hCTR9, a component of Paf1 complex, participates in the transcription of interleukin 6-responsive genes through regulation of STAT3-DNA interactions.
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 beta-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-beta, TNFalpha, or IL-1beta. The PAF complex was found in the promoter regions of IL-6-responsive HP and FGGgamma, 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.
Youn
Min-Young
MY
Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Yoo
Hyun-Seok
HS
Kim
Min-Jung
MJ
Hwang
Sun-Young
SY
Choi
Yongwook
Y
Desiderio
Stephen V
SV
Yoo
Joo-Yeon
JY
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C484387:CTR9 protein, human; D006657:Histones; D015850:Interleukin-6; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D004247:DNA