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J. Biol. Chem., Vol. 280, Issue 43, 36244-36253, October 28, 2005

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Pdx-1 Links Histone H3-Lys-4 Methylation to RNA Polymerase II Elongation during Activation of Insulin Transcription^*

Joshua Francis, Swarup K. Chakrabarti, James C. Garmey, and Raghavendra G. Mirmira1

From the Department of Pharmacology and the Department of Internal Medicine and the Diabetes Center, the University of Virginia, Charlottesville, Virginia 22908

Expression of the insulin gene is nearly exclusive to the cells of the pancreatic islets. Although the sequence-specific transcription factors that regulate insulin expression have been well studied, the interrelationship between these factors, chromatin structure, and transcriptional elongation by RNA polymerase II (pol II) has remained undefined. In this regard, recent studies have begun to establish a role for the methylation of histone H3 in the initiation or elongation of transcription by pol II. To determine a role for the transcriptional activator Pdx-1 in the maintenance of chromatin structure and pol II recruitment at the insulin gene, we performed small interfering RNA-mediated knockdown of Pdx-1 in TC3 cells and subsequently studied histone modifications and pol II recruitment by chromatin immunoprecipitation. We demonstrated here that the 50% fall in insulin transcription following knockdown of Pdx-1 is accompanied by a 60% fall in dimethylated histone H3-Lys-4 at the insulin promoter. H3-Lys-4 methylation at the insulin promoter may be mediated, at least partially, by the methyltransferase Set9. Immunohistochemical analysis revealed that Set9 is expressed in an islet-enriched pattern in the pancreas, similar to the pattern of Pdx-1 expression. The recruitment of Set9 to the insulin gene appears to be a consequence of its direct interaction with Pdx-1, and small interfering RNA-mediated knockdown of Set9 attenuates insulin transcription. Pdx-1 knockdown was also associated with an overall shift in the recruitment of pol II isoforms to the insulin gene, from an elongation isoform (Ser(P)-2) to an initiation isoform (Ser(P)-5). Our findings therefore suggest a model whereby Pdx-1 plays a novel role in linking H3-Lys-4 dimethylation and pol II elongation to insulin transcription.

Received for publication, May 26, 2005 , and in revised form, August 26, 2005.

^* This work was supported by Grant R01 DK60581 from the National Institutes of Health and a Thomas R. Lee Career Development Award from the American Diabetes Association (both to R. G. M.). 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.

¹ To whom correspondence should be addressed: University of Virginia Health System, 450 Ray C. Hunt Dr., Box 801407, Charlottesville, VA 22908. Tel.: 434-243-5036; Fax: 434-982-3796; E-mail: mirmira{at}virginia.edu.

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