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El modelo de enfermedad de la mutación GATA4 revela la cooperatividad del factor de transcripción en la cardiogénesis
Yen-Sin Ang1, Renee N Rivas1, Alexandre J S Ribeiro2
1Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
|December 17, 2016
Resumen
Una mutación del gen GATA4 altera la función de las células cardíacas y interrumpe la regulación génica, lo que lleva a defectos cardíacos. Este estudio revela cómo las mutaciones en los factores de transcripción causan enfermedades al afectar las interacciones proteicas y la unión al ADN.
Área de la Ciencia:
- Biología molecular
- La genética
- Cardiología
Sus antecedentes:
- Las mutaciones en los factores de transcripción altamente conservados pueden interrumpir las redes de genes, causando enfermedades humanas.
- GATA4, un factor de transcripción cardiogénico crucial, está implicado en los defectos del tabique cardíaco y la miocardiopatía cuando está mutado.
- Comprender los mecanismos moleculares de las mutaciones GATA4 es vital para diagnosticar y tratar enfermedades cardíacas congénitas.
Objetivo del estudio:
- Investigar las consecuencias funcionales de una mutación heterocigótica GATA4-G296S en los cardiomiocitos humanos.
- Para aclarar el impacto de la mutación GATA4-G296S en la interacción con TBX5 y su papel en la regulación del gen cardíaco.
- Explorar cómo esta mutación afecta los estados de la cromatina y la disfunción celular, contribuyendo a los defectos morfogenéticos cardíacos.
Principales métodos:
- Se utilizaron cardiomiocitos derivados de células madre pluripotentes inducidas (iPS) de pacientes con la mutación GATA4-G296S.
- Se analizó la contractilidad de los cardiomiocitos, el manejo del calcio y la actividad metabólica.
- Se realizaron estudios de co-ocupación de GATA4 y TBX5 en potenciadores cardíacos y se evaluó la expresión génica y la accesibilidad a la cromatina.
Principales resultados:
- La mutación GATA4-G296S alteró la contractilidad de los cardiomiocitos, el manejo del calcio y la función metabólica.
- Esta mutación interrumpió el reclutamiento de TBX5 a los super potenciadores cardíacos, lo que condujo a una desregulación de los genes involucrados en la septación cardíaca.
- La mutación también causó el fracaso de la represión mediada por GATA4/TBX5 en genes no cardíacos y estados alterados de cromatina en promotores endoteliales.
Conclusiones:
- Las mutaciones de malentendido causantes de enfermedades en GATA4 pueden interrumpir la cooperación transcripcional con TBX5.
- Los estados aberrantes de la cromatina y la disfunción celular, incluidos los defectos morfogenéticos, son el resultado de redes de transcripción interrumpidas.
- Este estudio proporciona información sobre la base molecular de las enfermedades cardíacas asociadas con GATA4.
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