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La exportación nuclear dependiente de la señal de una histona desacetilasa regula la diferenciación muscular
T A McKinsey1, C L Zhang, J Lu
1Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, 75390-9148, USA.
Nature
|November 18, 2000
Resumen
La diferenciación del músculo esquelético requiere la liberación de factores de transcripción MEF2 de los HDAC. La exportación nuclear HDAC5, desencadenada por la señalización CaMK, es crucial para este proceso, destacando el tráfico de enzimas remodeladoras de la cromatina en la diferenciación celular.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- La epigenética es la epigenética.
Sus antecedentes:
- Los factores de transcripción del factor 2 potenciador de miocitos (MEF2) son reguladores clave de la miogénesis esquelética.
- Las proteínas MEF2 interactúan con las histonas desacetilasas de clase II (HDAC), como HDAC4 y HDAC5, lo que lleva a la represión génica.
- La liberación de MEF2 de la represión mediada por HDAC es esencial para la diferenciación muscular.
Objetivo del estudio:
- Para investigar el papel de la navegación nucleo-citoplasmática HDAC5 en la miogénesis esquelética.
- Aclarar el mecanismo por el cual la señalización de la proteína quinasa dependiente de calcio/calmodulina (CaMK) influye en las interacciones MEF2-HDAC y la miogénesis.
- Determinar la importancia funcional de la fosforilación de HDAC y la exportación nuclear en el programa de diferenciación muscular.
Principales métodos:
- Utilizó ensayos de diferenciación celular en mioblastos y miotubos.
- Investigó la localización subcelular de HDAC5 usando microscopía.
- Mutagénesis dirigida en el sitio empleada para crear mutantes HDAC5 no fosforilables y constitutivamente citoplasmáticos.
- Se evaluó el impacto de estos mutantes en la expresión génica dependiente de MEF2 y la miogénesis esquelética.
Principales resultados:
- HDAC5 se somete a la exportación nuclear al citoplasma después de la diferenciación del mioblasto.
- CaMK señala los fosforilatos HDAC4 y HDAC5, induciendo su exportación nuclear y evitando la formación de complejos MEF2-HDAC.
- Un mutante HDAC5 que carecía de sitios de fosforilación de CaMK inhibió la miogénesis esquelética, mientras que un mutante citoplasmático fue menos efectivo para bloquear la diferenciación.
- La exportación nuclear demostrada de HDAC5 dependiente de la señal y la diferenciación es un mecanismo regulatorio crítico.
Conclusiones:
- El tráfico nucleo-citoplasmático de HDAC5 es un paso regulador clave en la diferenciación del músculo esquelético.
- La fosforilación mediada por CaMK y la subsiguiente exportación nuclear de HDACs controlan la actividad transcripcional MEF2.
- Este mecanismo destaca la regulación dinámica de las enzimas modificadoras de la cromatina en los procesos de diferenciación celular.
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