Abstract
The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset.
Highlights
Immediate-early genes are induced in response to a stimulus without the requirement of de novo protein synthesis [1]
Cells respond to stimuli through a set of genes that are primed for rapid activation
Immediate-early genes are involved in many cellular processes, including differentiation and proliferation, that are often dysregulated in cancer where they become continuously active
Summary
Immediate-early (or primary response) genes are induced in response to a stimulus without the requirement of de novo protein synthesis [1]. The activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) in the MCF7 breast cancer cell line exemplifies the impact of such transient or sustained signalling on cell fate [3, 4]. The well-studied mitogen-activated kinase (MAPK), and in particular extracellular signal-regulated kinase (ERK) pathways, play important roles in signal transduction in the immediateearly response as well as many other cellular responses [1]. The over-expression of immediate early genes is correlated with cancer progression, and some of the best studied are known oncogenes [5]. We lack a comprehensive account of how the mechanisms underlying these phenomena vary across stimuli and cell types, and few studies have explored the full diversity of transcripts involved
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