Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 7, Pages 1682-1693Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01411-08
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Funding
- Biotechnology and Biological Sciences Research Council
- Association for International Cancer Research
- Yorkshire Cancer Research
- BBSRC [BB/E023002/1] Funding Source: UKRI
- MRC [MC_U120027516] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E023002/1] Funding Source: researchfish
- Medical Research Council [MC_U120027516] Funding Source: researchfish
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The human interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating-factor (GM-CSF, or CSF2) gene cluster arose by duplication of an ancestral gene. Although just 10 kb apart and responsive to the same signals, the IL-3 and GM-CSF genes are nevertheless regulated independently by separate, tissue-specific enhancers. To understand the differential regulation of the IL-3 and GM-CSF genes we have investigated a cluster of three ubiquitous DNase I-hypersensitive sites (DHSs) located between the two genes. We found that each site contains a conserved CTCF consensus sequence, binds CTCF, and recruits the cohesin subunit Rad21 in vivo. The positioning of these sites relative to the IL-3 and GM-CSF genes and their respective enhancers is conserved between human and mouse, suggesting a functional role in the organization of the locus. We found that these sites effectively block functional interactions between the GM-CSF enhancer and either the IL-3 or the GM-CSF promoter in reporter gene assays. These data argue that the regulation of the IL-3 and the GM-CSF promoters depends on the positions of their enhancers relative to the conserved CTCF/cohesin-binding sites. We suggest that one important role of these sites is to enable the independent regulation of the IL-3 and GM-CSF genes.
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