biostudies-literaturePeslak SANIDDK NIH HHSNHLBI NIH HHSNCI NIH HHS452-465https://www.ebi.ac.uk/biostudies/studies/S-EPMC9958407biostudies-literatureUnknown31Transcriptional 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 (<i>HBG</i>) and adult-type (<i>HBB</i>) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and <i>HBG</i> genes in cultured adult-stage erythroid cells can activate <i>HBG</i> transcription. Activation of <i>HBG</i> 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 Molecular therapy. Nucleic acidsForced enhancer-promoter rewiring to alter gene expression in animal models.PMC9958407R01 HL119479T32 DK007780R01 DK127738R01 CA271523R01 HL095675K08 DK129716Leonard AJiang JWielgosz MBhardwaj SKAbdulmalik ODemirci SHinds MBonifacino ACTisdale JFWeiss MJThrom REChandra VLe ALinde NSFerrara FUchida NChu RGermino-Watnick PBlobel GARupon JWRyu BTong WHamagami NPeslak SAEssawi KKrouse AEDonahue REfalseForced enhancer-promoter rewiring to alter gene expression in animal models.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 (<i>HBG</i>) and adult-type (<i>HBB</i>) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and <i>HBG</i> genes in cultured adult-stage erythroid cells can activate <i>HBG</i> transcription. Activation of <i>HBG</i> 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 2023-01-01T00:00:00Z2023 Mar2025-05-18T12:54:12.213Z2025-05-18T12:54:12.213ZS-EPMC99584073685208810.1016/j.omtn.2023.01.016