Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.
Blood
; 139(16): 2534-2546, 2022 04 21.
Article
em En
| MEDLINE
| ID: mdl-35030251
ABSTRACT
Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Transcrição GATA1
/
Anemia
Limite:
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Marrocos