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Reprogramming Mouse Embryonic Fibroblasts with Transcription Factors to Induce a Hemogenic Program
Published on: December 16, 2016
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Los factores de transcripción LRF y BCL11A reprimen independientemente la expresión de la hemoglobina fetal
Takeshi Masuda1, Xin Wang2, Manami Maeda1
1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|January 28, 2016
Resumen
Los investigadores identificaron el factor de transcripción LRF como la clave para silenciar la hemoglobina fetal en los adultos. Este descubrimiento ofrece nuevos objetivos terapéuticos para el tratamiento de trastornos de la globina como la anemia falciforme y la talasemia.
Área de la Ciencia:
- Biología molecular
- La genética
- Hematología
Sus antecedentes:
- Los genes de globina tipo β humanos cambian de expresión en el desarrollo de formas embrionarias a fetales a adultas.
- Las mutaciones en la β-globina adulta causan hemoglobinopatías como la anemia falciforme y la talasemia.
- La inducción de la hemoglobina fetal (HbF) es una estrategia terapéutica potencial para estos trastornos, pero los mecanismos de represión en los adultos no se comprenden completamente.
Objetivo del estudio:
- Elucidar los mecanismos moleculares responsables de la represión de la expresión de la hemoglobina fetal (HbF) en los adultos.
- Identificar nuevos objetivos terapéuticos para las hemoglobinopatías mediante la comprensión del silenciamiento de la HbF.
Principales métodos:
- Se investigó el papel del factor de transcripción LRF/ZBTB7A en la regulación de la expresión génica de la γ-globina.
- Se analizó la interacción de LRF con complejos de cromatina y represores, incluidos NuRD y BCL11A.
- Se evaluó el impacto de LRF en la densidad de los nucleosomas en los genes de globina fetal.
Principales resultados:
- El factor de transcripción LRF/ ZBTB7A se une a los genes de la γ-globina fetal en las células adultas.
- LRF mantiene una alta densidad de nucleosomas en estos genes, contribuyendo a su silenciamiento.
- LRF ejerce su función represiva a través del complejo represor NuRD, independientemente de BCL11A.
Conclusiones:
- LRF/ZBTB7A es un factor crítico en el silenciamiento del desarrollo de los genes de la γ-globina fetal en adultos.
- El complejo LRF-NuRD representa un nuevo objetivo para las estrategias terapéuticas destinadas a reactivar la HbF.
- Este hallazgo abre nuevas vías para el tratamiento de las hemoglobinopatías hereditarias.
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