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Deoxyribonucleic Acid Methyltransferase 3B Promotes Epigenetic Silencing through Histone 3 Chromatin Modifications in Pituitary Cells

Departments of Medicine (X.Z., X.M., R.H., A.D.S., S.E.) and Pathology (S.L.A.), University Health Network, The Ontario Cancer Institute (X.Z., X.M., R.H., A.D.S., S.E., S.L.A.) Toronto, Ontario, Canada M5G-2M9

Address all correspondence and requests for reprints to: Dr. Sylvia L. Asa, Ontario Cancer Institute, 610 University Avenue 8-327, Toronto, Ontario, Canada M5G 2M9. 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. However, the upstream mediators of such events remain unknown.

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

Setting: This study was performed at a university-affiliated cancer research institute.

Main Outcome Measures: Gene expression, promoter DNA methylation, histone modifications, and cell proliferation were determined.

Results: In contrast to DNMT1 and DNMT3a, DNMT3b was expressed at relatively higher levels in neoplastic pituitary cells. However, examination of the human DNMT3b 5' region showed uniformly low DNA methylation levels with little difference between normal and tumor samples. Through pharmacological 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 retinoblastoma, p21, and p27, and reduction in cell proliferation. These targeted effects were associated with enhanced histone 3 acetylation and diminished histone methylation.

Conclusion: Our findings identify DNMT3b as a putative mediator of epigenetic control through histone modifications of gene expression in pituitary cells.

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