ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin
Summary: β-Hemoglobinopathies can trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin. However, the mechanisms underlying γ-globin production during cellular str...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720309785 |
| _version_ | 1818351669876883456 |
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| author | Mandy Y. Boontanrart Markus S. Schröder Gautier M. Stehli Marija Banović Stacia K. Wyman Rachel J. Lew Matteo Bordi Benjamin G. Gowen Mark A. DeWitt Jacob E. Corn |
| author_facet | Mandy Y. Boontanrart Markus S. Schröder Gautier M. Stehli Marija Banović Stacia K. Wyman Rachel J. Lew Matteo Bordi Benjamin G. Gowen Mark A. DeWitt Jacob E. Corn |
| author_sort | Mandy Y. Boontanrart |
| collection | DOAJ |
| description | Summary: β-Hemoglobinopathies can trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here, we use CRISPR-Cas genome editing to model the stress caused by reduced levels of adult β-globin. We find that decreased β-globin is sufficient to induce robust re-expression of γ-globin, and RNA sequencing (RNA-seq) of differentiating isogenic erythroid precursors implicates ATF4 as a causal regulator of this response. ATF4 binds within the HBS1L-MYB intergenic enhancer and regulates expression of MYB, a known γ-globin regulator. Overall, the reduction of ATF4 upon β-globin knockout decreases the levels of MYB and BCL11A. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could inform strategies to treat hemoglobinopathies. |
| first_indexed | 2024-12-13T18:41:25Z |
| format | Article |
| id | doaj.art-3fe47469212244e8974cbf8b70ce5d59 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T18:41:25Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3fe47469212244e8974cbf8b70ce5d592022-12-21T23:35:12ZengElsevierCell Reports2211-12472020-08-01325107993ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-GlobinMandy Y. Boontanrart0Markus S. Schröder1Gautier M. Stehli2Marija Banović3Stacia K. Wyman4Rachel J. Lew5Matteo Bordi6Benjamin G. Gowen7Mark A. DeWitt8Jacob E. Corn9Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Biology, ETH Zurich, Zurich 8092, SwitzerlandDepartment of Biology, ETH Zurich, Zurich 8092, SwitzerlandDepartment of Biology, ETH Zurich, Zurich 8092, SwitzerlandDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Biology, ETH Zurich, Zurich 8092, SwitzerlandDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Biology, ETH Zurich, Zurich 8092, Switzerland; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Corresponding authorSummary: β-Hemoglobinopathies can trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here, we use CRISPR-Cas genome editing to model the stress caused by reduced levels of adult β-globin. We find that decreased β-globin is sufficient to induce robust re-expression of γ-globin, and RNA sequencing (RNA-seq) of differentiating isogenic erythroid precursors implicates ATF4 as a causal regulator of this response. ATF4 binds within the HBS1L-MYB intergenic enhancer and regulates expression of MYB, a known γ-globin regulator. Overall, the reduction of ATF4 upon β-globin knockout decreases the levels of MYB and BCL11A. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could inform strategies to treat hemoglobinopathies.http://www.sciencedirect.com/science/article/pii/S2211124720309785Fetal hemoglobinadult hemoglobinstress erythropoiesisBCL11AHBS1L-MYBhemoglobinopathies |
| spellingShingle | Mandy Y. Boontanrart Markus S. Schröder Gautier M. Stehli Marija Banović Stacia K. Wyman Rachel J. Lew Matteo Bordi Benjamin G. Gowen Mark A. DeWitt Jacob E. Corn ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin Cell Reports Fetal hemoglobin adult hemoglobin stress erythropoiesis BCL11A HBS1L-MYB hemoglobinopathies |
| title | ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin |
| title_full | ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin |
| title_fullStr | ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin |
| title_full_unstemmed | ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin |
| title_short | ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin |
| title_sort | atf4 regulates myb to increase γ globin in response to loss of β globin |
| topic | Fetal hemoglobin adult hemoglobin stress erythropoiesis BCL11A HBS1L-MYB hemoglobinopathies |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720309785 |
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