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This article is part of the supplement: Epigenetics and Chromatin: Interactions and processes

Open Access Oral presentation

Controlling long-range genomic interactions to reprogram the β-globin locus

Wulan Deng12, Jeremy W Rupon1, Hongxin Wang1, Andreas Reik3, Philip D Gregory3 and Gerd A Blobel1*

  • * Corresponding author: Gerd A Blobel

Author Affiliations

1 The Children’s Hospital of Philadelphia, Hematology, Philadelphia, PA, 19104, USA

2 University of Pennsylvania, Department of Biology, Philadelphia, PA, 19104, USA

3 Sangamo BioSciences, Inc, Richmond, CA, 94804, USA

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Epigenetics & Chromatin 2013, 6(Suppl 1):O39  doi:10.1186/1756-8935-6-S1-O39

The electronic version of this article is the complete one and can be found online at: http://www.epigeneticsandchromatin.com/content/6/S1/O39


Published:18 March 2013

© 2013 Deng et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

Distal enhancers physically contact target promoters to confer high level transcription. At the mammalian β-globin loci long-range chromosomal interactions between a distal enhancer, called the locus control region (LCR), and the globin genes are developmentally dynamic such that the LCR loops to the embryonic, fetal and adult globin genes in a stage-appropriate fashion. LCR-globin gene interactions require the nuclear factor Ldb1. Recently, we employed artificial zinc finger (ZF) proteins to target Ldb1 to the endogenous β-globin locus to force an LCR-promoter loop. This led to substantial activation of β-globin transcription and suggested that forced chromatin looping could be employed as a powerful tool to manipulate gene expression in vivo (Deng et al., Cell 2012). Reactivation of the fetal globin genes in adult erythroid cells has been a long-standing goal in the treatment of patients with sickle cell anemia. Therefore, building on our findings, we investigated whether the developmentally silenced embryonic globin gene βh1 can be re-activated in adult murine erythroblasts by re-directing the LCR away from the adult type globin gene and towards its embryonic counterpart. To this end, Ldb1 was fused to artificial ZF proteins (ZF-Ldb1) designed to bind to the βh1 promoter. ZF-Ldb1 was introduced into definitive erythroid cells in which only the adult but not the embryonic β-like globin gene is expressed. In vivo binding of ZF-Ldb1 to its intended target was verified by chromatin immunoprecipitation assay. Strikingly, expression of ZF-Ldb1 re-activated βh1 transcription up to approximately ~24% of total cellular β-globin production. This suggests that forced tethering of a looping factor to a select promoter can be employed to override a pre-existing developmental long-range chromatin interaction to reprogram a developmentally controlled gene locus.