A catalog of stability-associated sequence elements in 3' UTRs of yeast mRNAs

BACKGROUND: In recent years, intensive computational efforts have been directed towards the discovery of promoter motifs that correlate with mRNA expression profiles. Nevertheless, it is still not always possible to predict steady-state mRNA expression levels based on promoter signals alone, suggesting that other factors may be involved. Other genic regions, in particular 3' UTRs, which are known to exert regulatory effects especially through controlling RNA stability and localization, were less comprehensively investigated, and deciphering regulatory motifs within them is thus crucial. RESULTS: By analyzing 3' UTR sequences and mRNA decay profiles of Saccharomyces cerevisiae genes, we derived a catalog of 53 sequence motifs that may be implicated in stabilization or destabilization of mRNAs. Some of the motifs correspond to known RNA-binding protein sites, and one of them may act in destabilization of ribosome biogenesis genes during stress response. In addition, we present for the first time a catalog of 23 motifs associated with subcellular localization. A significant proportion of the 3' UTR motifs is highly conserved in orthologous yeast genes, and some of the motifs are strikingly similar to recently published mammalian 3' UTR motifs. We classified all genes into those regulated only at transcription initiation level, only at degradation level, and those regulated by a combination of both. Interestingly, different biological functionalities and expression patterns correspond to such classification. CONCLUSION: The present motif catalogs are a first step towards the understanding of the regulation of mRNA degradation and subcellular localization, two important processes which - together with transcription regulation - determine the cell transcriptome

Metabolic and Chaperone Gene Loss Marks the Origin of Animals: Evidence for Hsp104 and Hsp78 Sharing Mitochondrial Clients

The evolution of animals involved acquisition of an emergent gene repertoire for gastrulation. Whether loss of genes also co-evolved with this developmental reprogramming has not yet been addressed. Here, we identify twenty-four genetic functions that are retained in fungi and choanoflagellates but undetectable in animals. These lost genes encode: (i) sixteen distinct biosynthetic functions; (ii) the two ancestral eukaryotic ClpB disaggregases, Hsp78 and Hsp104, which function in the mitochondria and cytosol, respectively; and (iii) six other assorted functions. We present computational and experimental data that are consistent with a joint function for the differentially localized ClpB disaggregases, and with the possibility of a shared client/chaperone relationship between the mitochondrial Fe/S homoaconitase encoded by the lost LYS4 gene and the two ClpBs. Our analyses lead to the hypothesis that the evolution of gastrulation-based multicellularity in animals led to efficient extraction of nutrients from dietary sources, loss of natural selection for maintenance of energetically expensive biosynthetic pathways, and subsequent loss of their attendant ClpB chaperones.Comment: This is a reformatted version from the recent official publication in PLoS ONE (2015). This version differs substantially from first three arXiV versions. This version uses a fixed-width font for DNA sequences as was done in the earlier arXiv versions but which is missing in the official PLoS ONE publication. The title has also been shortened slightly from the official publicatio

Transcriptional Regulation: a Genomic Overview

The availability of the Arabidopsis thaliana genome sequence allows a comprehensive analysis of transcriptional regulation in plants using novel genomic approaches and methodologies. Such a genomic view of transcription first necessitates the compilation of lists of elements. Transcription factors are the most numerous of the different types of proteins involved in transcription in eukaryotes, and the Arabidopsis genome codes for more than 1,500 of them, or approximately 6% of its total number of genes. A genome-wide comparison of transcription factors across the three eukaryotic kingdoms reveals the evolutionary generation of diversity in the components of the regulatory machinery of transcription. However, as illustrated by Arabidopsis, transcription in plants follows similar basic principles and logic to those in animals and fungi. A global view and understanding of transcription at a cellular and organismal level requires the characterization of the Arabidopsis transcriptome and promoterome, as well as of the interactome, the localizome, and the phenome of the proteins involved in transcription

Regulation of Ace2-dependent genes requires components of the PBF complex in schizosaccharomyces pombe

The division cycle of unicellular yeasts is completed with the activation of a cell separation program that results in the dissolution of the septum assembled during cytokinesis between the 2 daughter cells, allowing them to become independent entities. Expression of the eng1+ and agn1+ genes, encoding the hydrolytic enzymes responsible for septum degradation, is activated at the end of each cell cycle by the transcription factor Ace2. Periodic ace2+ expression is regulated by the transcriptional complex PBF (PCB Binding Factor), composed of the forkhead-like proteins Sep1 and Fkh2 and the MADS box-like protein Mbx1. In this report, we show that Ace2-dependent genes contain several combinations of motifs for Ace2 and PBF binding in their promoters. Thus, Ace2, Fkh2 and Sep1 were found to bind in vivo to the eng1+ promoter. Ace2 binding was coincident with maximum level of eng1+ expression, whereas Fkh2 binding was maximal when mRNA levels were low, supporting the notion that they play opposing roles. In addition, we found that the expression of eng1+ and agn1+ was differentially affected by mutations in PBF components. Interestingly, agn1+ was a major target of Mbx1, since its ectopic expression resulted in the suppression of Mbx1 deletion phenotypes. Our results reveal a complex regulation system through which the transcription factors Ace2, Fkh2, Sep1 and Mbx1 in combination control the expression of the genes involved in separation at the end of the cell division cycle

