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J. Biol. Chem., Vol. 282, Issue 48, 34727-34734, November 30, 2007

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hCTR9, a Component of Paf1 Complex, Participates in the Transcription of Interleukin 6-responsive Genes through Regulation of STAT3-DNA Interactions^*

Min-Young Youn¹, Hyun-Seok Yoo¹, Min-Jung Kim, Sun-Young Hwang, Yongwook Choi, Stephen V. Desiderio², and Joo-Yeon Yoo³

From the Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea and the Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

PAF, which is composed of Paf1, Cdc73, Ctr9, Leo1, and Rtf1, is a novel complex with multiple functions in transcription-related activities. The PAF complex interacts with histone-modifying enzymes and RNA polymerase II to regulate transcription. With general transcription regulatory potential in yeast, Hyrax/Cdc73 has been reported to associate with β-catenin to control Wnt/Wg signal-specific transcription in Drosophila. Here, we present the first evidence of IL-6 signal-specific transcriptional regulation by SH2BP1/CTR9 in mammals. Upon LPS injection of mice, we observed transient induction of the mammalian PAF complex in the liver. Inhibition of CTR9 specifically abrogated expression of IL-6-responsive genes, but had no effect on genes constitutively expressed or induced by interferon-β, TNF, or IL-1β. The PAF complex was found in the promoter regions of IL-6-responsive HP and FGG, but not in the promoter region of constitutively active GAPDH. Transcriptional activation by STAT3 was inhibited when CTR9 siRNA was introduced, whereas transcriptional activation was enhanced by mCtr9 overexpression. IL-6-activated Stat3 was found to co-localize and interact with CTR9. In CTR9-depleted cells, decreased STAT3 association with the promoter regions, as well as impaired K4-trimethylation of histone H3 in the coding regions, of target genes was observed. These data suggest that CTR9 participates in the transcription of IL-6-responsive genes through the regulation of DNA association of STAT3 and modification of histone methylation.

Received for publication, July 2, 2007 , and in revised form, September 20, 2007.

^* This work was supported in part by grants from the KBRDG Initiative Research Program for the Development of Biotechnologies (M10416020004-05N1602-00430), the MOST/KOSEF program of the National Core Research Center for Systems Bio-Dynamics (R15-2004-033), and the Postech Research Fund. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Both authors contributed equally to this work.

² Supported by the Howard Hughes Medical Institute and Grant R01HL07391 from the National Institutes of Health.

³ To whom correspondence should be addressed: 208 Life Science Bldg., Hyojadong 31, Pohang 790-784, Republic of Korea. Tel.: 82-54-279-2346; Fax: 82-54-279-2199; E-mail: jyoo{at}postech.ac.kr.

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