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Demarcación funcional de los dominios de cromatina activa y silenciosa en los loci HOX humanos mediante ARN no
John L Rinn1, Michael Kertesz, Jordon K Wang
1Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell
|July 3, 2007
Resumen
Este estudio identifica 231 nuevos ARN no codificantes (ARNnc) en los loci HOX humanos. Un ncRNA, HOTAIR, reprime la transcripción en un locus HOXD distante al interactuar con el Complejo Represor de Policombos 2 (PRC2).
Área de la Ciencia:
- Genética La genética.
- La epigenética es la epigenética.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Los ARN no codificantes (ARNnc) juegan un papel en la regulación epigenética, pero sus funciones no se comprenden completamente.
- El paisaje transcripcional de los loci HOX humanos y sus ncRNAs asociados requiere una caracterización adicional.
Objetivo del estudio:
- Mapear de manera exhaustiva el paisaje transcripcional de las HOX loci humanas.
- Identificar y caracterizar nuevos ncRNA dentro de los loci HOX e investigar sus funciones reguladoras.
- Explorar el potencial de los ncRNAs en la demarcación de los dominios cromosómicos del silenciamiento de genes.
Principales métodos:
- Perfil transcripcional de alta resolución (cinco pares de bases) de los cuatro loci HOX humanos en 11 sitios anatómicos.
- Identificación y caracterización de nuevos HOX ncRNAs.
- Investigando la interacción de los ncRNAs con los modificadores epigenéticos como el Complejo Represivo Polycomb 2 (PRC2).
- Evaluación del impacto de la expresión de ncRNA en la metilación de histonas y la accesibilidad de la ARN polimerasa.
Principales resultados:
- Descubrimiento de 231 HOX ncRNAs, extendiendo significativamente las regiones transcritas conocidas.
- Los ncRNA HOX exhiben patrones de expresión espacial a lo largo de los ejes de desarrollo y poseen motivos de secuencia únicos.
- La expresión de ncRNA se correlaciona con la metilación diferencial de histonas y la accesibilidad de la ARN polimerasa, que define los dominios cromosómicos.
- Identificación de HOTAIR, un ncRNA de 2,2 kb en el locus HOXC que reprime la transcripción en trans en el locus HOXD.
- HOTAIR interactúa con PRC2, mediando la ocupación de PRC2 y la trimetilación de H3K27 en el locus HOXD.
Conclusiones:
- La transcripción de los ncRNAs puede delinear dominios cromosómicos distantes de silenciamiento de genes.
- Los ncRNA, ejemplificados por HOTAIR, son reguladores críticos del silenciamiento de genes epigenéticos.
- Estos hallazgos tienen implicaciones significativas para la comprensión de la regulación génica en el desarrollo y la enfermedad.
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