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Variante de riesgo asociado a Parkinson en el potenciador distal de la α-sinucleína que modula la expresión génica

Frank Soldner¹, Yonatan Stelzer¹, Chikdu S Shivalila^1,2

¹The Whitehead Institute, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.

|April 21, 2016

Resumen

Los investigadores desarrollaron un nuevo método que combina la epigenética y la edición de genes CRISPR / Cas9 para comprender cómo las variantes de riesgo genético influyen en la expresión génica y enfermedades complejas como la enfermedad de Parkinson.

Área de la Ciencia:

La genómica
La epigenética
La neurociencia

Sus antecedentes:

Los estudios de asociación de todo el genoma (GWAS) identifican variantes genéticas vinculadas a enfermedades complejas.
Comprender el papel funcional de las variantes no codificantes en la patogénesis de la enfermedad sigue siendo un desafío.
Los estudios epigenéticos muestran que las variantes de GWAS se enriquecen en elementos de ADN reguladores.

Objetivo del estudio:

Desarrollar una nueva estrategia para diseccionar funcionalmente los efectos de acción cis de las variantes de riesgo genético.
Para conectar la variación genética en los elementos reguladores a los cambios en la expresión génica.
Aclarar el mecanismo por el cual una variante de riesgo de la enfermedad de Parkinson afecta la expresión de SNCA.

Principales métodos:

Datos epigenéticos combinados de todo el genoma con edición del genoma CRISPR/Cas9 en células madre pluripotentes humanas.
Creó un sistema experimental controlado genéticamente para estudiar los efectos de las variantes.
Investigó el papel de una variante de riesgo asociada a la enfermedad de Parkinson en un potenciador distal.

Principales resultados:

Se identificó una variante común de riesgo de enfermedad de Parkinson en un potenciador no codificante.
Se ha demostrado que esta variante regula la expresión del gen SNCA (α-sinucleína) asociado a la enfermedad de Parkinson.
Se encontró que la desregulación transcripcional de SNCA implica la unión dependiente de la secuencia de los factores de transcripción EMX2 y NKX6-1.

Conclusiones:

Estableció un paradigma experimental para vincular funcionalmente la variación genética con los fenotipos de las enfermedades.
Proporcionó información mecanicista sobre cómo una variante genética específica de riesgo contribuye a la patogénesis de la enfermedad de Parkinson.
Destacó el papel de las variantes reguladoras de acción cis en la variación de rasgos complejos y la susceptibilidad a la enfermedad.

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