The dynamic effec of genetic variation on the in vivo ER stress transcriptional response in different tissues
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PROVIDER: PRJNA782981 | ENA |
REPOSITORIES: ENA
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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:To measure natural variation in ER stress transcriptional response in a subset of lines from the Drosophila Genetic Reference Panel
2013-04-30 | GSE46425 | GEO
Project description:Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding how the ER stress response impacts human disease is to determine how the transcriptional response to ER stress varies among individuals. The genetic diversity of the eight mouse Collaborative Cross (CC) founder strains allowed us to determine how genetic variation impacts the ER stress transcriptional response. We used tunicamycin, a drug commonly used to induce ER stress, to elicit an ER stress response in mouse embryonic fibroblasts (MEFs) derived from the CC founder strains and measured their transcriptional responses. We identified hundreds of genes that differed in response to ER stress across these genetically diverse strains. Strikingly, inflammatory response genes differed most between strains; major canonical ER stress response genes showed relatively invariant responses across strains. To uncover the genetic architecture underlying these strain differences in ER stress response, we measured the transcriptional response to ER stress in MEFs derived from a subset of F1 crosses between the CC founder strains. We found a unique layer of regulatory variation that is only detectable under ER stress conditions. Over 80% of the regulatory variation under ER stress derives from cis-regulatory differences. This is the first study to characterize the genetic variation in ER stress transcriptional response in the laboratory mouse. Our findings indicate that the ER stress transcriptional response is highly variable among strains and arises from genetic variation in individual downstream response genes, rather than major signaling transcription factors. These results have important implications for understanding how genetic variation impacts the ER stress response, an important component of many human diseases.
2014-12-02 | GSE63756 | GEO
Project description:Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding how the ER stress response impacts human disease is to determine how the transcriptional response to ER stress varies among individuals. The genetic diversity of the eight mouse Collaborative Cross (CC) founder strains allowed us to determine how genetic variation impacts the ER stress transcriptional response. We used tunicamycin, a drug commonly used to induce ER stress, to elicit an ER stress response in mouse embryonic fibroblasts (MEFs) derived from the CC founder strains and measured their transcriptional responses. We identified hundreds of genes that differed in response to ER stress across these genetically diverse strains. Strikingly, inflammatory response genes differed most between strains; major canonical ER stress response genes showed relatively invariant responses across strains. To uncover the genetic architecture underlying these strain differences in ER stress response, we measured the transcriptional response to ER stress in MEFs derived from a subset of F1 crosses between the CC founder strains. We found a unique layer of regulatory variation that is only detectable under ER stress conditions. Over 80% of the regulatory variation under ER stress derives from cis-regulatory differences. This is the first study to characterize the genetic variation in ER stress transcriptional response in the laboratory mouse. Our findings indicate that the ER stress transcriptional response is highly variable among strains and arises from genetic variation in individual downstream response genes, rather than major signaling transcription factors. These results have important implications for understanding how genetic variation impacts the ER stress response, an important component of many human diseases. We investigated the genetic variation in ER stress transcriptional response in mouse embryonic fibroblasts (MEFs) across eight mouse strains: A/J, C57BL/6J, 129S1Sv/ImJ, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. MEFs from each strain were treated with a control DMSO or ER stress-inducing drug, Tunicamycin (TM). To identify the genetic architecture underlying this genetic variation, MEFs from F1 strains were also studied. MEFs from the following F1s were evaluated: C57BL/6J X CAST/EiJ, C57BL/6J X 129S1Sv/ImJ, C57BL/6J X NOD/ShiLtJ, C57BL/6J X NZO/H1LtJ, and C57BL/6J X WSB/EiJ. Again F1 MEFS were treated with either DMSO or TM. There are two or three replicates for each sample.
2014-12-02 | E-GEOD-63756 | biostudies-arrayexpress
Project description:To measure natural variation in ER stress transcriptional response in a subset of lines from the Drosophila Genetic Reference Panel Transcriptional response to Tunicamycin and control conditions was measured at 8 hours of exposure (20 lines) and 20 hours of exposure (8 lines).
2013-04-30 | E-GEOD-46425 | biostudies-arrayexpress
Project description:Perturbation of tissue homeostasis accompanies a diversity of inflammatory pathologies and imposes metabolic constraints at the cellular level that elicit ER stress, protein misfolding, and cell death. In response to ER stress, cells initiate the unfolded protein response (UPR), which determines divergent cell fate decisions, either promoting recovery of ER proteostasis and cell survival or triggering programmed cell death. However, the mechanisms by which the UPR transitions from the adaptive to terminal state are not fully understood. Here, we leverage single-cell genomics to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the intestinal epithelium. We recovered the terminal-UPR signature, which dictates adaptation versus programmed cell death in response to ER stress.
2021-02-17 | GSE149633 | GEO
Project description:Here, we use a microfluidics-based approach to prepare single-cell RNA-Seq libraries from over 1,700 primary mouse dendritic cells (DCs) stimulated with three pathogenic components and examine variation between individual cells exposed to the same stimulus and general strategies that multicellular populations use to establish complex dynamic responses. RNA seq libraries from 1775 single cells and population controls with SMARTer
2014-06-11 | E-GEOD-48968 | biostudies-arrayexpress
Project description:Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF- and TNF-, triggers ER tubulation by activating TAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/TAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/TAT1 pathway may be a key target in ER stress and dysfunction.
2024-06-16 | PXD045865 | Pride
Project description:Here, we use a microfluidics-based approach to prepare single-cell RNA-Seq libraries from over 1,700 primary mouse dendritic cells (DCs) stimulated with three pathogenic components and examine variation between individual cells exposed to the same stimulus and general strategies that multicellular populations use to establish complex dynamic responses.
2014-06-11 | GSE48968 | GEO
Project description:Advanced breast cancer is characterised by enhanced tumour adaptability to therapeutic pressure and the metastatic microenvironment. Targeting epi-transcriptomic modulators may reverse cellular adaptability, offering new therapeutic strategies to treat metastatic disease. This study looks into the dynamic adaptations that occur in cancer cells in response to therapeutic pressure and metastatic evolution by profiling mRNA epi-transcriptomic modifications in models of disease progression. ER positive (ER+) cell models were used to represent progressive breast cancer, MCF7 (endocrine sensitive), LY2 (endocrine resistant) and T347 (derived from an ER-positive, treatment resistant brain metastatic patient tumour) cells. MeRIP sequencing was undertaken to determine genome-wide RNA methylated regions.
2023-05-16 | GSE176533 | GEO