Publications by authors named "Maya Lotan-Pompan"

23 Publications

  • Page 1 of 1

Potential role of indolelactate and butyrate in multiple sclerosis revealed by integrated microbiome-metabolome analysis.

Cell Rep Med 2021 Apr 20;2(4):100246. Epub 2021 Apr 20.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Multiple sclerosis (MS) is an immune-mediated disease whose precise etiology is unknown. Several studies found alterations in the microbiome of individuals with MS, but the mechanism by which it may affect MS is poorly understood. Here we analyze the microbiome of 129 individuals with MS and find that they harbor distinct microbial patterns compared with controls. To study the functional consequences of these differences, we measure levels of 1,251 serum metabolites in a subgroup of subjects and unravel a distinct metabolite signature that separates affected individuals from controls nearly perfectly (AUC = 0.97). Individuals with MS are found to be depleted in butyrate-producing bacteria and in bacteria that produce indolelactate, an intermediate in generation of the potent neuroprotective antioxidant indolepropionate, which we found to be lower in their serum. We identify microbial and metabolite candidates that may contribute to MS and should be explored further for their causal role and therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xcrm.2021.100246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080254PMC
April 2021

Identification of bacteria-derived HLA-bound peptides in melanoma.

Nature 2021 04 17;592(7852):138-143. Epub 2021 Mar 17.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

A variety of species of bacteria are known to colonize human tumours, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03368-8DOI Listing
April 2021

A reference map of potential determinants for the human serum metabolome.

Nature 2020 12 11;588(7836):135-140. Epub 2020 Nov 11.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment. The origins of specific compounds are known, including metabolites that are highly heritable, or those that are influenced by the gut microbiome, by lifestyle choices such as smoking, or by diet. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts that were not available to us when we trained the algorithms. We used feature attribution analysis to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2896-2DOI Listing
December 2020

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Science 2020 05;368(6494):973-980

Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aay9189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757858PMC
May 2020

Structural variation in the gut microbiome associates with host health.

Nature 2019 04 27;568(7750):43-48. Epub 2019 Mar 27.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences. Here we systematically identify microbial genomic structural variants (SVs) and find them to be prevalent in the human gut microbiome across phyla and to replicate in different cohorts. SVs are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes, suggesting that they have a role in microbial adaptation. We find multiple associations between SVs and host disease risk factors, many of which replicate in an independent cohort. Exploring genes that are clustered in the same SV, we uncover several possible mechanistic links between the microbiome and its host, including a region in Anaerostipes hadrus that encodes a composite inositol catabolism-butyrate biosynthesis pathway, the presence of which is associated with lower host metabolic disease risk. Overall, our results uncover a nascent layer of variability in the microbiome that is associated with microbial adaptation and host health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1065-yDOI Listing
April 2019

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Mol Cell 2018 07;71(1):178-190.e8

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ∼30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ∼10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2018.06.012DOI Listing
July 2018

Environment dominates over host genetics in shaping human gut microbiota.

Nature 2018 03 28;555(7695):210-215. Epub 2018 Feb 28.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature25973DOI Listing
March 2018

Bread Affects Clinical Parameters and Induces Gut Microbiome-Associated Personal Glycemic Responses.

Cell Metab 2017 Jun;25(6):1243-1253.e5

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Bread is consumed daily by billions of people, yet evidence regarding its clinical effects is contradicting. Here, we performed a randomized crossover trial of two 1-week-long dietary interventions comprising consumption of either traditionally made sourdough-leavened whole-grain bread or industrially made white bread. We found no significant differential effects of bread type on multiple clinical parameters. The gut microbiota composition remained person specific throughout this trial and was generally resilient to the intervention. We demonstrate statistically significant interpersonal variability in the glycemic response to different bread types, suggesting that the lack of phenotypic difference between the bread types stems from a person-specific effect. We further show that the type of bread that induces the lower glycemic response in each person can be predicted based solely on microbiome data prior to the intervention. Together, we present marked personalization in both bread metabolism and the gut microbiome, suggesting that understanding dietary effects requires integration of person-specific factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2017.05.002DOI Listing
June 2017

Involvement of a gut-retina axis in protection against dietary glycemia-induced age-related macular degeneration.

