Monocyte chemoattractant protein-4 core promoter genetic variants: influence on YY-1 affinity and plasma levels.
Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site. The -887 variant alters a consensus binding motif for the transcription factor YY-1. Electrophoretic mobility shift assay demonstrated that YY-1 containing nuclear extracts from tumor necrosis factor-alpha-stimulated peripheral blood mononuclear cells had greater avidity for the wild-type (YY-1 motif intact) sequence than for the variant sequence. Increasing doses of a YY-1 expression vector induced significantly greater reporter activity from MCP-4 core promoter expression constructs of the wild-type compared with the variant sequence in transient transfection experiments. The external validity of these observations was demonstrated by measuring plasma levels of MCP-4 from individuals with the alternative forms of the gene. Individuals bearing haplotypic variants of the MCP-4 core promoter that avidly bind the transcription factor YY-1 had higher plasma levels of MCP-4 than did individuals with variants with lower binding avidity (490, 360, and 360 pg/ml; P < 0.01). Our findings suggest that the MCP-4 core promoter YY-1 binding motif is functional, modulates the transcriptional regulation of the MCP-4 gene, and that part of the variance in the systemic expression of MCP-4 is determined by core promoter genetic variants.
Kalayci
Omer
O
Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis Street, PBB 3rd Floor Clinics Building, Boston, MA 02115, USA.
Birben
Esra
E
Wu
Liqing
L
Oguma
Tsuyoshi
T
Storm Van's Gravesande
Karin
K
Subramaniam
Venkat
V
Sheldon
Holly K
HK
Silverman
Eric S
ES
Lilly
Craig M
CM
D050981:Erythroid-Specific DNA-Binding Factors; D017930:Genes, Reporter; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018945:Monocyte Chemoattractant Proteins / Q000097:blood* / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
C099677:CCL13 protein, human; D050981:Erythroid-Specific DNA-Binding Factors; D018945:Monocyte Chemoattractant Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors