近日，电子科技大学Qiuyue Guan等研究人员合作发现，m⁶A阅读器YTHDC2通过调节PPEF2和PDE6B的翻译维持视觉功能和视网膜感光细胞的存活。该研究于2023年12月28日在线发表于《遗传学报》。

研究人员表示，遗传性视网膜营养不良症（IRD）是全球视力损伤和不可逆失明的主要原因，但其确切的分子和遗传机制仍未确定。N⁶-甲基腺苷（m⁶A）修饰是真核生物mRNA中最常见的内部修饰。含YTH结构域2（YTHDC2）是一种m⁶A阅读蛋白，最近被确定为生殖系发育和人类癌症的关键角色。然而，它对视网膜功能的贡献仍然未知。

研究人员通过产生视杆细胞特异性Ythdc2基因敲除小鼠来探索了YTHDC2在视杆细胞视觉功能中的作用。结果表明，视杆细胞中Ythdc2的缺乏会导致光斑ERG反应减弱和进行性视网膜退化。多组学分析进一步确定了Ppef2和Pde6b是YTHdc2在视网膜中的潜在靶点。具体来说，通过其YTH结构域，YTHDC2在编码序列处识别并结合m⁶A修饰的Ppef2 mRNA，在 5'-UTR处识别并结合Pde6b mRNA，从而在不影响mRNA水平的情况下提高翻译效率。YTHDC2缺失后，Ppef2和Pde6b的翻译效率降低，最终导致视网膜中蛋白质水平下降、视网膜功能受损以及视杆细胞逐渐死亡。总之，这些发现突出了YTHDC2在视觉功能和感光细胞存活中的重要性，并通过表观转录组学阐明了IRD的发病机制。

附：英文原文

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

Author: anonymous

Issue&Volume: 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 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.

DOI: 10.1016/j.jgg.2023.12.007

Source: https://www.sciencedirect.com/science/article/pii/S167385272300259X