Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

Item Type:	Article
Title:	Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1
Creators Name:	Ludwig, L.S. and Lareau, C.A. and Bao, E.L. and Liu, N. and Utsugisawa, T. and Tseng, A.M. and Myers, S.A. and Verboon, J.M. and Ulirsch, J.C. and Luo, W. and Muus, C. and Fiorini, C. and Olive, M.E. and Vockley, C.M. and Munschauer, M. and Hunter, A. and Ogura, H. and Yamamoto, T. and Inada, H. and Nakagawa, S. and Ozono, S. and Subramanian, V. and Chiarle, R. and Glader, B. and Carr, S.A. and Aryee, M.J. and Kundaje, A. and Orkin, S. and Regev, A. and McCavit, T. and Kanno, H. and Sankaran, V.G.
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.
Keywords:	Red Cells, Iron, Erythropoiesis
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	139
Number:	16
Page Range:	2534-2546
Date:	21 April 2022
Additional Information:	Copyright © 2022 by The American Society of Hematology
Official Publication:	https://doi.org/10.1182/blood.2021013753
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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