論文 - 詳細
| RRC ID | 77254 |
|---|---|
| 著者 | Boontanrart MY, Mächler E, Ponta S, Nelis JC, Preiano VG, Corn JE. |
| タイトル | Engineering of the endogenous HBD promoter increases HbA2. |
| ジャーナル | Elife |
| Abstract |
The β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, are one of the most common genetic diseases worldwide and are caused by mutations affecting the structure or production of β-globin subunits in adult hemoglobin. Many gene editing efforts to treat the β-hemoglobinopathies attempt to correct β-globin mutations or increase γ-globin for fetal hemoglobin production. δ-globin, the subunit of adult hemoglobin A2, has high homology to β-globin and is already pan-cellularly expressed at low levels in adult red blood cells. However, upregulation of δ-globin is a relatively unexplored avenue to increase the amount of functional hemoglobin. Here, we use CRISPR-Cas9 to repair non-functional transcriptional elements in the endogenous promoter region of δ-globin to increase overall expression of adult hemoglobin 2 (HbA2). We find that insertion of a KLF1 site alone is insufficient to upregulate δ-globin. Instead, multiple transcription factor elements are necessary for robust upregulation of δ-globin from the endogenous locus. Promoter edited HUDEP-2 immortalized erythroid progenitor cells exhibit striking increases of HBD transcript, from less than 5% to over 20% of total β-like globins in clonal populations. Edited CD34 +hematopoietic stem and progenitors (HSPCs) differentiated to primary human erythroblasts express up to 46% HBD in clonal populations. These findings add mechanistic insight to globin gene regulation and offer a new therapeutic avenue to treat β-hemoglobinopathies. |
| 巻・号 | 12 |
| 公開日 | 2023-6-2 |
| DOI | 10.7554/eLife.85258 |
| PII | 85258 |
| PMID | 37265399 |
| PMC | PMC10270685 |
| MeSH | Adult Gene Editing Hemoglobinopathies* / genetics Humans Promoter Regions, Genetic beta-Globins / genetics delta-Globins* / genetics |
| IF | 7.08 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 22 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |