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The c-fms gene encodes the receptor for macrophage colony-stimulating factor-1. This gene is expressed selectively in the macrophage cell lineage. Previous studies have implicated sequences in intron 2 that control transcript elongation in tissue-specific and regulated expression of c-fms. Four macrophage-specific deoxyribonuclease I (DNase I)-hypersensitive sites (DHSs) were identified within mouse intron 2. Sequences of these DHSs were found to be highly conserved compared with those in the human gene. A 250-bp region we refer to as the fms intronic regulatory element (FIRE), which is even more highly conserved than the c-fms proximal promoter, contains many consensus binding sites for macrophage-expressed transcription factors including Sp1, PU.1, and C/EBP. FIRE was found to act as a macrophage-specific enhancer and as a promoter with an antisense orientation preference in transient transfections. In stable transfections of the macrophage line RAW264, as well as in clones selected for high- and low-level c-fms mRNA expression, the presence of intron 2 increased the frequency and level of expression of reporter genes compared with those attained using the promoter alone. Removal of FIRE abolished reporter gene expression, revealing a suppressive activity in the remaining intronic sequences. Hence, FIRE is shown to be a key regulatory element in the fms gene.

Type

Journal article

Journal

Journal of leukocyte biology

Publication Date

11/2001

Volume

70

Pages

812 - 820

Addresses

Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia.

Keywords

Cell Line, 3T3 Cells, Macrophages, Animals, Humans, Mice, Deoxyribonuclease I, Luciferases, Receptor, Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Transcription Factors, Oligodeoxyribonucleotides, Antisense, RNA, Messenger, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Transfection, Sequence Alignment, Gene Expression Regulation, Base Sequence, Regulatory Sequences, Nucleic Acid, Sequence Homology, Nucleic Acid, Genes, Reporter, Genes, fms, Introns, Molecular Sequence Data, Enhancer Elements, Genetic, Promoter Regions, Genetic