Tullai John W, Schaffer Michael E, Mullenbrock Steven, Sholder Gabriel, Kasif Simon, Cooper Geoffrey M
Department of Biology, Boston University, Boston, Massachusetts 02215, USA.
J Biol Chem. 2007 Aug 17;282(33):23981-95. doi: 10.1074/jbc.M702044200. Epub 2007 Jun 15.
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 immediate-early genes, 58 (44%) were delayed primary response genes, and 26 (19%) were secondary response genes. Comparison of immediate-early 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 immediate-early 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.
快速的不依赖蛋白质合成的即早基因诱导，随后是依赖蛋白质合成的次级反应基因诱导。在本研究中，我们获得了该转录程序的全面视图。如预期的那样，我们鉴定出了快速和延迟的基因诱导。然而，令人惊讶的是，很大一部分具有延迟动力学的诱导基因不需要蛋白质合成，因此代表延迟的初级反应基因而非次级反应基因。在生长因子刺激4小时内诱导的133个基因中，49个（37%）是即早基因，58个（44%）是延迟初级反应基因，26个（19%）是次级反应基因。即早基因和延迟初级反应基因的比较揭示了功能和调控上的差异。许多即早基因编码转录因子，而转录调节因子在延迟初级反应基因中并不普遍。与即早mRNA相比，延迟初级反应基因诱导的滞后是由于转录起始以及随后的延伸和加工阶段的延迟。与RNA聚合酶II在其启动子处丰度增加一致，即早基因的特征是转录因子结合位点和高亲和力TATA盒的过度表达。即早基因也具有短的初级转录本，外显子较少，而延迟初级反应基因更类似于基因组中的其他基因。这些发现表明，与延迟初级反应基因相比，即早基因的基因组特征是为快速诱导而选择的，这与其调控功能一致。
