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Se requiere Tet2 para resolver la inflamación mediante el reclutamiento de Hdac2 para reprimir específicamente la
Qian Zhang1,2, Kai Zhao1, Qicong Shen2
1National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
Nature
|August 20, 2015
Resumen
La proteína de translocación 2 (Tet2) reprime activamente la transcripción del gen de la interleucina-6 (IL-6) durante la resolución de la inflamación en las células mieloides. La pérdida de Tet2 conduce a un aumento de la IL-6 y a una mayor susceptibilidad a las condiciones inflamatorias.
Área de la Ciencia:
- La epigenética
- Inmunología
- Biología molecular
Sus antecedentes:
- Los modificadores epigenéticos establecen la identidad celular a través de la cromatina y la metilación.
- Diez de las once proteínas de translocación (Tet) son modificadores clave del ADN, con funciones más allá de la metilación del ADN.
- La función de las proteínas Tet en la inmunidad y la inflamación, independiente de la metilación del ADN, es en gran medida inexplorada.
Objetivo del estudio:
- Investigar el papel de las proteínas Tet en la regulación de la inmunidad y la inflamación independientemente de sus funciones de metilación del ADN.
- Para aclarar el mecanismo específico por el cual Tet2 regula la transcripción de la interleucina-6 (IL-6) durante la resolución de la inflamación.
Principales métodos:
- Se utilizaron modelos de ratón con deficiencia de Tet2 y células mieloides innatas (células dendríticas, macrófagos).
- Se evaluó la expresión de mediadores inflamatorios, incluida la IL-6, tras el desafío de los lipopolisacáridos.
- Investigó el reclutamiento de Tet2 al promotor Il6 y su interacción con IκBζ y Hdac2.
- Se analizó la desacetilación de histonas en el promotor Il6.
Principales resultados:
- Tet2 reprime selectivamente la transcripción de IL-6 durante la fase de resolución de la inflamación en las células mieloides.
- La deficiencia de Tet2 dio lugar a un aumento de la IL-6 y otros mediadores inflamatorios después del desafío lipopolisacárido.
- Los ratones con deficiencia de Tet2 mostraron una mayor susceptibilidad al shock de endotoxinas y a la colitis inducida por DSS con inflamación exacerbada.
- Tet2 fue reclutado para el promotor Il6 por IκBζ y la transcripción fue reprimida a través de la desacetilación de histonas mediada por Hdac2, independiente de los cambios en la metilación del ADN.
Conclusiones:
- Tet2 juega un papel crítico en la resolución activa de la inflamación mediante la represión de la transcripción de IL-6 a través de la desacetilación de histonas.
- Este mecanismo, independiente de la metilación del ADN, previene la activación inflamatoria sostenida a nivel de la cromatina.
- La actividad represiva específica del gen Tet2 es crucial para la resolución oportuna de la inflamación y el mantenimiento de la homeostasis inmune.
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