title: Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages.
abstract: Hereditary homozygous C1q deficiency is rare, but it almost certainly causes systemic lupus erythematosus. On the other hand, C1q levels can decline in systemic lupus erythematosus patients without apparent C1q gene defects and the versatility in C1q production is a likely cause. As an 18-subunit protein, C1q is assembled in a 1:1:1 ratio from three different subunits. The three human C1q genes are closely bundled on chromosome 1 (C1qA-C1qC-C1qB) and their basal and IFNγ-stimulated expression, largely restricted to macrophages and dendritic cells, is apparently synchronized. We cloned the three gene promoters and observed that although the C1qB promoter exhibited basal and IFNγ-stimulated activities consistent with the endogenous C1qB gene, the activities of the cloned C1qA and C1qC promoters were suppressed by IFNγ. To certain extents, these were corrected when the C1qB promoter was cloned at the 3' end across the luciferase reporter gene. A 53-bp element is essential to the activities of the C1qB promoter and the transcription factors PU.1 and IRF8 bound to this region. By chromatin immunoprecipitation, the C1qB promoter was co-precipitated with PU.1 and IRF8. shRNA knockdown of PU.1 and IRF8 diminished C1qB promoter response to IFNγ. STAT1 instead regulated C1qB promoter through IRF8 induction. Collectively, our results reveal a novel transcriptional mechanism by which the expression of the three C1q genes is synchronized.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, Block MD4, 5 Science Drive 2, Singapore 117597.
authors.forename: Guobao
authors.initials: G
authors.lastname: Chen
authors.forename: Carol Shurong
authors.initials: CS
authors.lastname: Tan
authors.forename: Boon King
authors.initials: BK
authors.lastname: Teh
authors.forename: Jinhua
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001483:Base Sequence; D015922:Complement C1q / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D015922:Complement C1q; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1