| RRC ID |
77297
|
| 著者 |
Sun Y, Habara A, Le CQ, Nguyen N, Chen R, Murphy GJ, Chui DHK, Steinberg MH, Cui S.
|
| タイトル |
Pharmacologic induction of PGC-1α stimulates fetal haemoglobin gene expression.
|
| ジャーナル |
Br J Haematol
|
| Abstract |
Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ-globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co-activator PGC-1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC-1α by infection with a lentivirus expressing PGC-1α or by the small-molecule PGC-1α agonist ZLN005 in human primary erythroid progenitor CD34+ cells induces both fetal γ-globin mRNA and protein expression as well as the percentage of HbF-positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ-globin and the generation of F cells from cultured CD34+ cells. In addition, ZLN005 induced robust expression of the murine embryonic βh1-globin gene and to a lesser extent, human γ-globin gene expression in sickle mice. These findings suggest that activation of PGC-1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in β-hemoglobinopathies.
|
| 巻・号 |
197(1)
|
| ページ |
97-109
|
| 公開日 |
2022-4-1
|
| DOI |
10.1111/bjh.18042
|
| PMID |
35118652
|
| MeSH |
Anemia, Sickle Cell* / drug therapy
Anemia, Sickle Cell* / genetics
Animals
Fetal Hemoglobin / metabolism
Gene Expression
Gene Expression Regulation
Hemoglobinopathies*
Humans
Mice
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
gamma-Globins / genetics
|
| IF |
5.518
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-1(RCB4556)
HUDEP-2(RCB4557) |
