@article{53bc502a7afc4224bbe96d448ce8c749,
title = "Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1",
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.",
author = "Ludwig, {Leif S.} and Lareau, {Caleb A.} and Bao, {Erik L.} and Nan Liu and Taiju Utsugisawa and Tseng, {Alex M.} and Myers, {Samuel A.} and Verboon, {Jeffrey M.} and Ulirsch, {Jacob C.} and Wendy Luo and Christoph Muus and Claudia Fiorini and Olive, {Meagan E.} and Vockley, {Christopher M.} and Mathias Munschauer and Abigail Hunter and Hiromi Ogura and Toshiyuki Yamamoto and Hiroko Inada and Shinichiro Nakagawa and Shuichi Ohzono and Vidya Subramanian and Roberto Chiarle and Bertil Glader and Carr, {Steven A.} and Aryee, {Martin J.} and Anshul Kundaje and Orkin, {Stuart H.} and Aviv Regev and McCavit, {Timothy L.} and Hitoshi Kanno and Sankaran, {Vijay G.}",
note = "Funding Information: L.S.L. is supported by an Emmy Noether fellowship by the German Research Foundation (LU 2336/2-1) and a Hector Fellow Academy Research Career Development Award. C.A.L. received support from National Cancer Institute, National Institutes of Health (NIH), grant F31 CA232670 and a Stanford Science Fellowship and a Parker Institute of Cancer Immunotherapy Scholarship. E.L.B. received support from the Howard Hughes Medical Institute Medical Research Fellows program. This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases, NIH, grant R01 DK103794 (V.G.S.), National Heart, Lung, and Blood Institute (NHLBI), NIH, grants R33 HL120791 (V.G.S.) and R01 HL146500 (V.G.S.), National Cancer Institute, grants U24 CA210986 (S.A.C.) and U01 CA214125 (S.A.C.); Japan Society for the Promotion of Science research grant KAKENHI JP16K10041 (H.K.), the Howard Hughes Medical Institute (A.R.), the Klarman Cell Observatory (A.R.), and the New York Stem Cell Foundation (NYSCF; V.G.S.). Funding for patient genomic sequencing was partially provided by the Broad Institute of Massachusetts Institute of Technology and Harvard Center for Mendelian Genomics and was funded by National Human Genome Research Institute, National Eye Institute, and National Heart, Lung, and Blood Institute grant UM1 HG008900 and by National Human Genome Research Institute grant R01 HG009141. V.G.S. is an NYSCF-Robertson Investigator. Funding Information: The authors thank the patients and families for participating in the study, as well as the members of the Sankaran and Regev laboratories for valuable comments and the Whitehead Institute and Broad Institute Flow Cytometry facilities for assistance with cell sorting and flow cytometric analysis. L.S.L. is supported by an Emmy Noether fellowship by the German Research Foundation (LU 2336/2-1) and a Hector Fellow Academy Research Career Development Award. C.A.L. received support from National Cancer Institute, National Institutes of Health (NIH), grant F31 CA232670 and a Stanford Science Fellowship and a Parker Institute of Cancer Immunotherapy Scholarship. E.L.B. received support from the Howard Hughes Medical Institute Medical Research Fellows program. This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases, NIH, grant R01 DK103794 (V.G.S.), National Heart, Lung, and Blood Institute (NHLBI), NIH, grants R33 HL120791 (V.G.S.) and R01 HL146500 (V.G.S.), National Cancer Institute, grants U24 CA210986 (S.A.C.) and U01 CA214125 (S.A.C.); Japan Society for the Promotion of Science research grant KAKENHI JP16K10041 (H.K.), the Howard Hughes Medical Institute (A.R.), the Klarman Cell Observatory (A.R.), and the New York Stem Cell Foundation (NYSCF; V.G.S.). Funding for patient genomic sequencing was partially provided by the Broad Institute of Massachusetts Institute of Technology and Harvard Center for Mendelian Genomics and was funded by National Human Genome Research Institute, National Eye Institute, and National Heart, Lung, and Blood Institute grant UM1 HG008900 and by National Human Genome Research Institute grant R01 HG009141. V.G.S. is an NYSCF-Robertson Investigator. Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = apr,
day = "21",
doi = "10.1182/blood.2021013753",
language = "English (US)",
volume = "139",
pages = "2534--2546",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "16",
}