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Cell. 2014 Aug 14;158(4):849-860. doi: 10.1016/j.cell.2014.05.050.

Reactivation of developmentally silenced globin genes by forced chromatin looping.

Author information

1
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
2
Transcription Imaging Consortium, Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.
3
Laboratory of Cellular and Developmental Biology, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Department of Pediatrics, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 10021.
5
Sangamo BioSciences, Inc., Richmond, CA 94804.
6
Department of Cell and Biology Development, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 10021.
7
The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
#
Contributed equally

Abstract

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.

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PMID:
25126789
PMCID:
PMC4134511
DOI:
10.1016/j.cell.2014.05.050
[Indexed for MEDLINE]
Free PMC Article
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