56 research outputs found
The relation between crosstalk and gene regulation form revisited
Genes differ in the frequency at which they are expressed and in the form of regulation used to control their activity. In particular, positive or negative regulation can lead to activation of a gene in response to an external signal. Previous works proposed that the form of regulation of a gene correlates with its frequency of usage: positive regulation when the gene is frequently expressed and negative regulation when infrequently expressed. Such network design means that, in the absence of their regulators, the genes are found in their least required activity state, hence regulatory intervention is often necessary. Due to the multitude of genes and regulators, spurious binding and unbinding events, called “crosstalk”, could occur. To determine how the form of regulation affects the global crosstalk in the network, we used a mathematical model that includes multiple regulators and multiple target genes. We found that crosstalk depends non-monotonically on the availability of regulators. Our analysis showed that excess use of regulation entailed by the formerly suggested network design caused high crosstalk levels in a large part of the parameter space. We therefore considered the opposite ‘idle’ design, where the default unregulated state of genes is their frequently required activity state. We found, that ‘idle’ design minimized the use of regulation and thus minimized crosstalk. In addition, we estimated global crosstalk of S. cerevisiae using transcription factors binding data. We demonstrated that even partial network data could suffice to estimate its global crosstalk, suggesting its applicability to additional organisms. We found that S. cerevisiae estimated crosstalk is lower than that of a random network, suggesting that natural selection reduces crosstalk. In summary, our study highlights a new type of protein production cost which is typically overlooked: that of regulatory interference caused by the presence of excess regulators in the cell. It demonstrates the importance of whole-network descriptions, which could show effects missed by single-gene models
Evolution of new regulatory functions on biophysically realistic fitness landscapes
Regulatory networks consist of interacting molecules with a high degree of
mutual chemical specificity. How can these molecules evolve when their function
depends on maintenance of interactions with cognate partners and simultaneous
avoidance of deleterious "crosstalk" with non-cognate molecules? Although
physical models of molecular interactions provide a framework in which
co-evolution of network components can be analyzed, most theoretical studies
have focused on the evolution of individual alleles, neglecting the network. In
contrast, we study the elementary step in the evolution of gene regulatory
networks: duplication of a transcription factor followed by selection for TFs
to specialize their inputs as well as the regulation of their downstream genes.
We show how to coarse grain the complete, biophysically realistic
genotype-phenotype map for this process into macroscopic functional outcomes
and quantify the probability of attaining each. We determine which evolutionary
and biophysical parameters bias evolutionary trajectories towards fast
emergence of new functions and show that this can be greatly facilitated by the
availability of "promiscuity-promoting" mutations that affect TF specificity
From cellular properties to population asymptotics in the Population Balance Equation
Proliferating cell populations at steady state growth often exhibit broad
protein distributions with exponential tails. The sources of this variation and
its universality are of much theoretical interest. Here we address the problem
by asymptotic analysis of the Population Balance Equation. We show that the
steady state distribution tail is determined by a combination of protein
production and cell division and is insensitive to other model details. Under
general conditions this tail is exponential with a dependence on parameters
consistent with experiment. We discuss the conditions for this effect to be
dominant over other sources of variation and the relation to experiments.Comment: Exact solution of Eq. 9 is adde
Intrinsic limits to gene regulation by global crosstalk
Gene regulation relies on the specificity of transcription factor (TF) - DNA
interactions. In equilibrium, limited specificity may lead to crosstalk: a
regulatory state in which a gene is either incorrectly activated due to
noncognate TF-DNA interactions or remains erroneously inactive. We present a
tractable biophysical model of global crosstalk, where many genes are
simultaneously regulated by many TFs. We show that in the simplest regulatory
scenario, a lower bound on crosstalk severity can be analytically derived
solely from the number of (co)regulated genes and a suitable parameter that
describes binding site similarity. Estimates show that crosstalk could present
a significant challenge for organisms with low-specificity TFs, such as
metazoans, unless they use appropriate regulation schemes. Strong cooperativity
substantially decreases crosstalk, while joint regulation by activators and
repressors, surprisingly, does not; moreover, certain microscopic details about
promoter architecture emerge as globally important determinants of crosstalk
strength. Our results suggest that crosstalk imposes a new type of global
constraint on the functioning and evolution of regulatory networks, which is
qualitatively distinct from the known constraints acting at the level of
individual gene regulatory elements
Effects of post-transcriptional regulation on phenotypic noise
ABSTRACT Cell-to-cell variations in protein abundance, called noise, give rise to phenotypic variability between isogenic cells. Studies of noise have focused on stochasticity introduced at transcription, yet the effects of post-transcriptional regulatory processes on noise remain unknown. We study the effects of RyhB, a small-RNA of Escherichia coli produced on iron stress, on the phenotypic variability of two of its downregulated target proteins, using dual chromosomal fusions to fluorescent reporters and measurements in live individual cells. The total noise of each of the target proteins is remarkably constant over a wide range of RyhB production rates despite cells being in stress. In fact, coordinate downregulation of the two target proteins by RyhB reduces the correlation between their levels. Hence, an increase in phenotypic variability under stress is achieved by decoupling the expression of different target proteins in the same cell, rather than by an increase in the total noise of each. Extrinsic noise provides the dominant contribution to the total protein noise over the total range of RyhB production rates. Stochastic simulations reproduce qualitatively key features of our observations and show that a feed-forward loop formed by transcriptional extrinsic noise, an sRNA and its target genes exhibits strong noise filtration capabilities
Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial
Background: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). / Methods: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years’ follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided α of 0·95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545. / Findings: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0·73 [95% CI 0·55–0·96]; nominal p=0·025, which did not meet the required threshold for statistical significance [p<0·0095]; median overall survival was 29·8 months [95% CI 26·9–35·7] for those treated with olaparib vs 27·8 months [24·9–33·7] for those treated with placebo), and in patients with BRCAm (HR 0·62 [95% CI 0·41–0·94] nominal p=0·025; 34·9 months [95% CI 29·2–54·6] vs 30·2 months [23·1–40·7]). The overall survival data in patients with BRCA wild-type were HR 0·83 (95% CI 0·55–1·24, nominal p=0·37; 24·5 months [19·8–35·0] for those treated with olaparib vs 26·6 months [23·1–32·5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment. / Interpretation: Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer. / Funding: AstraZeneca
Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer
Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19).status: publishe
Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy
BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients
Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci
Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p
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