43 research outputs found
Promoter decoding of transcription factor dynamics involves a trade-off between noise and control of gene expression
Numerous transcription factors (TFs) encode information about upstream signals in the dynamics of their activation, but how downstream genes decode these dynamics remains poorly understood. Using microfluidics to control the nucleocytoplasmic translocation dynamics of the budding yeast TF Msn2, we elucidate the principles that govern how different promoters convert dynamical Msn2 input into gene expression output in single cells. Combining modeling and experiments, we classify promoters according to their signal-processing behavior and reveal that multiple, distinct gene expression programs can be encoded in the dynamics of Msn2. We show that both oscillatory TF dynamics and slow promoter kinetics lead to higher noise in gene expression. Furthermore, we show that the promoter activation timescale is related to nucleosome remodeling. Our findings imply a fundamental trade-off: although the cell can exploit different promoter classes to differentially control gene expression using TF dynamics, gene expression noise fundamentally limits how much information can be encoded in the dynamics of a single TF and reliably decoded by promoters
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A systematic genetic screen for genes involved in sensing inorganic phosphate availability in Saccharomyces cerevisiae
Saccharomyces cerevisiae responds to changes in extracellular inorganic phosphate (P_i) availability by regulating the activity of the phosphate-responsive (PHO) signaling pathway, enabling cells to maintain intracellular levels of the essential nutrient P_i. P_i-limitation induces upregulation of inositol heptakisphosphate (IP_7) synthesized by the inositol hexakisphosphate kinase Vip1, triggering inhibition of the Pho80/Pho85 cyclin-cyclin dependent kinase (CDK) complex by the CDK inhibitor Pho81, which upregulates the PHO regulon through the CDK target and transcription factor Pho4. To identify genes that are involved in signaling upstream of the Pho80/Pho85/Pho81 complex and how they interact with each other to regulate the PHO pathway, we performed genome-wide screens with the synthetic genetic array method. We identified more than 300 mutants with defects in signaling upstream of the Pho80/Pho85/Pho81 complex, including AAH1, which encodes an adenine deaminase that negatively regulates the PHO pathway in a Vip1-dependent manner. Furthermore, we showed that even in the absence of VIP1, the PHO pathway can be activated under prolonged periods of P_i starvation, suggesting complexity in the mechanisms by which the PHO pathway is regulated
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A serine sensor for multicellularity in a bacterium
We report the discovery of a simple environmental sensing mechanism for biofilm formation in the bacterium Bacillus subtilis that operates without the involvement of a dedicated RNA or protein. Certain serine codons, the four TCN codons, in the gene for the biofilm repressor SinR caused a lowering of SinR levels under biofilm-inducing conditions. Synonymous substitutions of these TCN codons with AGC or AGT impaired biofilm formation and gene expression. Conversely, switching AGC or AGT to TCN codons upregulated biofilm formation. Genome-wide ribosome profiling showed that ribosome density was higher at UCN codons than at AGC or AGU during biofilm formation. Serine starvation recapitulated the effect of biofilm-inducing conditions on ribosome occupancy and SinR production. As serine is one of the first amino acids to be exhausted at the end of exponential phase growth, reduced translation speed at serine codons may be exploited by other microbes in adapting to stationary phase. DOI: http://dx.doi.org/10.7554/eLife.01501.00
Genome-Wide Characterization of the Phosphate Starvation Response in Schizosaccharomyces pombe
Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission
Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p
Speech and Language Pathologists Supporting Educators and Students in Elementary School Classrooms
This Masters of Teaching Research Project is a qualitative study that addresses the topics of supporting students with speech and language disorders in the classroom, specifically within the topic of collaboration between the speech and language pathologists (SLPs) and educators in terms of the importance of early intervention. Although limited, the existing literature on collaboration between SLPs and classroom educators is successful on addressing the early intervention needs of the student however, lacking on how the SLP actually supports the educator in a classroom setting. With this in mind, this study aims to explore if collaboration exists and in what form, guided by the following research question: How does a sample of elementary school teachers and SLPs work together to support students in inclusive classrooms with speech and language disorders? Overarching themes include additional learning opportunities for educators in order to support students with speech and language disorders, as well as the different collaborative efforts used to support these students and challenges or potential challenges that may arise when working with SLPs. Ultimately, as a beginning teacher, I intend to discover the most beneficial way to support students with speech and language disorders and successful ways to learn and collaborate with SLPs
An RpaA-Dependent Sigma Factor Cascade Sets the Timing of Circadian Transcriptional Rhythms in Synechococcus elongatus
Summary: The circadian clock of the cyanobacterium Synechococcus elongatus PCC 7942 drives oscillations in global mRNA abundances with 24-hr periodicity under constant light conditions. The circadian clock-regulated transcription factor RpaA controls the timing of circadian gene expression, but the mechanisms underlying this control are not well understood. Here, we show that four RpaA-dependent sigma factors—RpoD2, RpoD6, RpoD5, and SigF2—are sequentially activated downstream of active RpaA and are required for proper expression of circadian mRNAs. By measuring global gene expression in strains modified to individually lack rpoD2, rpoD6, rpoD5, and sigF2, we identify how expression of circadian mRNAs, including sigma factor mRNAs, is altered in the absence of each sigma factor. Broadly, our findings suggest that a single transcription factor, RpaA, is sufficient to generate complex circadian expression patterns in part by regulating an interdependent sigma factor cascade. : Fleming and O’Shea show that, as a master regulator of cyanobacterial circadian gene regulation, RpaA is sufficient to generate complex circadian expression patterns in part by regulating an interdependent sigma factor cascade
ppGpp Controls Global Gene Expression in Light and in Darkness in S. elongatus
The bacterial and plant stringent response involves production of the signaling molecules guanosine tetraphosphate and guanosine pentaphosphate ((p)ppGpp), leading to global reorganization of gene expression. The function of the stringent response has been well characterized in stress conditions, but its regulatory role during unstressed growth is less studied. Here, we demonstrate that (p)ppGpp-deficient strains of S. elongatus have globally deregulated biosynthetic capacity, with increased transcription rate, translation rate, and cell size in unstressed conditions in light and impaired viability in darkness. Synthetic restoration of basal guanosine tetraphosphate (ppGpp) levels is sufficient to recover transcriptional balance and appropriate cell size in light and to rescue viability in light/dark conditions, but it is insufficient to enable efficient dark-induced transcriptional shutdown. Our work underscores the importance of basal ppGpp signaling for regulation of cyanobacterial physiology in the absence of stress and for viability in energy-limiting conditions, highlighting that basal (p)ppGpp level is essential in cyanobacteria in the environmental light/dark cycle
cis Determinants of Promoter Threshold and Activation Timescale
Although the relationship between DNA cis-regulatory sequences and gene expression has been extensively studied at steady state, how cis-regulatory sequences affect the dynamics of gene induction is not known. The dynamics of gene induction can be described by the promoter activation timescale (AcTime) and amplitude threshold (AmpThr). Combining high-throughput microfluidics with quantitative time-lapse microscopy, we control the activation dynamics of the budding yeast transcription factor, Msn2, and reveal how cis-regulatory motifs in 20 promoter variants of the Msn2-target-gene SIP18 affect AcTime and AmpThr. By modulating Msn2 binding sites, we can decouple AmpThr from AcTime and switch the SIP18 promoter class from high AmpThr and slow AcTime to low AmpThr and either fast or slow AcTime. We present a model that quantitatively explains gene-induction dynamics on the basis of the Msn2-binding-site number, TATA box location, and promoter nucleosome organization. Overall, we elucidate the cis-regulatory logic underlying promoter decoding of TF dynamics