Proc Natl Acad Sci U S A 2017 05 15;114(22):E4472-E4481. Epub 2017 May 15.

Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111;

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf. LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1702302114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465926PMC
May 2017

Systematic Investigation of Transcription Factor Activity in the Context of Chromatin Using Massively Parallel Binding and Expression Assays.

Mol Cell 2017 Feb;65(4):604-617.e6

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Precise gene expression patterns are established by transcription factor (TFs) binding to regulatory sequences. While these events occur in the context of chromatin, our understanding of how TF-nucleosome interplay affects gene expression is highly limited. Here, we present an assay for high-resolution measurements of both DNA occupancy and gene expression on large-scale libraries of systematically designed regulatory sequences. Our assay reveals occupancy patterns at the single-cell level. It provides an accurate quantification of the fraction of the population bound by a nucleosome and captures distinct, even adjacent, TF binding events. By applying this assay to over 1,500 promoter variants in yeast, we reveal pronounced differences in the dependency of TF activity on chromatin and classify TFs by their differential capacity to alter chromatin and promote expression. We further demonstrate how different regulatory sequences give rise to nucleosome-mediated TF collaborations that quantitatively account for the resulting expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2017.01.007DOI Listing
February 2017

Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators.

Genome Res 2017 01 13;27(1):87-94. Epub 2016 Dec 13.

Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.

Transcription factors (TFs) are key mediators that propagate extracellular and intracellular signals through to changes in gene expression profiles. However, the rules by which promoters decode the amount of active TF into target gene expression are not well understood. To determine the mapping between promoter DNA sequence, TF concentration, and gene expression output, we have conducted in budding yeast a large-scale measurement of the activity of thousands of designed promoters at six different levels of TF. We observe that maximum promoter activity is determined by TF concentration and not by the number of binding sites. Surprisingly, the addition of an activator site often reduces expression. A thermodynamic model that incorporates competition between neighboring binding sites for a local pool of TF molecules explains this behavior and accurately predicts both absolute expression and the amount by which addition of a site increases or reduces expression. Taken together, our findings support a model in which neighboring binding sites interact competitively when TF is limiting but otherwise act additively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.212316.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204347PMC
January 2017

Massively Parallel Interrogation of the Effects of Gene Expression Levels on Fitness.

Cell 2016 Aug 18;166(5):1282-1294.e18. Epub 2016 Aug 18.

Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Data of gene expression levels across individuals, cell types, and disease states is expanding, yet our understanding of how expression levels impact phenotype is limited. Here, we present a massively parallel system for assaying the effect of gene expression levels on fitness in Saccharomyces cerevisiae by systematically altering the expression level of ∼100 genes at ∼100 distinct levels spanning a 500-fold range at high resolution. We show that the relationship between expression levels and growth is gene and environment specific and provides information on the function, stoichiometry, and interactions of genes. Wild-type expression levels in some conditions are not optimal for growth, and genes whose fitness is greatly affected by small changes in expression level tend to exhibit lower cell-to-cell variability in expression. Our study addresses a fundamental gap in understanding the functional significance of gene expression regulation and offers a framework for evaluating the phenotypic effects of expression variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2016.07.024DOI Listing
August 2016

Personalized Nutrition by Prediction of Glycemic Responses.

Cell 2015 Nov;163(5):1079-1094

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. VIDEO ABSTRACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2015.11.001DOI Listing
November 2015

Core promoter sequence in yeast is a major determinant of expression level.

