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This version published online on June 10, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2008-0578
A more recent version of this article appeared on September 1, 2008
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Submitted on March 12, 2008
Accepted on June 2, 2008

DNA Methyl-Transferase 3B Promotes Epigenetic Silencing through Histone 3 Chromatin Modifications in Pituitary Cells

Xuegong Zhu, Xinliang Mao, Rose Hurren, Aaron D. Schimmer, Shereen Ezzat, and Sylvia L. Asa*

Department of Medicine, and the Department of Pathology, University Health Network, The Ontario Cancer Institute, 610 University Avenue #8-327, Toronto, Ontario, Canada M5G-2M9

* To whom correspondence should be addressed. E-mail: sylvia.asa{at}uhn.on.ca.

Context and objective: Epigenetic dysregulation is implicated in pituitary neoplasia as the cause of silencing of several tumor suppressor genes. The upstream mediators of such events, however, remain unknown.

Design: We examined the 3 members of the DNA methyltransferase (DNMT) enzyme family in normal and neoplastic human and mouse pituitary cells.

Setting: University-affiliated Cancer Research Institute.

Main-outcome Measures: Gene expression, promoter DNA methylation, histone modifications, and cell proliferation.

Results: In contrast to DNMT1 and DNMT3a, DNMT3b was expressed at relatively higher levels in neoplastic pituitary cells. Examination of the human DNMT3b 5' region, however, showed uniformly low DNA methylation levels with little difference between normal and tumor samples. Through pharmacologic methylation inhibition or histone deacetylation inhibition, we identified that DNMT3b gene expression is subject to histone modifications. Down-regulation of DNMT3b resulted in induction of Rb, p21, and p27 and reduction in cell proliferation. These targeted effects were associated with enhanced histone 3 acetylation and diminished histone methylation.

Conclusions: Our findings identify DNMT3b as a putative mediator of epigenetic control through histone modifications of gene expression in pituitary cells.
Key words: DNA methylation • histone methylation • epigenetic control • pituitary tumors






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