RESUMO
Highly conserved non-coding DNA regions (HCNR) occur frequently in vertebrate genomes, but their functional roles remain unclear. Here, we provide evidence that a large portion of HCNRs are enriched for binding sites for Sox, POU and Homeodomain transcription factors, and such HCNRs can act as cis-regulatory regions active in neural stem cells. Strikingly, these HCNRs are linked to several hundreds of genes expressed in the developing CNS and they may exert locus-wide regulatory effects on multiple genes flanking their genomic location. Moreover, these data imply a unifying transcriptional logic for a large set of CNS-expressed genes in which Sox and POU proteins act as generic promoters of transcription while Homeodomain proteins control the spatial expression of genes through active repression.
Assuntos
Sistema Nervoso Central/metabolismo , Sequência Conservada/genética , Genoma/genética , Sequências Reguladoras de Ácido Nucleico/genética , Transcrição Gênica/genética , Animais , Sequência de Bases , Sítios de Ligação , Padronização Corporal/genética , Células Cultivadas , Embrião de Galinha , Regulação para Baixo/genética , Genômica , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Íntrons/genética , Camundongos , Dados de Sequência Molecular , Neurônios/metabolismo , Fatores do Domínio POU/metabolismo , Tetraodontiformes/genéticaRESUMO
The generation of neurons constitutes the foundation of nervous system development, yet the mechanisms underlying neurogenesis are not well established. The HMG-box transcription factors Sox1, Sox2 and Sox3 (Sox1-3) have previously been shown to suppress neurogenesis by maintaining neural cells in an undifferentiated state. Here we report that another HMG-box protein, Sox21, has the opposite activity and promotes neuronal differentiation. Using genetic studies in the chick embryo, we found that Sox21 mediates this function by counteracting the activity of Sox1-3. Accordingly, the balance of Sox21 and Sox1-3 activities determines whether neural cells remain as progenitors or commit to differentiation. Proneural basic helix-loop-helix proteins are essential for the establishment of neuronal fates. We now show that proneural proteins promote neurogenesis by upregulating Sox21 expression. These data establish a key role for Sox21 in the progression of neuronal differentiation and indicate that an important role of proneural proteins is their capacity to upregulate the expression of Sox21.
