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J. Biol. Chem., Vol. 282, Issue 33, 23981-23995, August 17, 2007

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

John W. Tullai¹, Michael E. Schaffer¹², Steven Mullenbrock¹, Gabriel Sholder, Simon Kasif^¶, and Geoffrey M. Cooper³

From the Department of Biology, Bioinformatics Program, and ^¶Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215

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.

Received for publication, March 8, 2007 , and in revised form, May 31, 2007.

^* This work was supported by National Institutes of Health Grants RO1 CA18689 (to G. M. C.) and ITR-048715 and National Human Genome Research Institute Grant R33 HG002850 (to S. K.). 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 microarray gene expression data from this study has been submitted to GEO (Gene Expression Omnibus) under accession number GSE8315 [NCBI GEO] .

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1–8 and Figs. 1–4.

¹ These authors contributed equally to this work.

² Present address: Pfizer Inc., Research Technology Center, 620 Memorial Dr., Cambridge, MA 02139.

³ To whom correspondence should be addressed: Dept. of Biology, Boston University, 5 Cummington St., Boston, MA 02215. Tel.: 617-353-8735; Fax: 617-353-8484; E-mail: gmcooper{at}bu.edu.

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