| Autor: |
Scott A. Peslak, Selami Demirci, Vemika Chandra, Byoung Ryu, Saurabh K. Bhardwaj, Jing Jiang, Jeremy W. Rupon, Robert E. Throm, Naoya Uchida, Alexis Leonard, Khaled Essawi, Aylin C. Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Robert E. Donahue, Francesca Ferrara, Matthew Wielgosz, Osheiza Abdulmalik, Nicole Hamagami, Paula Germino-Watnick, Anh Le, Rebecca Chu, Malikiya Hinds, Mitchell J. Weiss, Wei Tong, John F. Tisdale, Gerd A. Blobel |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Therapy: Nucleic Acids, Vol 31, Iss , Pp 452-465 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2162-2531 |
| DOI: |
10.1016/j.omtn.2023.01.016 |
| Popis: |
Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the β-globin locus as a model, we provide proof of concept at the organismal level that forced enhancer rewiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPCs) from mice bearing human β-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus macaque erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene-regulatory elements may be used to alter gene expression to treat disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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