Where do we look for answers?
We are convinced that gene expression changes in differentiating cells must be extensively coordinated at the post-transcriptional level.
First, transcription of mammalian genes often takes hours to complete. This includes time required to assemble initiation complexes at the promoter and to synthesize full-length messenger RNA precursors (pre-mRNAs) at an average elongation rate of just a few kilobases per minute. Since differentiation decisions are often made on a comparable time scale, many gene regulation functions have to be delegated to faster post-transcriptional processes.
Second, half-lives of many mammalian transcripts are measured in hours and, sometimes, days. This provides ample opportunity for implementing post-transcriptional controls of mRNA composition and abundance.
Third, mammalian gene expression is an inherently wasteful process. Only ~5% of a typical human gene encodes exons, elements that contribute to mature mRNA. The remaining bulk of intronic sequences are typically degraded following transcription and pre-mRNA splicing. This suggests that the energy wastage associated with regulating gene expression through controlled RNA processing, translation and degradation is probably negligible in comparison with the overall balance of cellular RNA metabolism.
Fourth, a number of post-transcriptional regulators orchestrating gene expression in differentiating cells have been identified in recent studies. These include RNA-binding proteins and non-coding RNAs that control processing, localization, translational efficiency and stability of multiple (pre-)mRNAs. We believe that our current understanding of these molecular components is incomplete and additional work in this area is bound to generate interesting new insights.
Finally, the extent of post-transcriptional control is underscored by a growing list of human diseases that are linked to defects in RNA processing.