| RRC ID |
67334
|
| Author |
Doerfler PA, Feng R, Li Y, Palmer LE, Porter SN, Bell HW, Crossley M, Pruett-Miller SM, Cheng Y, Weiss MJ.
|
| Title |
Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin.
|
| Journal |
Nat Genet
|
| Abstract |
Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.
|
| Volume |
53(8)
|
| Pages |
1177-1186
|
| Published |
2021-8-1
|
| DOI |
10.1038/s41588-021-00904-0
|
| PII |
10.1038/s41588-021-00904-0
|
| PMID |
34341563
|
| PMC |
PMC8610173
|
| MeSH |
Animals
Binding Sites
CCAAT-Binding Factor / genetics*
COS Cells
CRISPR-Cas Systems
Cell Line
Chlorocebus aethiops
Erythroid Cells
Fetal Hemoglobin / genetics*
GATA1 Transcription Factor / genetics*
Gene Editing / methods
Gene Expression Regulation, Developmental
Humans
Promoter Regions, Genetic
Repressor Proteins / genetics
Repressor Proteins / metabolism
gamma-Globins / genetics*
|
| IF |
27.605
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557) |
