A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient Cut&Run]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155253 | GEO | 2021/12/31

REPOSITORIES: GEO