Developing a translational polygenic score of biological sensitivity to context
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150812 | GEO | 2020/05/20
REPOSITORIES: GEO
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Project description:Aminoacyl tRNA synthetases (ARSs) are a class of enzymes with well-conserved housekeeping functions in cellular translation. Recent evidence suggests that ARS genes may participate in a wide array of cellular processes, and may contribute to the pathology of autoimmune disease, cancer, and other diseases. Several studies have suggested a role for the glutamyl prolyl tRNA synthetase (EPRS) in breast cancers, although none has demonstrated any underlying mechanism about how EPRS contributes to carcinogenesis. In this study, we identified EPRS as upregulated in estrogen receptor positive (ER+) human breast tumors in the TCGA and METABRIC cohorts, with copy number gains in nearly 50% of samples in both datasets. EPRS expression is associated with reduced overall survival in patients with ER+ tumors in TCGA and METABRIC datasets. EPRS expression was also associated with reduced distant relapse-free survival in patients treated with adjuvant tamoxifen monotherapy for five years, and EPRS-correlated genes were highly enriched for genes predictive of a poor response to tamoxifen. We demonstrated the necessity of EPRS for proliferation of tamoxifen-resistant ER+ breast cancer, but not ER- breast cancer cells. Transcriptomic profiling showed that EPRS regulated cell cycle and estrogen response genes. Finally, we constructed a causal gene network based on over 2500 ER+ breast tumor samples to build up an EPRS-estrogen signaling pathway. EPRS and its regulated estrogenic gene network may offer a promising alternative approach to target ER+ breast cancers that are refractory to current anti-estrogens.
2016-10-05 | GSE81162 | GEO
Project description:The risk for psychiatric disorders is strongly affected by environmental stressors. The underlying mechanisms are inevitably multifactorial still not fully understood. Glucocorticoids (GCs), which are prominent stress mediators that affect transcriptional activity and brain morphology, are implicated in the pathophysiology of multiple forms of psychopathology. The challenge is that of establishing the relevance of GC-related transcriptional effects for stress-related psychopathology in humans. We addressed this issue by generating gene expression data from hippocampal dentate gyrus from macaques and rats to identify clusters of co-expressed genes sensitive to GC exposure as the basis for a biologically-informed polygenic risk score (ePRS) to investigate neuropsychiatric outcomes in humans exposed to early life adversity. We used RNA-sequencing data to identify a cluster of GC-responsive genes co-expressed in the posterior dentate gyrus (pDG) of female Cynomologus monkeys and preserved in the rat model with the homologous region (the dorsal DG). In total 11395 SNPs derived from these genes (507 genes) were used to create an ePRS to explore the interaction with early life adversity on psychiatric phenotypes in human cohorts using the UK Biobank Resource and ALSPAC data sets. The biologically-informed ePRS significantly predicted psychotic behavior in adversity-exposed females as well as variation in brain volume. These findings reveal that GC exposure influences a specific group of genes in pDG, largely enriched for transcription processes and pathways related to development activity. Variations in the expression of this gene network can be used in a translational manner to predict risk for neuropsychiatric conditions and brain volume alterations after early stress exposure. These results highlight the importance of hippocampal GC-related transcriptional activity as a mediator for the effects of early life adversity on mental health outcomes.
2020-05-29 | GSE151342 | GEO
Project description:Ras is a key switch controlling cell behavior. In the GTP-bound form, Ras interacts with numerous effectors in a mutually exclusive manner, where individual Ras-effectors are likely part of larger cellular (sub)complexes. The molecular details of these (sub)complexes and their alteration in specific contexts is not understood. Focusing on KRAS, we performed affinity purification (AP)-mass spectrometry (MS) experiments of exogenous expressed Flag-KRAS WT and three oncogenic mutants (‘genetic contexts’) in the human Caco-2 cell line, each exposed to 11 different culture media (‘culture contexts’) that mimic conditions relevant in the colon and colorectal cancer. We identified four effectors present in complex with KRAS in all genetic and growth contexts (‘context-general effectors’). Seven effectors are found in KRAS complexes in only some contexts (‘context-specific effectors’). Analyzing all interactors in complex with KRAS per condition, we find that the culture contexts had a larger impact on interaction rewiring than genetic contexts. We analyzed how changes in the interactome impact functional outcomes and created interactive shiny app for interactive visualization. We validated some of the functional differences in metabolism and proliferation. Finally, we used networks to evaluate how KRAS effectors are involved in the modulation of functions by random walk analyses of effector-mediated (sub)complexes. Altogether, our work shows the impact of environmental contexts on network rewiring, which provides insides into tissue-specific signaling mechanisms. This may also explain why KRAS oncogenic mutants may be causing cancer only in specific tissues despite KRAS being expressed in most cells and tissues.
