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Destino celular alterado a través de mutaciones de ganancia de función en un lector de cromatina
Liling Wan1,2, Shasha Chong3,4, Fan Xuan5
1Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. Liling.Wan@Pennmedicine.upenn.edu.
Nature
|December 20, 2019
Resumen
Mutaciones en la proteína ENL
Área de la Ciencia:
- La epigenética
- Biología del cáncer
- Biología del desarrollo
Sus antecedentes:
- Las modificaciones de la histona regulan la expresión génica y son cruciales en el desarrollo y la enfermedad.
- Las proteínas lectoras interpretan las modificaciones histónicas, pero su papel en la patogénesis de la enfermedad no está claro.
- La proteína ENL, un lector de la acetilación de histonas, está implicada en la leucemia aguda y el tumor de Wilms.
Objetivo del estudio:
- Investigar cómo las mutaciones en el dominio ENL YEATS contribuyen al desarrollo del tumor de Wilms.
- Aclarar los mecanismos moleculares por los que las mutaciones de ENL afectan el reclutamiento de cromatina y la expresión génica.
- Comprender el papel de la autoasociación ENL en la oncogénesis.
Principales métodos:
- Utilizó líneas celulares humanas y de ratón.
- Se realizó la inmunoprecipitación de cromatina y el análisis de la expresión génica.
- Se evaluó la nefrogénesis utilizando ensayos de células de ratón.
- Investigó la autoasociación de proteínas y la formación de puntos nucleares.
Principales resultados:
- Las mutaciones ENL confieren una ganancia de función en el reclutamiento de cromatina y el control de la transcripción.
- La ENL mutante impulsa cambios en la expresión génica que favorecen el destino de las células premalignas.
- Los mutantes ENL exhiben una mayor autoasociación, formando puntos nucleares que mejoran la ocupación de la cromatina y la activación génica.
- ENL mutante en ensayos de nefrogénesis produjo estructuras indiferenciadas que se asemejan a los tumores de Wilms.
Conclusiones:
- Las mutaciones de puntos calientes en el dominio ENL YEATS interrumpen la regulación normal del destino celular durante el desarrollo.
- La autoasociación ENL impulsada por la mutación conduce a un reclutamiento de cromatina auto reforzado y resultados oncogénicos en el tumor de Wilms.
- Comprender estos mecanismos proporciona información sobre la patogénesis del cáncer de riñón pediátrico.
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