Auto-Regulation of Transcription and Translation: Oscillations, Excitability and Intermittency

Several members of the Hes/Her family, conserved targets of the Notch signalling pathway, encode transcriptional repressors that dimerise, bind DNA and self-repress. Such autoinhibition of transcription can yield homeostasis and, in the presence of delays that account for processes such as transcription, splicing and transport, oscillations. Whilst previous models of autoinhibition of transcription have tended to treat processes such as translation as being unregulated (and hence linear), here we develop and explore a mathematical model that considers autoinhibition of transcription together with nonlinear regulation of translation. It is demonstrated that such a model can yield, in the absence of delays, nonlinear dynamical behaviours such as excitability, homeostasis, oscillations and intermittency. These results indicate that regulation of translation as well as transcription allows for a much richer range of behaviours than is possible with autoregulation of transcription alone. A number of experiments are suggested that would that allow for the signature of autoregulation of translation as well as transcription to be experimentally detected in a Notch signalling system.

Impact of uORFs in mediating regulation of translation in stress conditions

Background A large fraction of genes contains upstream ORFs (uORFs) in the 5′ untranslated region (5’UTR). The translation of uORFs can inhibit the translation of the main coding sequence, for example by causing premature dissociation of the two ribosomal units or ribosome stalling. However, it is currently unknown if most uORFs are inhibitory or if this activity is restricted to specific cases. Here we interrogate ribosome profiling data from three different stress experiments in yeast to gain novel insights into this question. Results By comparing ribosome occupancies in different conditions and experiments we obtain strong evidence that, in comparison to primary coding sequences (CDS), which undergo translational arrest during stress, the translation of uORFs is mostly unaffected by changes in the environment. As a result, the relative abundance of uORF-encoded peptides increases during stress. In general, the changes in the translational efficiency of regions containing uORFs do not seem to affect downstream translation. The exception are uORFs found in a subset of genes that are significantly up-regulated at the level of translation during stress; these uORFs tend to be translated at lower levels in stress conditions than in optimal growth conditions, facilitating the translation of the CDS during stress. We find new examples of uORF-mediated regulation of translation, including the Gcn4 functional homologue fil1 and ubi4 genes in S. pombe. Conclusion We find evidence that the relative amount of uORF-encoded peptides increases during stress. The increased translation of uORFs is however uncoupled from the general CDS translational repression observed during stress. In a subset of genes that encode proteins that need to be rapidly synthesized upon stress uORFs act as translational switches.

Exon–Intron Differential Analysis Reveals the Role of Competing Endogenous RNAs in Post-Transcriptional Regulation of Translation

Stressful conditions induce the cell to save energy and activate a rescue program modulated by mammalian target of rapamycin (mTOR). Along with transcriptional and translational regulation, the cell relies also on post-transcriptional modulation to quickly adapt the translation of essential proteins. MicroRNAs play an important role in the regulation of protein translation, and their availability is tightly regulated by RNA competing mechanisms often mediated by long noncoding RNAs (lncRNAs). In our paper, we simulated the response to growth adverse condition by bimiralisib, a dual PI3K/mTOR inhibitor, in diffuse large B cell lymphoma cell lines, and we studied post-transcriptional regulation by the differential analysis of exonic and intronic RNA expression. In particular, we observed the upregulation of a lncRNA, lncTNK2-2:1, which correlated with the stabilization of transcripts involved in the regulation of translation and DNA damage after bimiralisib treatment. We identified miR-21-3p as miRNA likely sponged by lncTNK2-2:1, with consequent stabilization of the mRNA of p53, which is a master regulator of cell growth in response to DNA damage.

Impact of uORFs in mediating regulation of translation in stress conditions

Background: A large fraction of genes contain upstream ORFs (uORFs) in the 5' untranslated region (5'UTR). The translation of uORFs can inhibit the translation of the main coding sequence, for example by causing premature dissociation of the two ribosomal units or ribosome stalling. However, it is currently unknown if most uORFs are inhibitory or if this activity is restricted to specific cases. Here we interrogate ribosome profiling data from three different stress experiments in yeast to address this question. Results: By comparing ribosome occupancies in different conditions and experiments we obtain strong evidence that, in comparison to primary coding sequences (CDS), which undergo translational arrest during stress, the translation of uORFs is mostly unaffected by changes in the environment. As a result the relative abundance of uORF-encoded peptides increases during stress. In general, the changes in the translational efficiency of regions containing uORFs do not seem to affect downstream translation. The exception are uORFs found in a subset of genes that are strongly up-regulated at the level of translation during stress; these uORFs tend to be translated at lower levels during stress than in optimal growth conditions, facilitating the translation of the CDS during stress. We find new examples of uORF-mediated regulation of translation, including the Gcn4 functional homologue fil1 and ubi4 genes in S. pombe.Conclusion: We find evidence that the relative amount of uORF-encoded peptides increases during stress. The increased translation of uORFs is however uncoupled from the general CDS translational repression observed during stress. In a subset of genes that encode proteins that need to be rapidly synthesized upon stress uORFs act as translational switches.