Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [immortalized lymphoblastoid cell lines]
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PROVIDER: PRJNA777817 | ENA |
REPOSITORIES: ENA
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Project description:Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter’s DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.
2022-11-14 | GSE188130 | GEO
Project description:Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
| PRJNA777809 | ENA
Project description:Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [GM12878]
| PRJNA777788 | ENA
Project description:Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter’s DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.
2022-11-14 | GSE188099 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-14 | GSE188131 | GEO
Project description:We used microarrays to measure the expression levels of genes in irradiated immortalized B cells, lymphoblastoid cells, from members of Centre dEtude du Polymorphisme Humain (CEPH) Utah pedigrees. Data were collected for cells at baseline and 2 hour and 6 hour after exposure to 10 Gy of ionizing radiation (IR). Experiment Overall Design: We used microarrays to measure the expression levels of genes in irradiated immortalized B cells, lymphoblastoid cells, from members of 15 Centre dEtude du Polymorphisme Humain (CEPH) Utah pedigrees (CEPH 1333, 1341, 1346, 1362, 1408, 1416, 1420, 1421, 1423, 1424, 1444, 1447, 1451, 1454, 1582). Expression data was obtained for cell lines derived from 2 parents and 8 children per each family. Cells were irradiated at 10 Gy in a 137Cs irradiator. Cells were harvested prior to radiation and at 2 and 6 hours following exposure to IR.
2009-04-10 | E-GEOD-12626 | biostudies-arrayexpress
Project description:Proteomic analysis was performed, by means of MudPIT platform, on Lymphoblastoid cell lines (LCLs) immortalized from B-Lymphocytes. LCLs were collected from each subject of an italian family, native of a restricted area of northern Italy and consisted of seven components: two patients with homozygous C-to-T mutation at position 97 in exon 2 of TREM2 gene (Ho); four healthy carriers with heterozygous mutation (He), and one healthy individual (Wt).
2021-06-15 | MSV000087622 | MassIVE
Project description:This study describes a transcriptome-phenotype matching approach in which the starter L. lactis MG1363 was fermented under a variety of conditions that differed in the levels of oxygen and/or salt, as well as the fermentation pH and temperature. Samples derived from these fermentations in the exponential phase of bacterial growth were analyzed by full-genome transcriptomics and the assessment of heat and oxidative stress phenotypes. Variations in the fermentation conditions resulted in up to 1000-fold differences in survival during heat and oxidative stress. More specifically, aeration during fermentation induced protection against heat stress, whereas a relatively high fermentation temperature resulted in enhanced robustness towards oxidative stress. Concomitantly, oxygen levels and fermentation temperature induced differential expression of markedly more genes when compared with the other fermentation parameters. Correlation analysis of robustness phenotypes and gene expression levels revealed transcriptome signatures for oxidative and/or heat stress survival, including the metC-cysK operon involved in methionine and cysteine metabolism. To validate this transcriptome-phenotype association we grew L. lactis MG1363 in the absence of cysteine which led to enhanced robustness towards oxidative stress. Conclusions Overall, we demonstrated the importance of careful selection of fermentation parameters prior to industrial processing of starter cultures. Furthermore, established stress genes as well as novel genes were associated with robustness towards heat and/or oxidative stress. Assessment of the expression levels of this group of genes could function as an indicator for enhanced selection of fermentation parameters resulting in improved robustness during spray drying. The increased robustness after growth without cysteine appeared to confirm the role of expression of the metC-cysK operon as an indicator of robustness and suggests that sulfur amino acid metabolism plays a pivotal role in oxidative stress survival. two connected loops, both containing samples derived on a single day (sample 1-6, sample 7-13)
2014-08-01 | E-GEOD-58284 | biostudies-arrayexpress
Project description:Biological systems display extraordinary robustness. Robustness of transcriptional enhancers results mainly from clusters of binding sites for the same transcription factor, and it is not clear how robust enhancers can evolve loss of expression through point mutations. Here, we report the high-resolution functional dissection of a robust enhancer of the shavenbaby gene that has contributed to morphological evolution. We found that robustness is encoded by many binding sites for the transcriptional activator Arrowhead and that, during evolution, some of these activator sites were lost, weakening enhancer activity. Complete silencing of enhancer function, however, required evolution of a binding site for the spatially restricted potent repressor Abrupt. These findings illustrate that recruitment of repressor binding sites can overcome enhancer robustness and may minimize pleiotropic consequences of enhancer evolution. Recruitment of repression may be a general mode of evolution to break robust regulatory linkages.
2018-04-28 | GSE80790 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) consists in the progressive degeneration of motor neurons, caused by mechanisms that are poorly understood and for which there is no cure. Some of the cellular perturbations associated with ALS can be detected in peripheral cells, including lym-phocytes from blood. A related cell system that is very suitable for research consists in human lymphoblastoid cell lines (LCLs), which are immortalized lymphocytes. LCLs that can be easily expanded in culture and can be maintained for long periods of time as stable cultures. We inves-tigated, on a small set of LCLs, if proteomics analysis by liquid chromatography followed by tandem mass spectrometry reveals proteins that are differentially present in ALS versus healthy controls. We found that individual proteins and cellular and molecular pathways in which these proteins participate, are detected as differentially present in the ALS samples. Some of these proteins and pathways are already known to be perturbed in ALS, while others are new and present interest for further investigations. These observations suggest that more detailed pro-teomics analysis of LCLs, using a larger number of samples, represents a promising approach for investigating ALS mechanisms and to search for therapeutic agents.
2023-03-12 | PXD040240 | Pride