| First Author | Peslak SA | Year | 2023 |
| Journal | Mol Ther Nucleic Acids | Volume | 31 |
| Pages | 452-465 | PubMed ID | 36852088 |
| Mgi Jnum | J:354948 | Mgi Id | MGI:7736849 |
| Doi | 10.1016/j.omtn.2023.01.016 | Citation | Peslak SA, et al. (2023) Forced enhancer-promoter rewiring to alter gene expression in animal models. Mol Ther Nucleic Acids 31:452-465 |
| abstractText | Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the beta-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) beta-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 beta-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 beta-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. |
