The Rate of c-fos Transcription in Vivo Is Continuously Regulated at the Level of Elongation by Dynamic Stimulus-coupled Recruitment of Positive Transcription Elongation Factor b

In mammalian cells, multiple stimuli induce the expression of the immediate early gene c-fos. The specificity of c-fos transcriptional response depends on the activation of signaling protein kinases, transcription factors, and chromatin-modifying complexes but also on a regulated block to elongation in the first intron. Here we show by chromatin immunoprecipitation that finely tuned control of c-fos gene expression by distinct stimuli is associated with a dynamic regulation of transcription elongation and differential phosphorylation of the C-terminal domain of RNA polymerase II. Comparison of two stimuli of c-fos expression in the pituitary cell line GH4C1, namely the thyrotropin-releasing hormone versus depolarizing KCl, shows that both stimuli increase initiation, but only thyrotropin-releasing hormone is efficient to stimulate elongation and thus produce high transcription rates. To control elongation, the elongation factor P-TEFb is recruited to the 5′-end of the gene in a stimuli and time-dependent manner. Transition from initiation to elongation depends also on the dynamic recruitment of the initiation factors TFIIB and TFIIE but not TFIID, which remains constitutively bound on the promoter. It thus appears that tight coupling of signaling input to transcriptional output rate is achieved by c-fos gene-specific mechanisms, which control post-initiation steps rather than pre-initiation complex assembly. In mammalian cells, multiple stimuli induce the expression of the immediate early gene c-fos. The specificity of c-fos transcriptional response depends on the activation of signaling protein kinases, transcription factors, and chromatin-modifying complexes but also on a regulated block to elongation in the first intron. Here we show by chromatin immunoprecipitation that finely tuned control of c-fos gene expression by distinct stimuli is associated with a dynamic regulation of transcription elongation and differential phosphorylation of the C-terminal domain of RNA polymerase II. Comparison of two stimuli of c-fos expression in the pituitary cell line GH4C1, namely the thyrotropin-releasing hormone versus depolarizing KCl, shows that both stimuli increase initiation, but only thyrotropin-releasing hormone is efficient to stimulate elongation and thus produce high transcription rates. To control elongation, the elongation factor P-TEFb is recruited to the 5′-end of the gene in a stimuli and time-dependent manner. Transition from initiation to elongation depends also on the dynamic recruitment of the initiation factors TFIIB and TFIIE but not TFIID, which remains constitutively bound on the promoter. It thus appears that tight coupling of signaling input to transcriptional output rate is achieved by c-fos gene-specific mechanisms, which control post-initiation steps rather than pre-initiation complex assembly. Stimulus-transcription coupling mediates cellular responses, which require changes in gene expression such as proliferation, differentiation, or adaptive responses (e.g. neuronal plasticity) in higher eukaryotes. The induction of immediate early gene (IEG) 3The abbreviations used are: IEG, immediate early response gene; ChIP, chromatin immunoprecipitation; CTD, C-terminal domain; FAM, 6-carboxyfluorescein; pol II, RNA polymerase II; TRH, thyrotropin-releasing hormone; Ham's F10 serum-free medium, Ham's F10 serum-free medium; RT, reverse transcription; TAMRA, 6-carboxytetramethylrhodamine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PIC, pre-initiation complex; cdk, cyclin-dependent kinase; RCFRD, reconstituted c-fos rat DNA; P-TEFb, positive transcription elongation factor b; PD, promoter distal; PP, promoter proximal; TBP, tata-binding protein; TF, transcription factor; GTF, general transcription factor. transcription via multiple signal transduction pathways (1.Morgan J.I. Curran T. Trends Neurosci. 1989; 12: 459-462Abstract Full Text PDF PubMed Scopus (845) Google Scholar, 2.Sheng M. Greenberg M.E. Neuron. 1990; 4: 477-485Abstract Full Text PDF PubMed Scopus (1984) Google Scholar, 3.Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (946) Google Scholar) is the first step in stimulus-transcription coupling. IEGs code mainly for transcription factors, which in turn will control the expression of further genes leading to the cellular responses. Distinct extracellular stimuli can induce in the same cell a similar panel of IEGs with the same kinetics but with clear differences in their levels of expression. Therefore, during any particular stimulation, specific signal transduction and transcription mechanisms must act in a concerted manner to obtain a distinct level of gene transcription on each specific IEG. In a recent review, Hazzalin and Mahadevan (4.Hazzalin C.A. Mahadevan L.C. Nat. Rev. Mol. Cell Biol. 2002; 3: 30-40Crossref PubMed Scopus (342) Google Scholar) propose that the rate of IEG transcription varies continuously as a function of the strength of intracellular signaling events. Such dynamic control of IEG transcription implies an equally rapid reversal in addition to the well documented rapid induction of transcription. Transcription factors constitutively present on the promoter of IEGs may function as “rheostats,” sensing the degree of activation of several signal transduction pathways and driving continuously varying levels of gene transcription. In parallel, IEG transcription is also correlated