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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

J Leukoc Biol

Publication Date

11/2001

Volume

70

Pages

812 - 820

Keywords

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