Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

• Published in: Blood 2022-04, Vol.139 (16), p.2534-2546
• Main Authors: Ludwig, Leif S., Lareau, Caleb A., Bao, Erik L., Liu, Nan, Utsugisawa, Taiju, Tseng, Alex M., Myers, Samuel A., Verboon, Jeffrey M., Ulirsch, Jacob C., Luo, Wendy, Muus, Christoph, Fiorini, Claudia, Olive, Meagan E., Vockley, Christopher M., Munschauer, Mathias, Hunter, Abigail, Ogura, Hiromi, Yamamoto, Toshiyuki, Inada, Hiroko, Nakagawa, Shinichiro, Ohzono, Shuichi, Subramanian, Vidya, Chiarle, Roberto, Glader, Bertil, Carr, Steven A., Aryee, Martin J., Kundaje, Anshul, Orkin, Stuart H., Regev, Aviv, McCavit, Timothy L., Kanno, Hitoshi, Sankaran, Vijay G.
• Format: Article
• Language: English
• Subjects: Anemia; Cell Differentiation - genetics; Chromatin - genetics; Chromatin Immunoprecipitation; Erythropoiesis - genetics; GATA1 Transcription Factor - genetics; GATA1 Transcription Factor - metabolism; Humans; Red Cells, Iron, and Erythropoiesis
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021013753

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. •Novel hemolytic anemia with elevated erythrocyte adenosine deaminase levels is associated with missense mutations (p.R307C/H) in GATA1.•Transcription of target genes is selectively altered because of disruption of faithful chromatin occupancy of GATA1 mutants. [Display omitted]