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 transl...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.展开更多
基金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)。
文摘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.
