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La ligasa PIAS1 restringe la diferenciación natural de las células T reguladoras por la represión epigenética
Bin Liu1, Samuel Tahk, Kathleen M Yee
1Division of Hematology-Oncology, Department of Medicine, 11-934 Factor Building, 10833 Le Conte Avenue, University of California, Los Angeles, Los Angeles, CA 90095, USA. bliu@ucla.edu
Science (New York, N.Y.)
|October 23, 2010
Resumen
La SUMO E3 ligasa PIAS1 restringe la diferenciación reguladora de las células T al silenciar epigenéticamente el promotor Foxp3. La deleción de Pias1 mejora las poblaciones de células T reguladoras y la resistencia a las enfermedades autoinmunes.
Área de la Ciencia:
- Inmunología Inmunología.
- La epigenética es la epigenética.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Las células T reguladoras CD4 ((+) Foxp3 ((+)) (T ((reg)) son cruciales para la tolerancia inmune.
- La desregulación de las células T ((reg) está implicada en enfermedades autoinmunes.
- La comprensión de los mecanismos de diferenciación de T ((reg) es clave para el desarrollo terapéutico.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares que regulan la diferenciación natural de las células T.
- Investigar el papel de PIAS1 en el control de la expresión de Foxp3 y la función de T...
Principales métodos:
- Los ensayos de inmunoprecipitación de cromatina evalúan la unión de la proteína al promotor Foxp3.
- Análisis de metilación del ADN y ensayos de modificación de histonas (metilación H3K9).
- Análisis de las poblaciones de células T ((reg) y la encefalomielitis autoinmune experimental (EAE) en ratones Pias1 knockout.
Principales resultados:
- PIAS1 mantiene un estado de cromatina represivo en el promotor Foxp3.
- PIAS1 recluta ADN metiltransferasas y HP1 para el promotor Foxp3.
- La deleción de Pias1 conduce a la desmetilación del promotor de Foxp3, reducción de la metilación de H3K9 y mayor accesibilidad.
- Los ratones Pias1(-/-) exhiben poblaciones de células T(reg) expandidas y resistencia a la EAE.
Conclusiones:
- PIAS1 actúa como un regulador negativo de la diferenciación natural de las células T ((reg) a través del control epigenético.
- Este estudio identifica un nuevo mecanismo epigenético que rige el desarrollo de las células T.
- Dirigirse a PIAS1 puede ofrecer un potencial terapéutico para los trastornos autoinmunes.
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