with a dynamic regulation of phosphorylation and acetylation of histone (H3/H4) tails that modify the level of chromatin compaction within the gene (5.Thomson S. Clayton A.L. Mahadevan L.C. Mol. Cell. 2001; 8: 1231-1241Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Thus, transcription factors and chromatin components function as sensors/integrators for signal transduction inputs. How is this information related to the basal transcription machinery, which has to modulate RNA polymerase II (pol II) to produce a continuously varying output of mRNA? We speculated that pol II features associated with either initiation or elongation could be differentially regulated by distinct signal transduction pathways. Specifically, we looked for changes in the phosphorylation levels of the C-terminal domain (CTD) of pol II during the expression of an IEG to understand how quantitative information can be converted from input intracellular signaling events to output rates of mRNA. During the transcription cycle, transition from initiation to processive elongation and termination is associated with changes in the phosphorylation state of the CTD (6.Hirose Y. Manley J.L. Genes Dev. 2000; 14: 1415-1429Crossref PubMed Google Scholar, 7.Orphanides G. Reinberg D. Cell. 2002; 108: 439-451Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar). Different cyclin-dependent kinases (cdks) catalyze the differential phosphorylation of the serine residues in positions 2 and 5 in the YSPTSPS repeat of the CTD. These serine residues are phosphorylated in a dynamic fashion during the transcription of the entire gene (8.Schroeder S.C. Schwer B. Shuman S. Bentley D. Genes & Dev. 2000; 14: 2435-2440Crossref PubMed Scopus (302) Google Scholar, 9.Komarnitsky P. Cho E.J. Buratowski S. Genes Dev. 2000; 14: 2452-2460Crossref PubMed Scopus (802) Google Scholar, 10.Boehm A.K. Saunders A. Werner J. Lis J.T. Mol. Cell. Biol. 2003; 23: 7628-7637Crossref PubMed Scopus (188) Google Scholar, 11.Cheng C. Sharp P.A. Mol. Cell. Biol. 2003; 23: 1961-1967Crossref PubMed Scopus (69) Google Scholar). Ser-5 is predominantly phosphorylated in pol II transcribing the 5′ part of the gene and progressively dephosphorylated during elongation while Ser-2 phosphorylation increases. Post-translational modifications of the CTD are also crucial for the maturation of the nascent RNA to mRNA in pol II genes (6.Hirose Y. Manley J.L. Genes Dev. 2000; 14: 1415-1429Crossref PubMed Google Scholar, 7.Orphanides G. Reinberg D. Cell. 2002; 108: 439-451Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar): RNA capping enzyme and phospho-Ser-5 CTD are functionally associated (8.Schroeder S.C. Schwer B. Shuman S. Bentley D. Genes & Dev. 2000; 14: 2435-2440Crossref PubMed Scopus (302) Google Scholar, 9.Komarnitsky P. Cho E.J. Buratowski S. Genes Dev. 2000; 14: 2452-2460Crossref PubMed Scopus (802) Google Scholar, 12.Fabrega C. Shen V. Shuman S. Lima C.D. Mol. Cell. 2003; 11: 1549-1561Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar), and so are phospho-Ser-2 CTD and 3′-end RNA-processing enzymes (13.Ni Z. Schwartz B.E. Werner J. Suarez J.R. Lis J.T. Mol. Cell. 2004; 13: 55-65Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 14.Ahn S.H. Kim M. Buratowski S. Mol. Cell. 2004; 13: 67-76Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). CTD phosphorylation combined with other CTD modifications such as proline cis-trans isomerization (15.Verdecia M.A. Bowman M.E. Lu K.P. Hunter T. Noel J.P. Nat. Struct. Biol. 2000; 7: 639-643Crossref PubMed Scopus (428) Google Scholar) generates different pol II structural conformations, with major consequences on the rate of gene transcription and mRNA synthesis (16.Buratowski S. Nat. Struct. Biol. 2003; 10: 679-680Crossref PubMed Scopus (260) Google Scholar). 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In the 5′ and and are in the and of GAPDH, The and are as c-fos and c-fos c-fos c-fos c-fos c-fos c-fos 4: 5′ histone 5′ histone c-fos Transcription to Distinct to study the expression of the c-fos a IEG for which transcription control the level of initiation and a block to elongation in the first are well documented S. S. G. M. S. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. D. P. P. Mol. Cell Biol. 1991; 11: PubMed Scopus Google Scholar, G. D. B. M. J. Biol. Full Text PDF PubMed Google Scholar, V. J.L. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, T. Y. S. T. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). c-fos expression is a of cellular in T. J.I. J. PubMed Scopus Google Scholar). 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Full Text Full Text PDF PubMed Scopus Google Scholar). with to a rapid increase of pol II the gene of transcription activation during this is correlated with a high level of Ser-5 and Ser-2 phosphorylation of the CTD of pol II and initiation and elongation are during this of c-fos gene transcription. transcription and pol II on and with a in the of pol II phosphorylated on the two serine the level of pol II and pol II in the high with of and that the recruitment and initiation of pol II the promoter a the of pol II has by TRH, control of transcription initiation may be distinct from the control of transcription can be by the pol II from versus pol II this during the activation that elongation efficient to pol II than the of transcriptional the progressively to a which The to the kinetics of transcriptional rates versus that the kinetics of transcriptional rates from the dynamic control of In c-fos other immediate early genes kinetics of gene expression extracellular of c-fos by is by a and of gene transcription by a CTD phosphorylation of and of pol II changes during the different of gene transcription. the of gene transcription CTD is phosphorylated both on Ser-2 and for pol II on phospho-Ser-2 and phosphorylated pol II phospho-Ser-5 and for CTD kinases P. 