Pharmacologic induction of PGC-1α stimulates fetal haemoglobin gene expression.
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| 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.
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| Authors | Yanan Sun, Alawi Habara, Cuong Quang Le, Nicole Nguyen, Raymon Chen, George J Murphy, David H K Chui, Martin H Steinberg, Shuaiying Cui |
| Journal | British journal of haematology (Br J Haematol) Vol. 197 Issue 1 Pg. 97-109 (04 2022) ISSN: 1365-2141 [Electronic] England |
| PMID | 35118652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | © 2022 British Society for Haematology and John Wiley & Sons Ltd. |
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