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Molecular and Cellular Biology, November 2008, p. 6720-6729, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.00568-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

BAT3 and SET1A Form a Complex with CTCFL/BORIS To Modulate H3K4 Histone Dimethylation and Gene Expression ^,

Phuongmai Nguyen,^1, Gil Bar-Sela,^1, Lunching Sun,¹ Kheem S. Bisht,¹ Hengmi Cui,² Elise Kohn,³ Andrew P. Feinberg,^2* and David Gius^1*

Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ Institute of Genetic Medicine, Department of Medicine, Departments of Molecular Biology and Genetics, and Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,² Pathology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892³

Received 8 April 2008/ Returned for modification 20 June 2008/ Accepted 22 August 2008

Chromatin status is characterized in part by covalent posttranslational modifications of histones that regulate chromatin dynamics and direct gene expression. BORIS (brother of the regulator of imprinted sites) is an insulator DNA-binding protein that is thought to play a role in chromatin organization and gene expression. BORIS is a cancer-germ line gene; these are genes normally present in male germ cells (testis) that are also expressed in cancer cell lines as well as primary tumors. This work identifies SET1A, an H3K4 methyltransferase, and BAT3, a cochaperone recruiter, as binding partners for BORIS, and these proteins bind to the upstream promoter regions of two well-characterized procarcinogenic genes, Myc and BRCA1. RNA interference (RNAi) knockdown of BAT3, as well as SET1A, decreased Myc and BRCA1 gene expression but did not affect the binding properties of BORIS, but RNAi knockdown of BORIS prevented the assembly of BAT3 and SET1A at the Myc and BRCA1 promoters. Finally, chromatin analysis suggested that BORIS and BAT3 exert their effects on gene expression by recruiting proteins such as SET1A that are linked to changes in H3K4 dimethylation. Thus, we propose that BORIS acts as a platform upon which BAT3 and SET1A assemble and exert effects upon chromatin structure and gene expression.

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* Corresponding author. Mailing address for David Gius: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-5457. Fax: (301) 480-1434. E-mail: giusd{at}mail.nih.gov. Mailing address for Andrew P. Feinberg: Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 614-3489. Fax: (410) 614-9819. E-mail: afeinberg{at}jhu.edu

Published ahead of print on 2 September 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

The first two authors contributed equally to this paper.

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Molecular and Cellular Biology, November 2008, p. 6720-6729, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.00568-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.