Project description:Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation1. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood2,3. Here, we characterize a distinct 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 accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective 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.
Project description:Master regulators, such as the hematopoietic transcription factor GATA1, have numerous roles in lineage commitment and differentiation. While human GATA1 mutations result in several blood diseases, all characterized mutations act relatively early to impair hematopoietic differentiation. Here, we describe a distinct form of hemolytic anemia involving impaired terminal erythropoiesis with a reduced lifespan of circulating red blood cells. We show that this unique blood disorder results from mutations in a poorly characterized and intrinsically disordered C-terminal region of GATA1.
Project description:Master regulators, such as the hematopoietic transcription factor GATA1, have numerous roles in lineage commitment and differentiation. While human GATA1 mutations result in several blood diseases, all characterized mutations act relatively early to impair hematopoietic differentiation. Here, we describe a distinct form of hemolytic anemia involving impaired terminal erythropoiesis with a reduced lifespan of circulating red blood cells. We show that this unique blood disorder results from mutations in a poorly characterized and intrinsically disordered C-terminal region of GATA1.
Project description:Master regulators, such as the hematopoietic transcription factor GATA1, have numerous roles in lineage commitment and differentiation. While human GATA1 mutations result in several blood diseases, all characterized mutations act relatively early to impair hematopoietic differentiation. Here, we describe a distinct form of hemolytic anemia involving impaired terminal erythropoiesis with a reduced lifespan of circulating red blood cells. We show that this unique blood disorder results from mutations in a poorly characterized and intrinsically disordered C-terminal region of GATA1.