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Functional characterization of the matrix metalloproteinase-1 cigarette smoke-responsive region and association with the lung health study

D'Armiento, Jeanine Marie; Pare, Peter D.; Accili, Domenico; Sandford, Andrew J.; Foronjy, Robert F.; Wallace, Alison M.; Mercer, Becky A.; He, Jianqing

Background: Prior studies have demonstrated that the distal 1.5 kb of the MMP-1 promoter is fundamental in directing the induction of the MMP-1 gene by cigarette smoke. Methods: To characterize the genetic variants in the MMP-1 cigarette smoke-responsive element, deep re-sequencing of this element was performed on DNA samples from participants in the Lung Health Study. Furthermore, evidence of Sp1 binding to the MMP-1 promoter was assessed using chromatin immunoprecipitation assays and the influence of cigarette smoke exposure on this interaction was evaluated in cultured human small airway epithelial cells. Results: Ten polymorphisms (four novel) were detected in the cigarette smoke-responsive element. Chromatin immunoprecipitation assays to assess the protein-DNA interactions at Sp1 sites in the MMP-1 promoter showed increased binding to the Sp1 sites in the cigarette smoke-responsive element in small airway epithelial cells treated with cigarette smoke extract. In contrast, a Sp1 site outside of the element exhibited the opposite effect. None of the polymorphisms were more prevalent in the fast decliners versus the slow decliners (fast decliners = mean −4.14% decline in FEV1% predicted per year vs. decline in FEV1% predicted per year). Conclusions: Sequencing analyses identified four novel polymorphisms within the cigarette smoke-responsive element of the MMP-1 promoter. This study identifies functional activity within the cigarette smoke-responsive element that is influenced by cigarette smoke and examines this region of the promoter within a small patient population.

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Also Published In

Title
Respiratory Research
DOI
https://doi.org/10.1186/1465-9921-13-79

More About This Work

Academic Units
Medicine
Publisher
BioMed Central
Published Here
September 8, 2014

Notes

Chromatin immunoprecipitation, COPD, Metalloproteinase, Polymorphisms, Transcription factors