RESUMEN
In neurons, the timely and accurate expression of genes in response to synaptic activity relies on the interplay between epigenetic modifications of histones, recruitment of regulatory proteins to chromatin and changes to nuclear structure. To identify genes and regulatory elements responsive to synaptic activation in vivo, we performed a genome-wide ChIPseq analysis of acetylated histone H3 using somatosensory cortex of mice exposed to novel enriched environmental (NEE) conditions. We discovered that Short Interspersed Elements (SINEs) located distal to promoters of activity-dependent genes became acetylated following exposure to NEE and were bound by the general transcription factor TFIIIC. Importantly, under depolarizing conditions, inducible genes relocated to transcription factories (TFs), and this event was controlled by TFIIIC. Silencing of the TFIIIC subunit Gtf3c5 in non-stimulated neurons induced uncontrolled relocation to TFs and transcription of activity-dependent genes. Remarkably, in cortical neurons, silencing of Gtf3c5 mimicked the effects of chronic depolarization, inducing a dramatic increase of both dendritic length and branching. These findings reveal a novel and essential regulatory function of both SINEs and TFIIIC in mediating gene relocation and transcription. They also suggest that TFIIIC may regulate the rearrangement of nuclear architecture, allowing the coordinated expression of activity-dependent neuronal genes.
Asunto(s)
Epigénesis Genética , Elementos de Nucleótido Esparcido Corto/genética , Factores de Transcripción TFIII/genética , Transcripción Genética , Acetilación , Animales , Cromatina/genética , Histonas/genética , Ratones , Regiones Promotoras Genéticas , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de Transcripción TFIII/metabolismoAsunto(s)
Investigación Biomédica/economía , Colaboración de las Masas/economía , Oncología Médica/economía , Apoyo a la Investigación como Asunto/economía , Análisis de la Célula Individual/economía , Altruismo , Donaciones , Humanos , Sector Privado/economía , Evaluación de Programas y Proyectos de Salud , Sector Público/economía , Factores de TiempoRESUMEN
Spatiotemporal regulation of gene expression depends on the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. Here, we show that, in cortical neurons, a subset of short interspersed nuclear elements (SINEs) located in the proximity of activity-regulated genes bears features of enhancers. Enhancer SINEs (eSINEs) recruit the Pol III cofactor complex TFIIIC in a stimulus-dependent manner and are transcribed by Pol III in response to neuronal depolarization. Characterization of an eSINE located in proximity to the Fos gene (FosRSINE1) indicated that the FosRSINE1-encoded transcript interacts with Pol II at the Fos promoter and mediates Fos relocation to Pol II factories, providing an unprecedented molecular link between Pol III and Pol II transcription. Strikingly, knockdown of the FosRSINE1 transcript induces defects of both cortical radial migration in vivo and activity-dependent dendritogenesis in vitro, demonstrating that FosRSINE1 acts as a strong enhancer of Fos expression in diverse physiological contexts.
Asunto(s)
ARN Polimerasa III/metabolismo , ARN Polimerasa II/metabolismo , Animales , Ratones , Neuronas/metabolismo , Regiones Promotoras Genéticas/genética , ARN Polimerasa II/genética , ARN Polimerasa III/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Elementos de Nucleótido Esparcido Corto/genética , Factores de Transcripción TFIII/genética , Factores de Transcripción TFIII/metabolismo , Transcripción Genética/genéticaRESUMEN
miR-132 is a CREB-induced microRNA that is involved in dendritic spine plasticity. We found that visual experience regulated histone post-translational modifications at a CRE locus that is important for miR-212 and miR-132 cluster transcription, and regulated miR-132 expression in the visual cortex of juvenile mice. Monocular deprivation reduced miR-132 expression in the cortex contralateral to the deprived eye. Counteracting this miR-132 reduction with an infusion of chemically modified miR-132 mimic oligonucleotides completely blocked ocular dominance plasticity.