomics

    京ICP备09063187号-12

    No.1, West Beichen Road, Chaoyang District, Beijing 100101, P.R.China

    +86-10-64806528+86-10-64807786jgg@genetics.ac.cn

    Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return