Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Subramanian, Aravind; Tamayo, Pablo; Mootha, Vamsi K.; Mukherjee, Sayan; Ebert, Benjamin L.; Gillette, Michael A.; Paulovich, Amanda G.; Pomeroy, Scott L.; Golub, Todd R.; Lander, Eric S.; Mesirov, Jill P.

doi:10.1073/pnas.0506580102

Cited by 42,916 publications

(40,285 citation statements)

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“…gene expression data from liver, muscle, and heart tissue using GSEA (gene set enrichment analysis) (Mootha et al ., 2003; Subramanian et al ., 2005); unfortunately, adipose gene expression information was not available from the AGEMAP study, and an insufficient number of samples were available from the Pearson et al . study for GSEA.…”

Section: Resultsmentioning

confidence: 99%

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Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

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Section: Resultsmentioning

confidence: 99%

“…The mTOR pathway gene sets we used were obtained from the Molecular Signatures Database (MSigDB) and are listed in Table S3. The GSEA application was executed using default parameters as recommended by (Subramanian et al ., 2005). …”

Section: Methodsmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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“…MK was supported by the Swedish Cancer Society. The authors acknowledge the use of GSEA software and Molecular Signature Database (MSigDB)27 (http://www.broad.mit.edu/gsea/). …”

Section: Acknowledgementsmentioning

confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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“…To determine pathways that may be preferentially targeted for DNA methylation dysregulation, candidate genes were uploaded to gene set enrichment analysis (GSEA) (Subramanian et al ., 2005) and analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. The ‘GoSeq’ package (Young et al ., 2010) was utilized to normalize the genes based on number of HpaII sites per gene to eliminate bias.…”

Section: Resultsmentioning

confidence: 99%

“…To perform GSEA (Subramanian et al ., 2005), we first linked RefSeq genes (rn4) to our candidate differentially methylated loci. Differentially methylated loci overlapping candidate regulatory regions up to 10‐kb upstream of gene transcription start site and within gene bodies until transcription end site were used to link DNA methylation changes with specific genes.…”

Section: Experimental Methodsmentioning

confidence: 99%

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

et al. 2016

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SummaryAdverse environmental exposures of mothers during fetal period predispose offspring to a range of age‐related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers’ nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age‐matched young controls and aged (20‐month‐old) animals. HELP‐tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.

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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Cited by 42,916 publications

References 34 publications

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

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