Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

Author:

Ludwig Leif S.12345ORCID,Lareau Caleb A.12367ORCID,Bao Erik L.1238,Liu Nan12910ORCID,Utsugisawa Taiju11,Tseng Alex M.67,Myers Samuel A.312ORCID,Verboon Jeffrey M.123ORCID,Ulirsch Jacob C.12313,Luo Wendy123,Muus Christoph314,Fiorini Claudia123,Olive Meagan E.3ORCID,Vockley Christopher M.3,Munschauer Mathias31516,Hunter Abigail17,Ogura Hiromi11,Yamamoto Toshiyuki18ORCID,Inada Hiroko19,Nakagawa Shinichiro20,Ohzono Shuichi20ORCID,Subramanian Vidya3,Chiarle Roberto21ORCID,Glader Bertil22,Carr Steven A.3,Aryee Martin J.32324ORCID,Kundaje Anshul67ORCID,Orkin Stuart H.1225,Regev Aviv3252627,McCavit Timothy L.17,Kanno Hitoshi11,Sankaran Vijay G.12328ORCID

Affiliation:

1. 1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA;

2. 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;

3. 3Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA;

4. 4Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Berlin, Germany;

5. 5Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin, Germany;

6. 6Department of Computer Science and

7. 7Department of Genetics, Stanford University, Stanford, CA;

8. 8Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA;

9. 9Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;

10. 10Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China;

11. 11Department of Transfusion Medicine and Cell Processing, Faculty of Medicine, Tokyo Women’s Medical University, Tokyo, Japan;

12. 12La Jolla Institute for Immunology, La Jolla, CA;

13. 13Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA;

14. 14John A. Paulson School of Engineering and Applied Sciences, Faculty of Arts and Sciences, Harvard University, Cambridge, MA;

15. 15Helmholtz Institute for RNA-Based Infection Research, Helmholtz Center for Infection Research, Würzburg, Germany;

16. 16Infection and Immunity Department, Faculty of Medicine, University of Würzburg, Würzburg, Germany;

17. 17Cook Children’s Medical Center, Fort Worth, TX;

18. 18Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan;

19. 19Saga-Ken Medical Centre Koseikan, Saga, Japan;

20. 20Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan;

21. 21Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA;

22. 22Lucile Packard Children’s Hospital, Stanford University, Palo Alto, CA;

23. 23Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA;

24. 24Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA;

25. 25Howard Hughes Medical Institute, Chevy Chase, MD;

26. 26Department of Biology and

27. 27Koch Institute of Integrative Cancer Research, MIT, Cambridge, MA; and

28. 28Harvard Stem Cell Institute, Cambridge, MA

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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