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
Studies have indicated that oligodendrocytes in the spinal cord originate from a ventral progenitor domain defined by expression of the oligodendrocyte-determining bHLH proteins Olig1 and Olig2. Here, we provide evidence that progenitors in the dorsal spinal cord and hindbrain also produce oligodendrocytes and that the specification of these cells may result from a dorsal evasion of BMP signaling over time. Moreover, we show that the generation of ventral oligodendrocytes in the spinal cord depends on Nkx6.1 and Nkx6.2 function, while these homeodomain proteins in the anterior hindbrain instead suppress oligodendrocyte specification. The opposing roles for Nkx6 proteins in the spinal cord and hindbrain, in turn, appear to reflect that oligodendrocytes are produced by distinct ventral progenitor domains at these axial levels. Based on these findings, we propose that oligodendrocytes derive from several distinct positional origins and that the activation of Olig1/2 at different positions is controlled by distinct genetic programs.
Assuntos
Diferenciação Celular/genética , Oligodendroglia/metabolismo , Rombencéfalo/embriologia , Medula Espinal/embriologia , Células-Tronco/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Biomarcadores , Proteína Morfogenética Óssea 7 , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Hedgehog , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/citologia , Fator de Transcrição PAX7 , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Rombencéfalo/citologia , Rombencéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Evolutionarily conserved sequences within or adjoining orthologous genes often serve as critical cis-regulatory regions. Recent studies have identified long, non-coding genomic regions that are perfectly conserved between human and mouse, termed ultra-conserved regions (UCRs). Here, we focus on UCRs that cluster around genes involved in early vertebrate development; genes conserved over 450 million years of vertebrate evolution. RESULTS: Based on a high resolution detection procedure, our UCR set enables novel insights into vertebrate genome organization and regulation of developmentally important genes. We find that the genomic positions of deeply conserved UCRs are strongly associated with the locations of genes encoding key regulators of development, with particularly strong positional correlation to transcription factor-encoding genes. Of particular importance is the observation that most UCRs are clustered into arrays that span hundreds of kilobases around their presumptive target genes. Such a hallmark signature is present around several uncharacterized human genes predicted to encode developmentally important DNA-binding proteins. CONCLUSION: The genomic organization of UCRs, combined with previous findings, suggests that UCRs act as essential long-range modulators of gene expression. The exceptional sequence conservation and clustered structure suggests that UCR-mediated molecular events involve greater complexity than traditional DNA binding by transcription factors. The high-resolution UCR collection presented here provides a wealth of target sequences for future experimental studies to determine the nature of the biochemical mechanisms involved in the preservation of arrays of nearly identical non-coding sequences over the course of vertebrate evolution.
