Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.

Autor:	Ludwig LS; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin, Germany., Lareau CA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Department of Computer Science and.; Department of Genetics, Stanford University, Stanford, CA., Bao EL; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA., Liu N; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Utsugisawa T; Department of Transfusion Medicine and Cell Processing, Faculty of Medicine, Tokyo Women's Medical University, Tokyo, Japan., Tseng AM; Department of Computer Science and.; Department of Genetics, Stanford University, Stanford, CA., Myers SA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; La Jolla Institute for Immunology, La Jolla, CA., Verboon JM; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Ulirsch JC; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA., Luo W; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Muus C; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; John A. Paulson School of Engineering and Applied Sciences, Faculty of Arts and Sciences, Harvard University, Cambridge, MA., Fiorini C; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Olive ME; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Vockley CM; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Munschauer M; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Helmholtz Institute for RNA-Based Infection Research, Helmholtz Center for Infection Research, Würzburg, Germany.; Infection and Immunity Department, Faculty of Medicine, University of Würzburg, Würzburg, Germany., Hunter A; Cook Children's Medical Center, Fort Worth, TX., Ogura H; Department of Transfusion Medicine and Cell Processing, Faculty of Medicine, Tokyo Women's Medical University, Tokyo, Japan., Yamamoto T; Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan., Inada H; Saga-Ken Medical Centre Koseikan, Saga, Japan., Nakagawa S; Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan., Ohzono S; Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan., Subramanian V; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Chiarle R; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Glader B; Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA., Carr SA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA., Aryee MJ; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA., Kundaje A; Department of Computer Science and.; Department of Genetics, Stanford University, Stanford, CA., Orkin SH; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Howard Hughes Medical Institute, Chevy Chase, MD., Regev A; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Howard Hughes Medical Institute, Chevy Chase, MD.; Department of Biology and.; Koch Institute of Integrative Cancer Research, MIT, Cambridge, MA; and., McCavit TL; Cook Children's Medical Center, Fort Worth, TX., Kanno H; Department of Transfusion Medicine and Cell Processing, Faculty of Medicine, Tokyo Women's Medical University, Tokyo, Japan., Sankaran VG; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.; Harvard Stem Cell Institute, Cambridge, MA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Apr 21; Vol. 139 (16), pp. 2534-2546.
DOI:	10.1182/blood.2021013753
Abstrakt:	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. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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