Gene Expression and Genetic Variation in Response to Endoplasmic Reticulum Stress in Human Cells

Dombroski, Beth A.; Nayak, Renuka R.; Ewens, Kathryn G.; Ankener, Wendy; Cheung, Vivian G.; Spielman, Richard S.

doi:10.1016/j.ajhg.2010.03.017

Cited by 93 publications

(79 citation statements)

References 43 publications

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“…A comparison of the transcriptional response of whole flies to that of immortalized cell lines might nominate candidates for important conserved genes that show variation across species. To determine the overlap in variable ER stress genes in Drosophila and human, we compared our results with those reported by Dombroski et al for human cells (15). Of the conserved genes from our microarray study, 29% and 27% (early and late response, respectively) also showed expression variation in ER-stressed human cells (Dataset S2), as did, strikingly, 17% of the candidate ER stress genes from our association study (Dataset S5).…”

Section: Discussionmentioning

confidence: 90%

“…Only one other published study investigated variation in ER stress response in any organism (15). That study measured the variation in ER stress transcriptional response in a collection of human cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in the mouse, null mutations of H6PD, a gene encoding an ER resident protein, result in up-regulation of UPR associated genes in skeletal muscle (33). Additionally, five genes with TM survival-associated SNPs have orthologs induced by TM in human cells (15): Cbs, Xbp1, CG9518 (CHDH), shep (RBMS3), and pyd (TJP2).…”

Section: Snp In Xbp1mentioning

confidence: 99%

“…Only one published study has addressed ER stress-response variation (15). That study demonstrated that there was extensive variation in ER stress-induced transcription among cultured cells derived from different human individuals and that some genes underlying the variation had no previous known function in ER stress response (15). However, no studies have examined the variation in ER stress response in model organisms like Drosophila, where follow-up functional studies can be performed.…”

mentioning

confidence: 99%

“…Although many aspects of the ER stress response are being studied in depth, little is known of how the pathway might vary in healthy individuals. Only one published study has addressed ER stress-response variation (15). That study demonstrated that there was extensive variation in ER stress-induced transcription among cultured cells derived from different human individuals and that some genes underlying the variation had no previous known function in ER stress response (15).…”

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confidence: 99%

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Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Chow

Wolfner

Clark

2013

Proc. Natl. Acad. Sci. U.S.A.

111

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Natural genetic variation is a rich resource for identifying novel elements of cellular pathways such as endoplasmic reticulum (ER) stress. ER stress occurs when misfolded proteins accumulate in the ER and cells respond with the conserved unfolded protein response (UPR), which includes large-scale gene expression changes. Although ER stress can be a cause or a modifying factor of human disease, little is known of the amount of variation in the response to ER stress and the genes contributing to such variation. To study natural variation in ER stress response in a model system, we measured the survival time in response to tunicamycin-induced ER stress in flies from 114 lines from the sequenced Drosophila Genetic Reference Panel of wildderived inbred strains. These lines showed high heterogeneity in survival time under ER stress conditions. To identify the genes that may be driving this phenotypic variation, we profiled ER stressinduced gene expression and performed an association study. Microarray analysis identified variation in transcript levels of numerous known and previously unknown ER stress-responsive genes. Survival time was significantly associated with polymorphisms in candidate genes with known (i.e., Xbp1) and unknown roles in ER stress. Functional testing found that 17 of 25 tested candidate genes from the association study have putative roles in ER stress. In both approaches, one-third of ER stress genes had human orthologs that contribute to human disease. This study establishes Drosophila as a useful model for studying variation in ER stress and identifying ER stress genes that may contribute to human disease.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Snp In Xbp1mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Chow

Wolfner

Clark

2013

Proc. Natl. Acad. Sci. U.S.A.

111

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RASSF1 is identified by transcriptome coordination analysis as a target of ATF4

et al. 2023

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Evaluation of gene co‐regulation is a powerful approach for revealing regulatory associations between genes and predicting biological function, especially in genetically diverse samples. Here, we applied this strategy to identify transcripts that are co‐regulated with unfolded protein response (UPR) genes in cultured fibroblasts from outbred deer mice. Our analyses showed that the transcriptome associated with RASSF1, a tumor suppressor involved in cell cycle regulation and not previously linked to UPR, is highly correlated with the transcriptome of several UPR‐related genes, such as BiP/GRP78, DNAJB9, GRP94, ATF4, DNAJC3, and CHOP/DDIT3. Conversely, gene ontology analyses for genes co‐regulated with RASSF1 predicted a previously unreported involvement in UPR‐associated apoptosis. Bioinformatic analyses indicated the presence of ATF4‐binding sites in the RASSF1 promoter, which were shown to be operational using chromatin immunoprecipitation. Reporter assays revealed that the RASSF1 promoter is responsive to ATF4, while ablation of RASSF1 mitigated the expression of the ATF4 effector BBC3 and abrogated tunicamycin‐induced apoptosis. Collectively, these results implicate RASSF1 in the regulation of endoplasmic reticulum stress‐associated apoptosis downstream of ATF4. They also illustrate the power of gene coordination analysis in predicting biological functions and revealing regulatory associations between genes.

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A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol‐regulated transcription and the endoplasmic reticulum stress response

Strong

March

Cardinale

et al. 2021

American J of Med Genetics Pt A

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Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X‐linked disorder caused by pathogenic variants in membrane‐bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research‐based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol‐depleted media, attenuated activation of the sterol regulatory element‐binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.

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Gene Expression and Genetic Variation in Response to Endoplasmic Reticulum Stress in Human Cells

Cited by 93 publications

References 43 publications

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

RASSF1 is identified by transcriptome coordination analysis as a target of ATF4

A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol‐regulated transcription and the endoplasmic reticulum stress response

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