RESUMEN
Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3'UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.
Asunto(s)
Adenosina/análogos & derivados , Envejecimiento/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Células de la Granulosa/metabolismo , Ovario/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Regiones no Traducidas 3'/genética , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Estudios de Casos y Controles , Línea Celular , Regulación hacia Abajo/genética , Femenino , Silenciador del Gen , Humanos , Metilación , Modelos Biológicos , Proteínas Proto-Oncogénicas c-fos/genética , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.