2023-02-23 | PXD035399 | Pride
Project description:Purpose: In mammals, glutamyl-prolyl-tRNA synthetase (EPRS) catalyzes the attachment of two amino acids, glutamic acid (E) and proline (P), to their cognate tRNAs for protein synthesis. We aim to study the mechanism of EPRS in translational regulation of cardiac fibrosis and establish EPRS or its downstream target genes as potential anti-fibrosis therapeutic targets. The goals of this study are to use next generation sequencing (NGS)-derived fibroblast transcriptome profiling (RNA-seq) and translatome profiling (polysome-seq) followed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) methods to identify the downstream effector genes that are preferentially regulated by EPRS at the transcriptional and translational levels. Results: Using a well established data analysis workflow from the Genomic Research Center from University of Rochester Medical Center, we analyzed RNA-seq and polysome-seq data. We have identified novel Pro-rich (PRR) gene pathways that are preferentially regulated by EPRS via enhanced translation elongation at Pro-rich codons and antagonized by Halofuginone. Considering the translation active state in both light and heavy polysome fractions, we redefined the 4 groups by overlapping genes from heavy and light polysome associated transcripts compared to their total RNA expression change (p value <0.05 for differential expressed genes). 1371 genes were downregulated at translation (indicated by polysome-seq) and steady-state mRNA (indicated by RNA-seq) levels, and 775 genes were upregulated at both levels. There are a small number of genes whose gene regulation was changed in the opposite direction at the mRNA and translation levels. These observations indicate a coordinated regulatory effect between steady-state mRNA level and translation efficiency under the EPRS inhibitory condition. KEGG analysis of the genes that are reduced at RNA and translation levels revealed multiple pro-fibrotic pathways, including ECM-receptor interaction and proteoglycans. In contrast, the genes that are induced at RNA and translation levels are enriched in general translation factors, including ribosome and aminoacyl-tRNA biosynthesis, which suggests a compensatory amino acid starvation response upon EPRS inhibition. Altered expression of typical Pro-rich collagen and other genes was confirmed with qRT-PCR. Conclusions: Our study represents the first detailed analysis of fibroblast translatome in comparison with transcriptome under EPRS inhibitory condition (halofuginone treatment), with biological triplicates, generated by RNA-seq and polysome-seq technology. Our results show that the next generation sequencing offers a comprehensive qualitative and quantitative evaluation of mRNA content and its translation state within cells treated with translation inhibitory drug halofuginone (EPRS inhibitor). Based on our results, we conclude that Pro-rich motif bearing genes are preferential targets of EPRS, and mild inhibition of EPRS leads to inefficient translation of these PRR genes.
2021-09-09 | GSE136838 | GEO
Project description:Decoding the genetic architecture of gene expression remains one of the most important problems in human genetics. Because cellular context is often reflective of environmental exposure, mapping context-specific quantitative trait loci (QTLs) and identifying the cellular contexts that modify their effects is critical for understanding the mechanisms by which gene by environment interactions confer disease risk. Here, we introduce a compressed pooling framework for performing genetically multiplexed arrayed single-cell sequencing experiments without the need for prior genotyping. To this end, we developed freemuxlet, an extension of demuxlet, that enables genotype-free demultiplexing of pooled single-cell data applicable to multiplexed single cell RNA- and CITE-seq data. In total, we performed multiplexed CITE-seq across 384 samples from 64 donors over 12 pools in a single day. These results allowed us to generate a map of cell-type specific gene regulatory networks in response to each stimulus. Finally, by integrating imputed genotypes from the individuals, we map genetic variants associated with stimulation in each specific cell type and assess their enrichment for disease associations. Freemuxlet and clue together demonstrate the feasibility of performing population-scale gene-by-environment studies using single-cell RNA-sequencing scalable to between 100 – 1000 individuals.
2021-08-12 | GSE181897 | GEO
Project description:The genetic regulation of gene expression varies greatly across tissue-type and individuals and can be strongly influenced by the environment. Many variants, under healthy control conditions, may be silent or even have the opposite effect under diseased stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with cellular stress across different tissues. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to restore homeostasis. This transcriptional response, despite being a conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study the dynamic effects of genetic variation. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans- regulatory variation underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. The majority of the regulatory effects we identified were acting in cis-, which in turn, contribute to the variable ER stress- and tissue-specific transcriptional response. This study demonstrates the need for incorporating environmental stressors across multiple different tissues in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.
2022-11-01 | GSE189419 | GEO
Project description:Chromosomal instability (CIN) is defined by the propensity to acquire structural and/or numerical aberration in the normal cellular karyotype and is often associated with cancer. Autophagy is a catabolic process that leads to the recycling of cellular components that may positively or negatively impact on cancer development and progression, depending on the context. Recent work postulated that the depletion of the pro-autophagic and tumor suppressive protein Beclin 1 triggers CIN by interfering with mitotic chromosome segregation, providing a possible mechanism for how Beclin 1 can act as a tumor suppressor (Fremont et al., PMID: 23478334). Here, we present data supporting the notion that the phenotypes described in Fremont et al., depend on a siRNA off-target effect. The transcriptomic analysis shown here was designed to identify the factor(s) that are responsible for such phenotype. HeLa cells synchronized in mitosis have been transfected in 3 independent experiments with either Beclin 1-ER or Beclin 1-II siRNA. RNA was extracted and subjected to gene expression profiling. Differentially expressed probe sets/genes have been identified between the ER and II siRNA using the moderated t-test from Bioconductor's limma package with the resulting p-values being adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg.
2015-09-02 | E-GEOD-69052 | biostudies-arrayexpress
Project description:Developing a translational polygenic score of biological sensitivity to context
| PRJNA633782 | ENA
Project description:Glutamyl-prolyl-transfer RNA synthetase (EPRS) is a class of enzymes that catalyze the attachment of 2 amino acids (i.e., glutamic acid and proline) to cognate transfer RNA for subsequent protein synthesis. Herein, we evaluated the effect of EPRS on the progression of tubulointerstitial nephritis using the mouse model with adenine-mixed diet. One single-cell RNA transcriptomic dataset was originated from wild-type mice, and other one was from heterozygous knockout mice, all of these were harvested at 2 weeks after adenine-mixed diet.
2022-09-24 | GSE213683 | GEO