Genome Res 2015 Jul 12;25(7):1008-17. Epub 2015 May 12.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 7610001 Rehovot, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel;

The core promoter is the regulatory sequence to which RNA polymerase is recruited and where it acts to initiate transcription. Here, we present the first comprehensive study of yeast core promoters, providing massively parallel measurements of core promoter activity and of TSS locations and relative usage for thousands of native and designed sequences. We found core promoter activity to be highly correlated to the activity of the entire promoter and that sequence variation in different core promoter regions substantially tunes its activity in a predictable way. We also show that location, orientation, and flanking bases critically affect TATA element function, that transcription initiation in highly active core promoters is focused within a narrow region, that poly(dA:dT) orientation has a functional consequence at the 3' end of promoters, and that orthologous core promoters across yeast species have conserved activities. Our results demonstrate the importance of core promoters in the quantitative study of gene regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.188193.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484384PMC
July 2015

Systematic dissection of the sequence determinants of gene 3' end mediated expression control.

PLoS Genet 2015 Apr 15;11(4):e1005147. Epub 2015 Apr 15.

Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.

The 3'end genomic region encodes a wide range of regulatory process including mRNA stability, 3' end processing and translation. Here, we systematically investigate the sequence determinants of 3' end mediated expression control by measuring the effect of 13,000 designed 3' end sequence variants on constitutive expression levels in yeast. By including a high resolution scanning mutagenesis of more than 200 native 3' end sequences in this designed set, we found that most mutations had only a mild effect on expression, and that the vast majority (~90%) of strongly effecting mutations localized to a single positive TA-rich element, similar to a previously described 3' end processing efficiency element, and resulted in up to ten-fold decrease in expression. Measurements of 3' UTR lengths revealed that these mutations result in mRNAs with aberrantly long 3'UTRs, confirming the role for this element in 3' end processing. Interestingly, we found that other sequence elements that were previously described in the literature to be part of the polyadenylation signal had a minor effect on expression. We further characterize the sequence specificities of the TA-rich element using additional synthetic 3' end sequences and show that its activity is sensitive to single base pair mutations and strongly depends on the A/T content of the surrounding sequences. Finally, using a computational model, we show that the strength of this element in native 3' end sequences can explain some of their measured expression variability (R = 0.41). Together, our results emphasize the importance of efficient 3' end processing for endogenous protein levels and contribute to an improved understanding of the sequence elements involved in this process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398552PMC
April 2015

Molecular dissection of the genetic mechanisms that underlie expression conservation in orthologous yeast ribosomal promoters.

Genome Res 2014 Dec 7;24(12):1991-9. Epub 2014 Oct 7.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 7610001, Israel

Recent studies have shown a surprising phenomenon, whereby orthologous regulatory regions from different species drive similar expression levels despite being highly diverged in sequence. Here, we investigated this phenomenon by genomically integrating hundreds of ribosomal protein (RP) promoters from nine different yeast species into S. cerevisiae and accurately measuring their activity. We found that orthologous RP promoters have extreme expression conservation even across evolutionarily distinct yeast species. Notably, our measurements reveal two distinct mechanisms that underlie this conservation and which act in different regions of the promoter. In the core promoter region, we found compensatory changes, whereby effects of sequence variations in one part of the core promoter were reversed by variations in another part. In contrast, we observed robustness in Rap1 transcription factor binding sites, whereby significant sequence variations had little effect on promoter activity. Finally, cases in which orthologous promoter activities were not conserved could largely be explained by the sequence variation within the core promoter. Together, our results provide novel insights into the mechanisms by which expression is conserved throughout evolution across diverged promoter sequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.179259.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248315PMC
December 2014

Promoters maintain their relative activity levels under different growth conditions.

Mol Syst Biol 2013 Oct 29;9:701. Epub 2013 Oct 29.

1] Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel [2] Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel [3] Department of Plant Sciences, Weizmann Institute of Science, Rehovot, Israel.

Most genes change expression levels across conditions, but it is unclear which of these changes represents specific regulation and what determines their quantitative degree. Here, we accurately measured activities of ~900 S. cerevisiae and ~1800 E. coli promoters using fluorescent reporters. We show that in both organisms 60-90% of promoters change their expression between conditions by a constant global scaling factor that depends only on the conditions and not on the promoter's identity. Quantifying such global effects allows precise characterization of specific regulation-promoters deviating from the global scale line. These are organized into few functionally related groups that also adhere to scale lines and preserve their relative activities across conditions. Thus, only several scaling factors suffice to accurately describe genome-wide expression profiles across conditions. We present a parameter-free passive resource allocation model that quantitatively accounts for the global scaling factors. It suggests that many changes in expression across conditions result from global effects and not specific regulation, and provides means for quantitative interpretation of expression profiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/msb.2013.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817408PMC
October 2013

Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast.

