Mechanisms of Transcriptional Regulation of the Human IL-3/GM-CSF Locus by Inducible Tissue-Specific Promoters and Enhancers

Abstract

The IL-3 and GM-CSF genes are closely linked in the genome and reside within a cluster of cytokine genes. IL-3 and GM-CSF are expressed in a highly inducible and tissue-specific pattern, and this review attempts to provide a comprehensive description of the key regulatory elements in this locus that control their expression. Although these genes are typically coexpressed in T cells, they are differentially regulated in many other cell types, whereby cells such as monocytes and endothelial cells express GM-CSF, but not IL-3. This suggests that they are likely to be regulated by distinct mechanisms. This view is reinforced by the identification of three inducible enhancers in the locus that have different specificities. These enhancers are embedded within arrays of tissue-specific DNaseI hypersensitive sites that most likely play additional roles in establishing distinct patterns of gene expression. This locus also represents a valuable model system for studying the role of chromatin remodeling in cytokine gene activation. NFAT is one inducible factor that appears to play a major role in the formation of DNaseI hypersensitive sites within enhancers, and which functions in a highly cooperative manner with other classes of transcription factors to direct specific patterns of cytokine gene expression.