Reactivation of developmentally silenced globin genes by forced chromatin looping.

ABSTRACT: Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts ?-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 ?-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 ?-globin promoter in primary adult human erythroblasts increases ?-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total ?-globin synthesis, with a reciprocal reduction in adult ?-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.

SUBMITTER: Deng W 

PROVIDER: S-EPMC4134511 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature