Forced enhancer-promoter rewiring to alter gene expression in animal models
Molecular therapy. Nucleic acids(2023)
摘要
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 () and adult-type () β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and genes in cultured adult-stage erythroid cells can activate transcription. Activation of 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- contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated 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 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.
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关键词
MT: Oligonucleotides,Therapies and Applications,enhancer-promoter interactions,forced chromatin looping,sickle cell disease,hemoglobin switching,fetal hemoglobin,preclinical animal models,vector optimization
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