Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts β-type globin genes in a developmental stage-specific manner to stimulate transcription. Previously, we induced LCR-promoter looping by tethering the self-association domain (SA) of Ldb1 to the β-globin promoter via artificial zinc fingers. Here, we show that targeting the SA to a developmentally silenced embryonic globin gene in adult murine erythroblasts triggers its transcriptional reactivation. This activity depends on the LCR, consistent with an LCR-promoter looping mechanism. Strikingly, targeting the SA to the fetal γ-globin promoter in primary adult human erythroblasts increases γ-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total β-globin synthesis, with a reciprocal reduction in adult β-globin expression. Our findings demonstrate that forced chromatin looping can override a stringent developmental gene expression program and suggest a novel approach to control the balance of globin gene transcription for therapeutic applications.
|Titolo:||Reactivation of developmentally silenced globin genes by forced chromatin looping|
|Parole Chiave:||Animals; Antigens, CD34; Chromatin; Embryo, Mammalian; Erythroblasts; Fetal Hemoglobin; Hemoglobinopathies; Humans; Mice; Primary Cell Culture; beta-Globins; Genetic Techniques; Locus Control Region; Transcriptional Activation; Biochemistry, Genetics and Molecular Biology (all)|
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
|Data di pubblicazione:||14-ago-2014|
|Digital Object Identifier (DOI):||10.1016/j.cell.2014.05.050|
|Appare nelle tipologie:||01 - Articolo su periodico|