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El factor de remodelación de la cromatina Mll1 es esencial para la neurogénesis de las células madre neurales
Daniel A Lim1, Yin-Cheng Huang, Tomek Swigut
1Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Street M779, San Francisco, California 94143, USA. limd@neurosurg.ucsf.edu
Nature
|February 13, 2009
Resumen
La leucemia de linaje mixto 1 (Mll1) es esencial para la neurogénesis en adultos. Mll1 resuelve los loci genéticos silenciados, permitiendo la diferenciación neuronal en el cerebro postnatal.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- La epigenética es la epigenética.
- Biología de las células madre Biología de las células madre
Sus antecedentes:
- La neurogénesis adulta se basa en mecanismos epigenéticos, con los genes del grupo Trithorax (trxG) y el grupo Polycomb (PcG) que regulan la cromatina.
- Si bien se sabe que el miembro PcG Bmi1 es crucial para la auto-renovación de las células madre neurales, el papel de los genes trxG en este proceso es inexplorado.
Objetivo del estudio:
- Para investigar el papel del gen trxG Mll1 (leucemia de linaje mixto 1) en la neurogénesis postnatal.
- Para dilucidar los mecanismos moleculares por los cuales Mll1 influye en la diferenciación neuronal en la zona subventricular.
Principales métodos:
- Análisis de ratones con deficiencia de Mll1 para evaluar la neurogénesis en el cerebro postnatal.
- Análisis de la expresión génica (Mash1, Olig2, Dlx2) en células madre neurales.
- Inmunoprecipitación de la cromatina para identificar objetivos de MLL.
- Análisis de la modificación de la histona (H3K4me3, H3K27me3) en las localizaciones de los genes objetivo.
Principales resultados:
- Las células madre neurales deficientes de Mll1 exhiben una diferenciación neuronal deteriorada pero una diferenciación glial normal.
- La expresión del regulador clave de la neurogénesis Dlx2 se suprime en las células deficientes de Mll1.
- Dlx2 es un objetivo directo de MLL, y su locus muestra marcas de histona bivalente (H3K4me3 y H3K27me3) en células deficientes de Mll1, impidiendo la activación.
Conclusiones:
- Mll1 es indispensable para la neurogénesis postnatal al activar la expresión de genes clave como Dlx2.2.
- Mll1 funciona resolviendo las marcas de cromatina bivalente en los loci críticos del desarrollo, promoviendo así la diferenciación neuronal.
- Estos hallazgos ponen de relieve un nuevo mecanismo epigenético que regula la neurogénesis en adultos.
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