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Role for DNA methylation in the control of cell type–specific maspin expression

Nature Genetics volume 31, pages 175–179 (2002)Cite this article

Abstract

The nucleotide 5-methylcytosine is involved in processes crucial in mammalian development, such as X-chromosome inactivation and gene imprinting1,2,3,4,5. In addition, cytosine methylation has long been speculated to be involved in the establishment and maintenance of cell type–specific expression of developmentally regulated genes6,7; however, it has been difficult to identify clear examples of such genes, particularly in humans8. Here we provide evidence that cytosine methylation of the maspin gene (SERPINB5) promoter controls, in part, normal cell type–specific SERPINB5 expression. In normal cells expressing SERPINB5, the SERPINB5 promoter is unmethylated and the promoter region has acetylated histones and an accessible chromatin structure. By contrast, normal cells that do not express SERPINB5 have a completely methylated SERPINB5 promoter with hypoacetylated histones, an inaccessible chromatin structure and a transcriptional repression that is relieved by inhibition of DNA methylation. These findings indicate that cytosine methylation is important in the establishment and maintenance of cell type–restricted gene expression.

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Figure 1: SERPINB5 expression is restricted to a subset of normal human cell types.
Figure 2: The SERPINB5 promoter shows differential cytosine methylation of SERPINB5-positive and SERPINB5-negative normal human cells.
Figure 3: The SERPINB5 promoter is not an imprinted region.
Figure 4: The histone acetylation state of the SERPINB5 promoter is associated with cytosine methylation and expression status in normal human cells.
Figure 5: Different chromatin structures exist for the SERPINB5 promoter in SERPINB5-positive breast epithelial cells and skin keratinocytes and SERPINB5-negative lymphocytes and skin fibroblasts.
Figure 6: Activation of SERPINB5 expression by 5-aza-2′-deoxycytidine in SERPINB5-negative cell types.

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Acknowledgements

We thank J. Munoz-Rodriguez and M. Fitzgerald for technical assistance. This work was supported by grants from the National Institutes of Health to B.W.F. and F.E.D. as well as to the Arizona Cancer Center and the Gene Therapy Center at the Univ. of Iowa. M.O. was supported by a Cancer Biology Training grant from the National Institutes of Health, R.W. received support from a Toxicology Training grant from the National Institute of Environmental Health Sciences, and H.D. received support from the Milheim Foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Bone Marrow Transplant Program, Arizona Cancer Center, The University of Arizona, Tucson, 85724, Arizona, USA

    Bernard W. Futscher, Marc M. Oshiro, Ryan J. Wozniak & Nicholas Holtan

  2. Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, 52242, Iowa, USA

    Christin L. Hanigan, Hong Duan & Frederick E. Domann

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  1. Bernard W. Futscher
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Correspondence to Bernard W. Futscher.

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Futscher, B., Oshiro, M., Wozniak, R. et al. Role for DNA methylation in the control of cell type–specific maspin expression. Nat Genet 31, 175–179 (2002). https://doi.org/10.1038/ng886

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