Immediate-Early and Delayed Primary Response Genes Are Distinct in Function and Genomic Architecture

The transcriptional program induced by growth factor stimulation is classically described in two stages as follows: the rapid protein synthesis-independent induction of immediate-early genes, followed by the subsequent protein synthesis-dependent induction of secondary response genes. In this study, we obtained a comprehensive view of this transcriptional program. As expected, we identified both rapid and delayed gene inductions. Surprisingly, however, a large fraction of genes induced with delayed kinetics did not require protein synthesis and therefore represented delayed primary rather than secondary response genes. Of 133 genes induced within 4 h of growth factor stimulation, 49 (37%) were immediateearly genes, 58 (44%) were delayed primary response genes, and 26 (19%) were secondary response genes. Comparison of immediateearly and delayed primary response genes revealed functional and regulatory differences. Whereas many immediate-early genes encoded transcription factors, transcriptional regulators were not prevalent among the delayed primary response genes. The lag in induction of delayed primary response compared with immediateearly mRNAs was because of delays in both transcription initiation and subsequent stages of elongation and processing. Consistent with increased abundance of RNA polymerase II at their promoters, immediate-early genes were characterized by over-representation of transcription factor binding sites and high affinity TATA boxes. Immediate-early genes also had short primary transcripts with few exons, whereas delayed primary response genes more closely resembled other genes in the genome. These findings suggest that genomic features of immediate-early genes, in contrast to the delayed primary response genes, are selected for rapid induction, consistent with their regulatory functions. The transcriptional program induced by growth factor stimulation is classically described in two stages as follows: the rapid protein synthesis-independent induction of immediate-early genes, followed by the subsequent protein synthesis-dependent induction of secondary response genes. In this study, we obtained a comprehensive view of this transcriptional program. As expected, we identified both rapid and delayed gene inductions. Surprisingly, however, a large fraction of genes induced with delayed kinetics did not require protein synthesis and therefore represented delayed primary rather than secondary response genes. Of 133 genes induced within 4 h of growth factor stimulation, 49 (37%) were immediateearly genes, 58 (44%) were delayed primary response genes, and 26 (19%) were secondary response genes. Comparison of immediateearly and delayed primary response genes revealed functional and regulatory differences. Whereas many immediate-early genes encoded transcription factors, transcriptional regulators were not prevalent among the delayed primary response genes. The lag in induction of delayed primary response compared with immediateearly mRNAs was because of delays in both transcription initiation and subsequent stages of elongation and processing. Consistent with increased abundance of RNA polymerase II at their promoters, immediate-early genes were characterized by over-representation of transcription factor binding sites and high affinity TATA boxes. Immediate-early genes also had short primary transcripts with few exons, whereas delayed primary response genes more closely resembled other genes in the genome. These findings suggest that genomic features of immediate-early genes, in contrast to the delayed primary response genes, are selected for rapid induction, consistent with their regulatory functions. The binding of growth factors to cell surface receptors leads to the activation of signaling pathways that ultimately control cell proliferation, differentiation, and survival. The critical targets of these signaling cascades include transcription factors, and many of the changes in cell behavior resulting from growth factor stimulation are because of altered programs of gene expression. The canonical model of a highly ordered program of gene expression induced by growth factor stimulation is the coordinate regulation of primary and secondary response genes. The initial transcriptional response to growth factor stimulation is the induction of ∼100 primary response genes (1Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (942) Google Scholar, 2Winkles J.A. Prog. Nucleic Acids Res. Mol. Biol. 1998; 58: 41-78Crossref PubMed Scopus (80) Google Scholar). Induction of these genes does not require de novo protein synthesis and is therefore mediated by pre-existing transcription factors. Most of the characterized primary response genes (termed immediate-early genes) are maximally induced within 30 min of growth factor stimulation, although a few examples of primary response genes that are induced with slower kinetics have been described (3Burger C. Wick M. Brusselbach S. Muller R. J. Cell Sci. 1994; 107: 241-252Crossref PubMed Google Scholar, 4Dixon B.S. Sharma R.V. Dennis M.J. J. Biol. Chem. 1996; 271: 13324-13332Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 5Freter R.R. Alberta J.A. Hwang G.Y. Wrentmore A.L. Stiles C.D. J. Biol. Chem. 1996; 271: 17417-17424Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6Sewing A. Burger C. Brusselbach S. C. Muller R. J. Cell Sci. PubMed Google Scholar, M. R. J. PubMed Scopus Google Scholar, Mol. Biol. PubMed Scopus Google Scholar). of the characterized primary response genes transcription factors, secondary response genes as of a transcriptional program (1Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (942) Google Scholar, 2Winkles J.A. Prog. Nucleic Acids Res. Mol. Biol. 1998; 58: 41-78Crossref PubMed Scopus (80) Google Scholar). response genes are induced than immediate-early genes, and their induction is from that of primary response genes in de novo protein the model of growth gene expression two the initial induction of primary response genes, followed by a of their mRNAs to the transcription factors that the secondary response genes. In this study, we expression to the program of transcriptional induced by growth factor stimulation of As expected, we identified of rapid and delayed gene inductions. Surprisingly, however, we that a large fraction of delayed did not require protein and therefore represented delayed induction of primary response genes rather than induction of secondary response genes. These that the transcriptional program induced by growth factor stimulation not the induction of immediate-early and secondary response genes also the induction of a large of delayed primary response genes that had been The delayed primary response genes from immediate-early genes in both their and genomic Whereas many immediate-early genes transcription factors, transcriptional regulators were not prevalent among the delayed primary response genes. transcriptional induction of immediate-early genes was with of these genes, of transcription factor binding sites in of this gene high affinity TATA in their promoters, and short primary transcripts with few In of these delayed primary response genes more closely resembled other genes in the genome. 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Wick M. Brusselbach S. Muller R. J. Cell Sci. 1994; 107: 241-252Crossref PubMed Google Scholar, 6Sewing A. Burger C. Brusselbach S. C. Muller R. J. Cell Sci. PubMed Google Scholar, J. PubMed Scopus Google B.S. Sharma R.V. Dennis M.J. J. Biol. Chem. 1996; 271: 13324-13332Abstract Full Text Full Text PDF PubMed Scopus (21) Google and R.R. Alberta J.A. Hwang G.Y. Wrentmore A.L. Stiles C.D. J. Biol. Chem. 1996; 271: 17417-17424Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, M. R. J. PubMed Scopus Google Scholar, Mol. Biol. PubMed Scopus Google the large of primary response genes we to induced with delayed kinetics was a more regulatory in programs are represented as gene of genes secondary gene regulation to the canonical response gene to from in gene expression PubMed Scopus Google Scholar). the high of delayed primary response genes, have for that regulatory from in gene expression. many genes that are induced with a lag growth factor stimulation are primary response genes, that delayed gene expression the induction of transcriptional delayed primary response genes represented a of the transcriptional response to growth factor stimulation, we both and to the of this of genes. to the delayed primary response genes with the immediateearly genes. the functional of the immediate-early and delayed primary response genes were compared the The immediate-early genes were in to transcriptional with their as transcriptional in the induction of secondary response genes. 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