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La pantalla CRISPR enfocada en el dominio identifica a HRI como un regulador de la hemoglobina fetal en las células

Jeremy D Grevet^1,2, Xianjiang Lan¹, Nicole Hamagami¹

¹Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Science (New York, N.Y.)

|July 21, 2018

Resumen

Los investigadores identificaron el HRI (inhibidor regulado por el hemo) como un inhibidor clave de la hemoglobina fetal (HbF) en adultos. La inhibición de HRI aumenta la producción de HbF, ofreciendo una nueva terapia potencial para la anemia falciforme y la beta-talasemia.

Área de la Ciencia:

Hematología
Biología molecular
La genética

Sus antecedentes:

El aumento de la hemoglobina fetal (HbF) en adultos ofrece beneficios terapéuticos para la anemia falciforme y la beta-talasemia.
La identificación de reguladores de HbF en células eritroides adultas es crucial para el desarrollo de nuevos tratamientos.

Objetivo del estudio:

Para descubrir los reguladores de la HbF en las células eritroides humanas adultas.
Investigar el papel de las quinasas en el control de los niveles de HbF.

Principales métodos:

Utilizó una pantalla genética CRISPR-Cas9 dirigida a los dominios de la proteína quinasa.
Empleó un andamio de ARN de guía única optimizado para una detección mejorada.
Se analizó el impacto del agotamiento de la quinasa en la producción de HbF y en la formación de células rojas falciformes.

Principales resultados:

HRI identificado (inhibidor regulado por el hemo/EIF2AK1) como un represor de HbF específico de las eritroides.
El agotamiento de HRI aumentó significativamente los niveles de HbF y redujo el número de glóbulos rojos falciformes in vitro.
Se observó una disminución en la expresión de BCL11A, un conocido represor de HbF, después del agotamiento de HRI.

Conclusiones:

HRI es un nuevo represor de la hemoglobina fetal en las células eritroides adultas.
La orientación de HRI presenta una estrategia terapéutica prometedora para las hemoglobinopatías.
El eje HRI-BCL11A es una vía clave que regula la producción de HbF.

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