The first instance of regulation is at transcription (transcriptional regulation) where due to the chromatin arrangement and due to the activity of transcription factors, genes are differentially transcribed. After being produced, the stability and distribution of the different transcripts is regulated (post-transcriptional regulation) by means of RNA binding protein (RNP) that control the various steps and rates of the transcripts: events such as alternative splicing, nuclear degradation (exosome), processing, nuclear export (three alternative pathways), sequestration in DCP2-bodies for storage or degradation, and ultimately translation. These proteins achieve these events thanks to a RNA recognition motif (RRM) that binds a specific sequence or secondary structure of the transcripts, typically at the 5’ and 3’ UTR of the transcript.
This area of study has recently gained more importance due to the increasing evidence that post-transcriptional regulation plays a larger role than previously expected. Even though protein with DNA binding domains are more abundant than protein with RNA binding domains*, a recent study by Cheadle et al (2005) showed that during T-cell activation 55% of significant changes at the steady-state level had no corresponding changes at the transcriptional level, meaning they were a result of stability regulation alone.
Furthermore RNA found in the nucleus is more complex than that found in the cytoplasm: more than 95% (bases) of the RNA synthesized by RNA polymerase II never reaches the cytoplasm. The main reason for this is due to the removal of introns which account for 80% of the total bases. Some studies have shown that even after processing the levels of mRNA between the cytoplasm and the nucleus differ greatly.
Developmental biology is a good source of models of regulation, but due to the technical difficulties it was easier to determine the transcription factor cascades than regulation at the RNA level. In fact seveal key genes such as nanos are known to bind RNA but often their targets are unknown. Although RNA binding proteins may regulate post transcriptionally large amount of the transcriptome, the targeting of a single gene is of interest to the scientific comunity for medical reasons, this is RNA interference and microRNAs which are both examples of posttranscriptional regulation, which regulate the destruction of RNA and change the chromatin structure. To study post-transcriptional regulation several techniques are used, such as RIP-Chip (RNA immunoprecipitation on chip).
- Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (2007). Molecular Biology of the Cell (Fifth Edition ed.). Garland Science. pp. 1268 pages. ISBN 0-8153-4105-9.
- Weaver, Robert J. (2007). "Part V: Post-transcriptional events". Molecular Biology. Boston: McGraw Hill Higher Education. ISBN 0-07-110216-7.
- Cheadle C, Fan J, Cho-Chung YS, Werner T, Ray J, Do L, Gorospe M, Becker KG (2005). "Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability". BMC Genomics. 6 (1): 75. doi:10.1186/1471-2164-6-75. PMID 15907206.
- Jackson DA, Pombo A, Iborra F (2000). "The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells". FASEB J. 14 (2): 242–54. PMID 10657981.
- Schwanekamp JA, Sartor MA, Karyala S, Halbleib D, Medvedovic M, Tomlinson CR (2006). "Genome-wide analyses show that nuclear and cytoplasmic RNA levels are differentially affected by dioxin". Biochim. Biophys. Acta. 1759 (8–9): 388–402. doi:10.1016/j.bbaexp.2006.07.005. PMID 16962184.
- Keene JD, Komisarow JM, Friedersdorf MB (2006). "RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts". Nat Protoc. 1 (1): 302–7. doi:10.1038/nprot.2006.47. PMID 17406249.