RESUMEN
Fat mass and obesity-associated gene (FTO) is a member of the Fe (II)- and oxoglutarate-dependent AlkB dioxygenase family and is linked to both obesity and intellectual disability. The role of FTO in neurodevelopment and neurogenesis, however, remains largely unknown. Here we show that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to decreased brain size and body weight. We find that FTO deficiency could reduce the proliferation and neuronal differentiation of adult neural stem cells in vivo, which leads to impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we went on to perform genome-wide m6A profiling and observed dynamic m6A modification during postnatal neurodevelopment. The loss of FTO led to the altered expression of several key components of the brain derived neurotrophic factor pathway that were marked by m6A. These results together suggest FTO plays important roles in neurogenesis, as well as in learning and memory.
Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Neurogénesis/genética , Animales , Peso Corporal/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diferenciación Celular/genética , Regulación de la Expresión Génica , Memoria , Ratones , Ratones Noqueados , Neuronas/metabolismo , Obesidad/genéticaRESUMEN
Epigenetic modulations play essential roles in diverse biological processes. During the past several years, DNA demethylation has been discovered in embryonic and postnatal development. Although some potential functions of DNA methylation have been demonstrated already, many questions remain in terms of unveiling the role of 5hmC; whether it serves either merely as an intermediate of DNA demethylation or as a stable epigenetic marker. 5-hydroxymethylcytosine (5hmC) is proved to be not merely serving as an intermediate of DNA demethylation, but also acts as a stable epigenetic marker. This review summarizes the current knowledge of the function of 5hmC in brain with the focus on the neuronal activity, neurodevelopment, aging, and neurological diseases.
Asunto(s)
5-Metilcitosina/metabolismo , Metilación de ADN , Neuronas/fisiología , Envejecimiento/genética , Animales , Citosina/análogos & derivados , Citosina/metabolismo , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Humanos , Enfermedades del Sistema Nervioso/genéticaRESUMEN
BACKGROUND: Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases. DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals. RESULTS: DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development. CONCLUSIONS: DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.