RESUMEN
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.
Asunto(s)
Trastorno del Espectro Autista , Histona Demetilasas con Dominio de Jumonji , Ratones Noqueados , Transmisión Sináptica , Animales , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Transmisión Sináptica/genética , Trastorno del Espectro Autista/genética , Ratones , Encéfalo/metabolismo , Plasticidad Neuronal/genética , Conducta Animal , Hipocampo/metabolismo , Epigénesis Genética , Masculino , Sinapsis/metabolismoRESUMEN
Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated 38 epigenetic targets for their potential role in metastatic NSCLC. The potential candidates were ranked by a streamlined approach using in silico and in vitro experiments based on publicly available databases and evaluated by real-time qPCR target gene expression, cell viability and invasion assays, and transcriptomic analysis. The survival rate of patients with lung adenocarcinoma is inversely correlated with the gene expression of eight epigenetic targets, and a systematic review of the literature confirmed that four of them have already been identified as targets for the treatment of NSCLC. Using nontoxic doses of the remaining inhibitors, KDM6B and PADI4 were identified as potential targets affecting the invasion and migration of metastatic lung cancer cell lines. Transcriptomic analysis of KDM6B and PADI4 treated cells showed altered expression of important genes related to the metastatic process. In conclusion, we showed that KDM6B and PADI4 are promising targets for inhibiting the metastasis of lung adenocarcinoma cancer cells.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Histona Demetilasas con Dominio de Jumonji , Neoplasias Pulmonares , Arginina Deiminasa Proteína-Tipo 4 , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Detección Precoz del Cáncer , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Arginina Deiminasa Proteína-Tipo 4/genéticaRESUMEN
The discovery in mammals that fetal testes are required in order to develop the male phenotype inspired research efforts to elucidate the mechanisms underlying gonadal sex determination and differentiation in vertebrates. A pioneer work in 1966 that demonstrated the influence of incubation temperature on sexual phenotype in some reptilian species triggered great interest in the environment's role as a modulator of plasticity in sex determination. Several chelonian species have been used as animal models to test hypotheses concerning the mechanisms involved in temperature-dependent sex determination (TSD). This brief review intends to outline the history of scientific efforts that corroborate our current understanding of the state-of-the-art in TSD using chelonian species as a reference.