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La inhibición de la actividad de PRC2 por una mutación H3 de ganancia de función encontrada en el glioblastoma
Peter W Lewis1, Manuel M Müller, Matthew S Koletsky
1Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Science (New York, N.Y.)
|March 30, 2013
Resumen
Los gliomas pediátricos con mutaciones en la histona H3 Lys27Met (K27M) muestran niveles reducidos de H3K27me3. Esta mutación K27M inhibe el complejo represivo 2 de Polycomb, lo que sugiere un nuevo mecanismo de alteración epigenética en los cánceres.
Área de la Ciencia:
- Oncología Oncología.
- La epigenética es la epigenética.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Los gliomas pediátricos, incluidos los gliomas pontinos intrínsecos difusos (DIPG), a menudo se caracterizan por mutaciones específicas en los genes de la histona.
- Las mutaciones de Lys27Met (K27M) y Gly34Arg/Val (G34R/V) en H3F3A y HIST3H1B han sido identificadas en gliomas pediátricos.
Objetivo del estudio:
- Para investigar las consecuencias funcionales de las mutaciones de la histona H3, en particular K27M, en la metilación de la histona.
- Determinar el mecanismo por el cual H3K27M afecta los niveles de H3K27me3 y la actividad del complejo represivo 2 (PRC2) de Polycomb.
Principales métodos:
- Análisis de los niveles de H3K27me3 en DIPG humanos con mutaciones K27M.
- Expresión de los transgenes H3K27M in vitro e in vivo para evaluar los efectos sobre el H3K27me3.
- Ensayos bioquímicos para estudiar la interacción entre H3K27M y la subunidad EZH2 de PRC2.2.
- Investigando el impacto de otras sustituciones de lisina por metionina (H3K9, H3K36) en la metilación de histonas.
Principales resultados:
- Los DIPG humanos con mutaciones K27M exhiben niveles significativamente reducidos de H3K27me3.
- Los transgenes H3K27M son suficientes para disminuir H3K27me3 en modelos celulares y animales.
- H3K27M inhibe directamente la actividad enzimática de PRC2 al interactuar con EZH2.2.
- Las sustituciones de lisina por metionina en H3K9 y H3K36 también conducen a reducciones específicas en la metilación al inhibir las enzimas del dominio SET.
Conclusiones:
- La mutación H3 K27M es un factor clave de la reducción de H3K27me3 en los gliomas pediátricos.
- Las sustituciones K-a-M de la histona H3 representan un mecanismo potencial para alterar los estados epigenéticos en diversas patologías.
- Dirigirse a PRC2 o comprender estas alteraciones epigenéticas podría ofrecer nuevas estrategias terapéuticas para los gliomas pediátricos.
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