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Distinct and Ser-5 versus Ser-2 CTD that different stimuli or signal transduction pathways distinct mechanisms of CTD we pol II on with pol II in the 5′ of the gene and with similar In pol II in the CTD pol II in the a similar rate and and but on and CTD Ser-2 or phosphorylation with In with recruitment of pol II to the 5′ of the c-fos CTD phosphorylated on this could not elongation or the associated phosphorylation of CTD on Ser-2 and for factor not of the in this transition to elongation is the positive transcription elongation factor which is of and the cyclin-dependent which CTD on We looked for a in P-TEFb recruitment and with an to stimulation, on the c-fos the of transcription P-TEFb recruited to the the levels of with a in the elongation only recruitment of P-TEFb to the c-fos that the control of c-fos elongation by different stimuli in the 5′ by post-initiation recruitment of P-TEFb is thus to pol II of the c-fos gene and to to the block to elongation in the first intron. and of c-fos Transcription of pol II to the of c-fos and pol II Ser-5 CTD phosphorylation are during the of gene transcription could be to either a level of transcription initiation by or the of the block to elongation in the first S. 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Dev. 2001; 11: PubMed Scopus Google Scholar, S. Nat. Struct. Mol. Biol. 2004; 11: PubMed Scopus Google Scholar, M. Cell. 2002; 108: Full Text Full Text PDF PubMed Scopus Google Scholar). recruitment to the block may modulate pol II in a manner for P-TEFb quantitative of the of pol II and CTD phosphorylation on the immediate early response gene c-fos in mammalian the regulation of elongation, which appears to be the transcriptional is from the of two and TRH, with in c-fos mRNA output than both stimuli in recruitment to of pol II, which is phosphorylated on the Ser-5 residues of the CTD, only can the elongation coupling of signaling input to transcriptional output is thus achieved by mechanisms that control elongation rather than initiation and pre-initiation complex assembly. The in part and for the is a for finely tuned elongation control to be the mechanisms that control elongation, the phosphorylation by P-TEFb of Ser-2 in the of the CTD of pol II Transcription initiation and elongation on the dynamic changes of the of pol II, and phosphorylated in the of the c-fos is as the recruitment of pol II to the promoter and the synthesis of the first RNA which are mechanisms that CTD Ser-5 phosphorylation S. Reinberg D. PubMed Scopus Google Scholar, Kim J. Sharp P.A. S. A. PubMed Scopus Google Scholar). To further the initiation steps for c-fos we the of the by for the of specific with the 5′ of the gene We specific and quantitative changes in the associated with the of elongation, which we in the in of the are namely a basal a state of transcriptional rate and an state either or with the The basal state is by a but of pol II on the 5′ of the c-fos with CTD Ser-5 in part is bound to the promoter. clear of and TFIIE with of the 5′ of c-fos by the signal rather than In the pol II in the basal state will not the nascent the first intron. Transcription will be in the of the to from the which as a to M.A. D. P. P. Mol. Cell Biol. 1991; 11: PubMed Scopus Google Scholar, M. P. B. Mol. Cell Biol. 1991; 11: PubMed Scopus Google Scholar). a basal transcription rates will be of The state is by the recruitment to the and of pol II with CTD The recruitment of and TFIIE is in are associated with pol II. TFIIB is present on the promoter. The of TFIIB and TFIIE with the and factors may higher rates. In addition this of the promoter may the transition by P-TEFb to the same P-TEFb pol II by Ser-2 residues in the CTD. The important for elongation is the and tight coupling and elongation pol II phosphorylated on both Ser-5 and Ser-2 of the CTD associated with P-TEFb can be by on of the c-fos Such a high by pol II of the c-fos gene in a in transcriptional The or state in by a TFIIB to the promoter and an equally P-TEFb pol II present on the part of the gene of The CTD of pol II phosphorylated on Ser-5 and to a also on a of pol II transcription of the c-fos gene can a a of pol II complexes on and the of pol II in 2 a of pol II on the of the response and with this may in part be to initiation, may be by an of pol II of the block to of the implies input changes in transcriptional rate can and c-fos transcription is The transcription is thus in the in we in this kinetics of pol II of the 5′ part of the c-fos gene to for phospho-Ser-2 CTD pol II and P-TEFb with and and TRH, in to KCl, could the positive elongation factor P-TEFb to the of the We are the signaling of the which may P-TEFb activation of elongation factors by signaling protein kinases has not so distinct signaling pathways and the elongation may be that the of several transcription factors with and the general transcription is to pol II elongation via the recruitment of elongation factors C. 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In the on transcription control of the the and of the on which dynamic from and the differentially control and of transcriptional information on the entire We are to C. for information for with the and We A. for and D. A. for and of the