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Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.
Blood ( IF 21.0 ) Pub Date : 2022-04-21 , DOI: 10.1182/blood.2021013753
Leif S Ludwig 1, 2, 3, 4, 5 , Caleb A Lareau 1, 2, 3, 6, 7 , Erik L Bao 1, 2, 3, 8 , Nan Liu 1, 2, 9, 10 , Taiju Utsugisawa 11 , Alex M Tseng 6, 7 , Samuel A Myers 3, 12 , Jeffrey M Verboon 1, 2, 3 , Jacob C Ulirsch 1, 2, 3, 13 , Wendy Luo 1, 2, 3 , Christoph Muus 3, 14 , Claudia Fiorini 1, 2, 3 , Meagan E Olive 3 , Christopher M Vockley 3 , Mathias Munschauer 3, 15, 16 , Abigail Hunter 17 , Hiromi Ogura 11 , Toshiyuki Yamamoto 18 , Hiroko Inada 19 , Shinichiro Nakagawa 20 , Shuichi Ohzono 20 , Vidya Subramanian 3 , Roberto Chiarle 21 , Bertil Glader 22 , Steven A Carr 3 , Martin J Aryee 3, 23, 24 , Anshul Kundaje 6, 7 , Stuart H Orkin 1, 2, 25 , Aviv Regev 3, 25, 26, 27 , Timothy L McCavit 17 , Hitoshi Kanno 11 , Vijay G Sankaran 3, 28
Affiliation  

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.

中文翻译:


先天性贫血揭示了主转录因子 GATA1 的独特靶向机制。



主调节因子,例如造血转录因子 (TF) GATA1,在协调谱系定型和分化方面发挥着重要作用。然而,此类转录因子通过与特定顺式调控元件相互作用来调控转录的精确机制仍不完全清楚。在这里,我们描述了一种由 GATA1 本质上紊乱区域的错义突变引起的先天性溶血性贫血,其在转录调控中的作用尚不清楚。通过综合功能方法,我们证明这些突变通过部分损害核定位并选择性改变 GATA1 精确的染色质占据来扰乱 GATA1 转录活性。染色质占据的这些改变和一致的染色质可及性变化改变了忠实的基因表达,无法有效地沉默和激活有效的终末红细胞产生所需的选择基因。我们展示了致病突变如何揭示调控机制,从而在细胞分化过程中实现主转录因子的忠实基因组靶向。
更新日期:2022-01-14
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