MCB Accepts, published online ahead of print on 14 July 2008

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Mol. Cell. Biol. doi:10.1128/MCB.00246-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Genome analysis identifies the p15ink4b tumour suppressor as a direct target of the ZNF217/Corest complex

Gobi Thillainadesan, Majdina Isovic, Esther Loney, Joseph Andrews, Marc Tini, and Joseph Torchia^*

Dept. of Oncology, London Regional Cancer Program and the Lawson Health Research Institute Dept. of Biochemistry, Dept. of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada

^* To whom correspondence should be addressed. Email: jtorchia{at}uwo.ca.

The ZNF217 oncoprotein is a constituent of a core transcriptional complex that includes CoREST, histone deacetylase 1/2 (HDAC 1/2), lysine demethylase 1 (LSD1) and the C terminal binding protein 1/2 (CtBP 1/2). We have combined genome wide expression profiling and chromatin immunoprecipitation with directed selection and ligation (ChIP-DSL) to identify a subset of genes directly regulated by ZNF217. Our results establish p15ink4b as a direct target of the ZNF217 complex. Downregulation of ZNF217 in MCF7 breast cancer cells resulted in a dramatic increase in p15ink4b expression and coincided with increases in dimethylation of H3-K4 and surprisingly, a decrease in K9/K14-H3 acetylation. Stimulation of HaCaT cells with TGF resulted in a release of ZNF217 and a concomitant binding of SMAD2 to the proximal promoter, which preceded increases in ink4b protein expression. Furthermore, the changes in chromatin marks at the p15ink4b promoter, following TGF stimulation were similar to those observed following ZNF217 downregulation. Collectively, these results establish the ZNF217 complex as a novel negative regulator of the p15ink4b gene and may consititute an important link between amplification of ZNF217 and the loss of TGF responsiveness in breast cancer.

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