Nat Genet 2012 May 27;44(7):743-50. Epub 2012 May 27.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Understanding how precise control of gene expression is specified within regulatory DNA sequences is a key challenge with far-reaching implications. Many studies have focused on the regulatory role of transcription factor-binding sites. Here, we explore the transcriptional effects of different elements, nucleosome-disfavoring sequences and, specifically, poly(dA:dT) tracts that are highly prevalent in eukaryotic promoters. By measuring promoter activity for a large-scale promoter library, designed with systematic manipulations to the properties and spatial arrangement of poly(dA:dT) tracts, we show that these tracts significantly and causally affect transcription. We show that manipulating these elements offers a general genetic mechanism, applicable to promoters regulated by different transcription factors, for tuning expression in a predictable manner, with resolution that can be even finer than that attained by altering transcription factor sites. Overall, our results advance the understanding of the regulatory code and suggest a potential mechanism by which promoters yielding prespecified expression patterns can be designed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2305DOI Listing
May 2012

Compensation for differences in gene copy number among yeast ribosomal proteins is encoded within their promoters.

Genome Res 2011 Dec 18;21(12):2114-28. Epub 2011 Oct 18.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.

Coordinate regulation of ribosomal protein (RP) genes is key for controlling cell growth. In yeast, it is unclear how this regulation achieves the required equimolar amounts of the different RP components, given that some RP genes exist in duplicate copies, while others have only one copy. Here, we tested whether the solution to this challenge is partly encoded within the DNA sequence of the RP promoters, by fusing 110 different RP promoters to a fluorescent gene reporter, allowing us to robustly detect differences in their promoter activities that are as small as ~10%. We found that single-copy RP promoters have significantly higher activities, suggesting that proper RP stoichiometry is indeed partly encoded within the RP promoters. Notably, we also partially uncovered how this regulation is encoded by finding that RP promoters with higher activity have more nucleosome-disfavoring sequences and characteristic spatial organizations of these sequences and of binding sites for key RP regulators. Mutations in these elements result in a significant decrease of RP promoter activity. Thus, our results suggest that intrinsic (DNA-dependent) nucleosome organization may be a key mechanism by which genomes encode biologically meaningful promoter activities. Our approach can readily be applied to uncover how transcriptional programs of other promoters are encoded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.119669.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227101PMC
December 2011

Trifluralin herbicide-induced resistance of melon to fusarium wilt involves expression of stress- and defence-related genes.

Mol Plant Pathol 2007 Jan;8(1):9-22

Department of Vegetable Crops, Newe Ya'ar Research Center, Agricultural Research Organization, PO Box 1021, Ramat-Yishay 30095, Israel.

SUMMARY To identify genes involved in trifluralin herbicide-induced resistance of melon to Fusarium oxysporum f. sp. melonis, suppression subtractive hybridization (SSH) and cDNA-amplified fragment-length polymorphism (cDNA-AFLP) were used. A total of 123 clones-60 of which have never been isolated from melon-were isolated, sequenced and annotated. A significant proportion (35%) of the total 123 clones exhibited similarity to genes that have been formerly described as stress- or defence-related. Thirty-two selected clones were subjected to a detailed expression analysis, one-third of which were found to be up-regulated in response to trifluralin treatment and/or fusarium inoculation. The putative roles of seven of these clones in stress are discussed. Furthermore, the expression of four stress-related and up-regulated genes was enhanced when the plants were subjected to salinity stress, suggesting that trifluralin induces a general stress response which protects the plant against fusarium wilt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1364-3703.2006.00365.xDOI Listing
January 2007