TY - JOUR
T1 - The inducible tissue-specific expression of the human IL-3/GM-CSF locus is controlled by a complex array of developmentally regulated enhancers
AU - Baxter, Euan W.
AU - Mirabella, Fabio
AU - Bowers, Sarion R.
AU - James, Sally R.
AU - Bonavita, Aude Marine
AU - Bertrand, Elisabeth
AU - Strogantsev, Ruslan
AU - Hawwari, Abbas
AU - Bert, Andrew G.
AU - Gonzalez De Arce, Andrea
AU - West, Adam G.
AU - Bonifer, Constanze
AU - Cockerill, Peter N.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - The closely linked human IL-3 and GM-CSF genes are tightly regulated and are expressed in activated T cells and mast cells. In this study, we used transgenic mice to study the developmental regulation of this locus and to identify DNA elements required for its correct activity in vivo. Because these two genes are separated by a CTCF-dependent insulator, and the GM-CSF gene is regulated primarily by its own upstream enhancer, the main objective in this study was to identify regions of the locus required for correct IL-3 gene expression. We initially found that the previously identified proximal upstream IL-3 enhancers were insufficient to account for the in vivo activity of the IL-3 gene. However, an extended analysis of DNase I-hypersensitive sites (DHSs) spanning the entire upstream IL-3 intergenic region revealed the existence of a complex cluster of both constitutive and inducible DHSs spanning the 234- to 240-kb region. The tissue specificity of these DHSs mirrored the activity of the IL-3 gene, and included a highly inducible cyclosporin A-sensitive enhancer at 237 kb that increased IL-3 promoter activity 40-fold. Significantly, inclusion of this region enabled correct in vivo regulation of IL-3 gene expression in T cells, mast cells, and myeloid progenitor cells.
AB - The closely linked human IL-3 and GM-CSF genes are tightly regulated and are expressed in activated T cells and mast cells. In this study, we used transgenic mice to study the developmental regulation of this locus and to identify DNA elements required for its correct activity in vivo. Because these two genes are separated by a CTCF-dependent insulator, and the GM-CSF gene is regulated primarily by its own upstream enhancer, the main objective in this study was to identify regions of the locus required for correct IL-3 gene expression. We initially found that the previously identified proximal upstream IL-3 enhancers were insufficient to account for the in vivo activity of the IL-3 gene. However, an extended analysis of DNase I-hypersensitive sites (DHSs) spanning the entire upstream IL-3 intergenic region revealed the existence of a complex cluster of both constitutive and inducible DHSs spanning the 234- to 240-kb region. The tissue specificity of these DHSs mirrored the activity of the IL-3 gene, and included a highly inducible cyclosporin A-sensitive enhancer at 237 kb that increased IL-3 promoter activity 40-fold. Significantly, inclusion of this region enabled correct in vivo regulation of IL-3 gene expression in T cells, mast cells, and myeloid progenitor cells.
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U2 - 10.4049/jimmunol.1201915
DO - 10.4049/jimmunol.1201915
M3 - Article
C2 - 23024272
AN - SCOPUS:84867911442
SN - 0022-1767
VL - 189
SP - 4459
EP - 4469
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -