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A molecular mechanism for the differential regulation of TGF-β1 expression due to the common SNP −509C-T (c. −1347C > T)

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Abstract

Transforming growth factor β1 (TGF-β1) levels influence many cellular, immunologic and pathologic processes. Activator protein 1 (AP1) and hypoxia are key regulators of TGF-β1 expression levels. The common TGFB1 promoter SNP c.−1347C > T (−509C-T, rs1800469) has been linked to a nearly twofold difference in plasma levels among individuals and with risk, progression, and outcome of numerous diseases. We demonstrate exclusive in vitro and in vivo recruitment of AP1 containing JunD to −1347C. This study also is the first to demonstrate hypoxia inducible factor 1 (HIF-1) binding to the TGFB1 promoter. HIF-1 was found to associate with both −1347C and −1347T and compete with AP1 for binding to −1347C. Reporter constructs demonstrate that expression differences between −1347C and −1347T are due to selective AP1 recruitment to the TGFB1 promoter. As AP1 is known to down-regulate transcription of other genes, we suggest that the molecular mechanism for the difference in TGF-β1 plasma levels linked to −1347 is due to transcriptional suppression by AP1 binding to −1347C. These data should aid in our understanding of the association of the −1347 SNP with the pathogenesis of certain TGF-β1-related diseases.

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Abbreviations

SNP:

Single nucleotide polymorphism

IHWS:

International Histocompatibility Workshop

YY1:

Yin-yang 1

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Acknowledgement

We would like to thank Dr. Nathalie Gualt for the generous gift of the TGFB1 promoter PGL3 construct. Funding from the Office of Naval Research N00014-99-1-055 and N00014-00-1-0898 to the C. W. Bill Young Marrow Donor Recruitment and Research Program supported this research. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Navy, the Department of Defense or the US Government. This investigation was conducted using a tissue culture core facility constructed with support from the Research Facilities Improvement Grant C06 RR14567 from the National Center for Research Resources, National Institute of health.

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Authors and Affiliations

  1. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Riddhish Shah & Carolyn K. Hurley

  2. Department of Microbiology and Immunology, E408 New Research Building, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA

    Phillip E. Posch

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  1. Riddhish Shah
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  2. Carolyn K. Hurley
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  3. Phillip E. Posch
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Correspondence to Phillip E. Posch.

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Shah, R., Hurley, C.K. & Posch, P.E. A molecular mechanism for the differential regulation of TGF-β1 expression due to the common SNP −509C-T (c. −1347C > T). Hum Genet 120, 461–469 (2006). https://doi.org/10.1007/s00439-006-0194-1

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