Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers

The human genome contains regulatory DNA elements, enhancers, that can activate gene transcription over long chromosomal distances. Here, we show that enhancer distance can be critical for gene silencing. We demonstrate that linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters, through deletion or inversion of intervening DNA sequences, results in their strongly reactivated expression in adult erythroid cells and ex vivo differentiated hematopoietic stem and progenitor cells. A similar observation is made in the HBA locus, where deletion-to-recruit of the distal enhancer strongly reactivates embryonic HBZ expression. Overall, our work assigns function to seemingly non-regulatory genomic segments: by providing linear separation they may support genes to autonomously control their transcriptional response to distal enhancers.