Stochastic Modeling of Expression Kinetics Identifies Messenger Half-Lives and Reveals Sequential Waves of Co-ordinated Transcription and Decay

The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli. Citation: Cacace F, Paci P, Cusimano V, Germani A, Farina L (2012) Stochastic Modeling of Expression Kinetics Identifies Messenger Half-Lives and Reveals Sequential Waves of Co-ordinated Transcription and Decay. PLoS Comput Biol 8(11): e1002772. doi:10.1371/journal.pcbi.100277

Super-paramagnetic clustering of yeast gene expression profiles

High-density DNA arrays, used to monitor gene expression at a genomic scale, have produced vast amounts of information which require the development of efficient computational methods to analyze them. The important first step is to extract the fundamental patterns of gene expression inherent in the data. This paper describes the application of a novel clustering algorithm, Super-Paramagnetic Clustering (SPC) to analysis of gene expression profiles that were generated recently during a study of the yeast cell cycle. SPC was used to organize genes into biologically relevant clusters that are suggestive for their co-regulation. Some of the advantages of SPC are its robustness against noise and initialization, a clear signature of cluster formation and splitting, and an unsupervised self-organized determination of the number of clusters at each resolution. Our analysis revealed interesting correlated behavior of several groups of genes which has not been previously identified

Balancing noise and plasticity in eukaryotic gene expression

Coupling the control of expression stochasticity (noise) to the ability of expression change (plasticity) can alter gene function and influence adaptation. A number of factors, such as transcription re-initiation, strong chromatin regulation or genome neighboring organization, underlie this coupling. However, these factors do not necessarily combine in equivalent ways and strengths in all genes. Can we identify then alternative architectures that modulate in distinct ways the linkage of noise and plasticity? Here we first show that strong chromatin regulation, commonly viewed as a source of coupling, can lead to plasticity without noise. The nature of this regulation is relevant too, with plastic but noiseless genes being subjected to general activators whereas plastic and noisy genes experience more specific repression. Contrarily, in genes exhibiting poor transcriptional control, it is translational efficiency what separates noise from plasticity, a pattern related to transcript length. This additionally implies that genome neighboring organization -as modifier- appears only effective in highly plastic genes. In this class, we confirm bidirectional promoters (bipromoters) as a configuration capable to reduce coupling by abating noise but also reveal an important trade-off, since bipromoters also decrease plasticity. This presents ultimately a paradox between intergenic distances and modulation, with short intergenic distances both associated and disassociated to noise at different plasticity levels. Balancing the coupling among different types of expression variability appears as a potential shaping force of genome regulation and organization. This is reflected in the use of different control strategies at genes with different sets of functional constraints

One-two punch mechanism of gene repression: a fresh perspective on gene regulation.

Cellular differentiation depends on temporally controlled waves of gene activation and inactivation that ultimately transform one cell type into another. It is well established that transcription factor cascades coordinate the timely activation of gene expression clusters during development. In comparison, much less is understood about how gene repression events are coordinated with the transcription factor-driven waves of gene activation and how this repression is achieved at a mechanistic level. Using budding yeast as a model, we recently discovered a new gene regulatory event, whereby a central meiotic transcription factor induces the expression of an mRNA isoform to repress gene expression through an integrated transcriptional and translational mechanism. This new model could explain how gene activation and inactivation waves can be temporally coordinated. In this review, we discuss our findings and their potential implications

Transcriptional coupling of neighbouring genes and gene expression noise: evidence that gene orientation and non-coding transcripts are modulators of noise

For some genes, notably essential genes, expression when expression is needed is vital hence low noise in expression is favourable. For others noise is necessary for coping with stochasticity or for providing dice-like mechanisms to control cell fate. But how is noise in gene expression modulated? We hypothesise that gene orientation may be crucial, as for divergently organized gene pairs expression of one gene could affect chromatin of a neighbour thereby reducing noise. Transcription of antisense non-coding RNA from a shared promoter is similarly argued to be a noise-reduction mechanism. Stochastic simulation models confirm the expectation. The model correctly predicts: that protein coding genes with bi-promoter architecture, including those with a ncRNA partner, have lower noise than other genes; divergent gene pairs uniquely have correlated expression noise; distance between promoters predicts noise; ncRNA divergent transcripts are associated with genes that a priori would be under selection for low noise; essential genes reside in divergent orientation more than expected; bi-promoter pairs are rare subtelomerically, cluster together and are enriched in essential gene clusters. We conclude that gene orientation and transcription of ncRNAs, even if unstable, are candidate modulators of noise levels