title: CTR9, a component of PAF complex, controls elongation block at the c-Fos locus via signal-dependent regulation of chromatin-bound NELF dissociation.
abstract: PAF complex (PAFc) is an RNA polymerase II associated factor that controls diverse steps of transcription. Although it is generally associated with actively transcribed genes, a repressive PAFc has also been suggested. Here, we report that PAFc regulates the transition from transcription initiation to transcription elongation. PAFc repressed IL-6-induced, but not TNF-α-induced, immediate early gene expression. PAFc constitutively associated with the 5'-coding region of the c-Fos locus, then transiently dissociated upon IL-6 stimulation. When CTR9, a component of PAFc, was depleted, higher levels of serine 5-phosphorylated or serine 2-phosphorylated forms of RNA Polymerase II were associated with the unstimulated c-Fos locus. We also observed an increased association of CDK9, a kinase component of the pTEF-b elongation factor, with the c-Fos locus in the CTR9-depleted condition. Furthermore, association of negative elongation factor, NELF, which is required to proceed to the elongation phase, was significantly reduced by CTR9 depletion, whereas elongation factor SPT5 recruitment was enhanced by CTR9 depletion. Finally, the chromatin association of CTR9 was specifically controlled by IL-6-induced kinase activity, because a JAK2 kinase inhibitor, AG-490, blocked its association. In conclusion, our data suggest that PAFc controls the recruitment of NELF and SPT5 to target loci in a signal- and locus-specific manner.
authors.affiliation: Division of Molecular and Life Sciences, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Yoo
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Seo
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D016762:Genes, fos / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D034622:RNA Interference; D061805:Transcription Elongation, Genetic / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D061785:Transcription Initiation, Genetic / Q000502:physiology*; D035602:Transcriptional Elongation Factors / Q000378:metabolism; D020032:Tyrphostins
chemical_list: C484387:CTR9 protein, human; D002843:Chromatin; D017931:DNA Primers; D018076:DNA, Complementary; D015850:Interleukin-6; C411985:NSMF protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C112224:SUPT5H protein, human; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide