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Pooled shRNA Screen for Reactivation of MeCP2 on the Inactive X Chromosome
Published on: March 2, 2018
Proteínas policombadas dirigidas por un ARN de repetición corta al cromosoma X del ratón
Jing Zhao1, Bryan K Sun, Jennifer A Erwin
1Howard Hughes Medical Institute, Boston, MA 02115, USA.
Science (New York, N.Y.)
|November 1, 2008
Resumen
Las hembras de los mamíferos silencian un cromosoma X a través de la inactivación del cromosoma X (XCI). Un nuevo ncRNA, RepA, dentro del ARN Xist recluta PRC2, un complejo clave, iniciando el XCI y el silenciamiento de genes.
Área de la Ciencia:
- Genética La genética.
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
Sus antecedentes:
- Las hembras de mamíferos igualan la dosis del cromosoma X inactivando un cromosoma X.
- La iniciación de la inactivación del cromosoma X (XCI) se basa en el ARN no codificante Xist (ncRNA) que se acumula en el cis.
- El mecanismo preciso del silenciamiento genético mediado por Xist sigue sin estar claro debido a factores de interacción no identificados.
Objetivo del estudio:
- Para dilucidar el mecanismo del silenciamiento genético inducido por Xist.
- Para identificar los factores que interactúan con Xist durante la inactivación del cromosoma X.
- Para investigar el papel de los ncRNA en el reclutamiento de complejos silenciadores.
Principales métodos:
- Descubrimiento y caracterización de un 1,6-kilobase ncRNA (RepA) dentro del Xist.
- Identificación del Complejo Represivo de Policombos 2 (PRC2) como objetivo directo del RepA.
- Evaluación del impacto del agotamiento de RepA y la deficiencia de PRC2 en la expresión de Xist y las modificaciones de la histona.
Principales resultados:
- RepA fue identificado como un ncRNA dentro de Xist, que interactúa directamente con PRC2.
- Ezh2 fue identificado como la subunidad PRC2 que se une al ARN RepA.
- Se encontró que el antisense Tsix RNA inhibe la interacción RepA-PRC2.
- El agotamiento de RepA abolió la inducción de Xist de longitud completa y la trimetilación de H3K27.
- La deficiencia de PRC2 comprometió la regulación ascendente de Xist, confirmando su necesidad de iniciación de XCI.
Conclusiones:
- El ARN RepA actúa como un cofactor crucial, reclutando a PRC2 para iniciar la inactivación del cromosoma X.
- La interacción RepA-PRC2 es esencial para el inicio y la propagación de XCI.
- Este estudio revela un nuevo mecanismo donde los ncRNA reclutan complejos de Polycomb para apuntar a los loci para el silenciamiento epigenético.
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