| RRC ID |
77333
|
| Author |
Boontanrart MY, Schröder MS, Stehli GM, Banović M, Wyman SK, Lew RJ, Bordi M, Gowen BG, DeWitt MA, Corn JE.
|
| Title |
ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin.
|
| Journal |
Cell Rep
|
| Abstract |
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.
|
| Volume |
32(5)
|
| Pages |
107993
|
| Published |
2020-8-4
|
| DOI |
10.1016/j.celrep.2020.107993
|
| PII |
S2211-1247(20)30978-5
|
| PMID |
32755585
|
| MeSH |
Activating Transcription Factor 4 / genetics
Activating Transcription Factor 4 / metabolism*
Base Sequence
Cell Differentiation / genetics
Cell Line
DNA, Intergenic / genetics
Down-Regulation / genetics
Enhancer Elements, Genetic / genetics
Fetal Hemoglobin / genetics
Gene Expression Regulation*
Hematopoietic Stem Cells / metabolism
Humans
Mutation / genetics
Protein Binding
Proto-Oncogene Proteins c-myb / genetics*
Proto-Oncogene Proteins c-myb / metabolism
Repressor Proteins / metabolism
Time Factors
Transcription, Genetic
Transcriptome / genetics
Up-Regulation / genetics
beta-Globins / metabolism*
gamma-Globins / genetics*
gamma-Globins / metabolism
|
| IF |
8.109
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557)
HUDEP-1(RCB4556) |
