Single-cell sequencing analysis reveals the essential role of the m^(6)A reader YTHDF1 in retinal visual function by regulating TULP1 and DHX38 translationOACSCDCSTPCD
N6-methyladenosine(m^(6)A)modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function.The m^(6)A reader YTHDF1 has been shown to enhance the translational efficiency of m^(6)A-modified mRNAs in the brain and is essential for learning and memory.However,its role in the mature retina remains unclear.Herein,we report a novel role of Ythdf1 in the maintenance of retinal function using a genetic knockout model.Loss of Ythdf1 resulted in impaired scotopic electroretinogram(ERG)responses and progressive retinal degeneration.Detailed analyses of rod photoreceptors confirmed substantial degenerative changes in the absence of ciliary defects.Single-cell RNA sequencing revealed comprehensive molecular alterations across all retinal cell types in Ythdf1-deficient retinas.Integrative analysis of methylated RNA immunoprecipitation(MeRIP)sequencing and RIP sequencing identified Tulp1 and Dhx38,two inheritable retinal degeneration disease-associated gene homologs,as direct targets of YTHDF1 in the retina.Specifically,YTHDF1 recognized and bound m^(6)A-modified Tulp1 and Dhx38 mRNA at the coding sequence(CDS),enhancing their translational efficiency without altering mRNA levels.Collectively,these findings highlight the essential role of YTHDF1 in preserving visual function and reveal a novel regulatory mechanism of m^(6)A reader proteins in retinal degeneration,identifying potential therapeutic targets for severe retinopathies.
Xian-Jun Zhu;Xiao-Yan Jiang;Wen-Jing Liu;Yu-Di Fan;Guo Liu;Shun Yao;Kuan-Xiang Sun;Jun-Yao Chen;Bo Lei;Ye-Ming Yang
Henan Branch of National Clinical Research Center for Ocular Diseases,Henan Eye Hospital,People’s Hospital of Zhengzhou University,Henan Provincial People’s Hospital,Zhengzhou,Henan 450003,China 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 Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine,Jinfeng Laboratory,Chongqing 400039,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,ChinaSichuan 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,ChinaSichuan 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,ChinaSichuan 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,ChinaSichuan 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 Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine,Jinfeng Laboratory,Chongqing 400039,ChinaHenan Branch of National Clinical Research Center for Ocular Diseases,Henan Eye Hospital,People’s Hospital of Zhengzhou University,Henan Provincial People’s Hospital,Zhengzhou,Henan 450003,China Eye Institute,Henan Academy of Innovations in Medical Science,Zhengzhou,Henan 451162,ChinaSichuan 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,ChinaSichuan 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,ChinaHenan Branch of National Clinical Research Center for Ocular Diseases,Henan Eye Hospital,People’s Hospital of Zhengzhou University,Henan Provincial People’s Hospital,Zhengzhou,Henan 450003,China Eye Institute,Henan Academy of Innovations in Medical Science,Zhengzhou,Henan 451162,ChinaSichuan 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 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
医药卫生
EpitranscriptomicsN6-methyladenosine(m^(6)A)Inherited retinal dystrophies(IRDs)YTHDF1Single-cell RNA sequencingPhotoreceptor degeneration
《Zoological Research》 2025 (2)
P.429-445,17
supported by the National Natural Science Foundation of China(82371083,82471100,82121003,82271084)Program of Science and Technology International Cooperation Project of Qinghai province(China)(2022-HZ-814)。
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