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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
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La desacetilasa dependiente de NAD+ SIRT1 modula la remodelación de la cromatina mediada por CLOCK y el control
Yasukazu Nakahata1, Milota Kaluzova, Benedetto Grimaldi
1Department of Pharmacology, University of California, Irvine, CA 92697, USA.
Cell
|July 30, 2008
Resumen
La proteína del reloj circadiano CLOCK acetila la histona H3 y BMAL1. La desacetilasa dependiente de NAD (((+) SIRT1 regula el ritmo circadiano desacetilando estas proteínas, actuando como un sensor metabólico clave.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Cronobiología cronobiología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los ritmos circadianos regulan los procesos metabólicos y fisiológicos esenciales.
- La proteína CLOCK posee actividad de la histona acetiltransferasa (HAT), crucial para la función circadiana.
- CLOCK acetila la histona H3 y su socio BMAL1 en residuos específicos de lisina.
Objetivo del estudio:
- Para investigar el papel de la deacetilasa dependiente de NAD (((+) SIRT1 en la regulación del ritmo circadiano.
- Para determinar si la actividad de SIRT1 está regulada rítmicamente y asociada con los componentes del reloj circadiano.
- Para dilucidar la función in vivo de SIRT1 en el mantenimiento de la homeostasis circadiana.
Principales métodos:
- Se evaluó la regulación circadiana de la actividad de la histona desacetilasa (HDAC) de SIRT1.
- Se examinó la acetilación rítmica de BMAL1 y la histona H3.
- Investigó la asociación de SIRT1 con el complejo CLOCK:BMAL1 en promotores circadianos.
- Utilizó la ablación genética del gen Sirt1 y la inhibición farmacológica.
- Se emplearon ratones mutantes SIRT1 específicos del hígado para estudios in vivo.
Principales resultados:
- La actividad HDAC de SIRT1 está regulada por el ritmo circadiano, correlacionándose con la acetilación rítmica de BMAL1 y H3.
- SIRT1 se asocia físicamente con CLOCK y es reclutado para los promotores circadianos.
- La ablación o inhibición del gen Sirt1 interrumpe los ciclos circadianos y la acetilación de histonas/BMAL1.
- La deficiencia de SIRT1 específica del hígado afecta el control circadiano in vivo.
Conclusiones:
- SIRT1 actúa como un regulador circadiano por desacetilación de la histona H3 y BMAL1.
- SIRT1 funciona como un reóstato enzimático, que vincula el metabolismo celular con el reloj circadiano.
- SIRT1 es esencial para mantener el ritmo circadiano y la regulación epigenética de los genes del reloj.
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