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J. Biol. Chem., Vol. 279, Issue 50, 52685-52693, December 10, 2004

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NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of the Kcnq1 Imprinting Control Region^*

Radha Raman Pandey, Michele Ceribelli, Prim B. Singh¶, Johan Ericsson||, Roberto Mantovani, and Chandrasekhar Kanduri**

From the Department of Development and Genetics, Evolutionary Biology Centrum, Norbyvägen 18A, Uppsala SE-75236 University, Uppsala, Sweden, Department of Biomolecular Sciences and Biotechnology, Via Celoria 26, Milan 20133, Italy, ^¶Division of Gene Expression and Development, Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, Scotland, and ^||Gene Expression Laboratory, Ludwig Institute for Cancer Research, Biomedical Center, Box 595, Uppsala S-751 24, Sweden

Antisense transcription has been shown to be one of the hierarchies that control gene expression in eukaryotes. Recently, we have documented that the mouse Kcnq1 imprinting control region (ICR) harbors bidirectional silencing property, and this feature is linked to an antisense RNA, Kcnq1ot1. In this investigation, using genomic footprinting, we have identified three NF-Y transcription factor binding sites appearing in a methylation-sensitive manner in the Kcnq1ot1 promoter. By employing a dominant negative mutant to the NF-Y transcription factor, we have shown that the NF-Y transcription factor positively regulates antisense transcription. Selective mutation of the conserved nucleotides in the NF-Y binding sites resulted in the loss of antisense transcription. The loss of antisense transcription from the Kcnq1ot1 promoter coincides with an enrichment in the levels of deacetylation and methylation at the lysine 9 residue of histone H3 and DNA methylation at the CpG residues, implying a crucial role for the NF-Y transcription factor in organizing the parent of origin-specific chromatin conformation in the Kcnq1 ICR. Parallel to the loss of antisense transcription, the loss of silencing of the flanking reporter genes was observed, suggesting that NF-Y-mediated Kcnq1ot1 transcription is critical in the bidirectional silencing process of the Kcnq1 ICR. These data highlight the NF-Y transcription factor as a crucial regulator of antisense promoter-mediated bidirectional silencing and the parent of origin-specific epigenetic marks at the Kcnq1 ICR. More importantly, for the first time, we document that NF-Y is involved in maintaining the antisense promoter activity against strong silencing conditions.

Received for publication, July 16, 2004 , and in revised form, September 17, 2004.

^* This work was supported by grants from Göran Gustafssons Stif-telse, Swedish Research Council etenskaprådet and the Swedish Cancer Research Foundation (to C. K.) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence and requests for materials should be addressed. Tel.: 46-739600450; Fax: 46-18-4712683; E-mail: kanduri.chandrasekhar{at}ebc.uu.se.

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