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La supresión de la sobreactivación del potenciador por un complejo de RACK7-histona desmetilasa

Hongjie Shen¹, Wenqi Xu¹, Rui Guo²

¹Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Key Laboratory of Epigenetics, Department of Cellular and Genetic Medicine, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China.

|April 9, 2016

Resumen

El complejo RACK7/KDM5C actúa como un frenador potenciador, controlando la expresión génica. Su pérdida conduce a la sobreactivación del potenciador y promueve el desarrollo del cáncer al suprimir los oncogenes.

Área de la Ciencia:

La bioquímica
Biología molecular
La epigenética

Sus antecedentes:

La expresión génica está estrictamente regulada por la actividad del potenciador.
Comprender los mecanismos que controlan los potenciadores es crucial para descifrar la regulación genética y el desarrollo de la enfermedad.

Objetivo del estudio:

Investigar el papel del complejo RACK7/KDM5C en la regulación de la actividad del potenciador.
Aclarar los mecanismos moleculares mediante los cuales RACK7/KDM5C controla la expresión génica y sus implicaciones en el cáncer.

Principales métodos:

Aislamiento y caracterización de complejos bioquímicos.
Secuenciación de la inmunoprecipitación de la cromatina (ChIP-seq) para analizar las modificaciones histónicas (H3K4me3, H3K4me1, H3K27Ac).
PCR cuantitativa en tiempo real (qRT-PCR) para el análisis de ARNr y la expresión génica.
Análisis fenotípico de los fenotipos relacionados con el cáncer.

Principales resultados:

El complejo RACK7/KDM5C se encuentra en los potenciadores activos, incluidos los super potenciadores.
La pérdida de RACK7 o KDM5C causa una sobreactivación del potenciador, marcada por un aumento de H3K4me3 y H3K27Ac.
La alteración de RACK7/KDM5C conduce a un aumento de eRNA y de la transcripción génica cercana.
El agotamiento de RACK7/KDM5C resulta en la desrepresión de los oncogenes S100A y promueve los fenotipos del cáncer.

Conclusiones:

RACK7/KDM5C actúa como un frenado potenciador, regulando el intercambio dinámico entre H3K4me1 y H3K4me3.
La función comprometida de RACK7/KDM5C contribuye a la tumorigénesis a través de la actividad del potenciador aberrante y la desrepresión oncogénica.

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