Targeted exploration and analysis of large cross-platform human transcriptomic compendia

Zhu, Qi; Wong, Aaron K.; Krishnan, Arjun; Aure, Miriam Ragle; Tadych, Alicja; Zhang, Ran; Corney, David C.; Greene, Casey S.; Bongo, Lars Ailo; Kristensen, Vessela N.; Charikar, Moses; Li, Kai; Troyanskaya, Olga G.

doi:10.1038/nmeth.3249

Cited by 145 publications

(142 citation statements)

References 33 publications

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“…To test the relevance of these findings in clinical disease sets, we conducted a search-based exploration of expression compendia analysis (SEEK) of human datasets across the Gene Expression Omnibus and Cancer Genome Atlas (TCGA) (Zhu et al, 2015) (Figure 3A). The 227 signature had markedly higher co-expression scores (i.e., dataset weight) across the SEEK compendia as compared to random queries of matched size, with such scores highly significant (at p ≤ 0.001) in over 87% of the datasets.…”

Section: Resultsmentioning

confidence: 99%

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Nirschl

Suárez‐Fariñas

Izar

et al. 2017

Cell

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153

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Summary Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.

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Section: Resultsmentioning

confidence: 99%

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Nirschl

Suárez‐Fariñas

Izar

et al. 2017

Cell

Self Cite

153

124

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“…Although CoREST, mSin3 and HDAC1/2 were expressed in HEK293T cell based on microarray data of HEK293T cell (One of ENCODE transcriptome data41; GEO accession: GSE1580542), their expression was not that high. In addition, CoREST is known to be negatively co-expressed with REST from SEEK database43. Thus, endogenous expression level of each protein in HEK293 cells should affect the detection of REST-interacting proteins.…”

Section: Discussionmentioning

confidence: 99%

Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation

Lee

Park

Haddad

et al. 2016

Sci Rep

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RE-1 silencing transcription factor (REST) is a transcriptional repressor that regulates gene expression by binding to repressor element 1. However, despite its critical function in physiology, little is known about its interaction proteins. Here we identified 204 REST-interacting proteins using affinity purification and mass spectrometry. The interactome included proteins associated with mRNA processing/splicing, chromatin organization, and transcription. The interactions of these REST-interacting proteins, which included TRIM28, were confirmed by co-immunoprecipitation and immunocytochemistry, respectively. Gene Ontology (GO) analysis revealed that neuronal differentiation-related GO terms were enriched among target genes that were co-regulated by REST and TRIM28, while the level of CTNND2 was increased by the knockdown of REST and TRIM28. Consistently, the level of CTNND2 increased while those of REST and TRIM28 decreased during neuronal differentiation in the primary neurons, suggesting that CTNND2 expression may be co-regulated by both. Furthermore, neurite outgrowth was increased by depletion of REST or TRIM28, implying that reduction of both REST and TRIM28 could promote neuronal differentiation via induction of CTNND2 expression. In conclusion, our study of REST reveals novel interacting proteins which could be a valuable resource for investigating unidentified functions of REST and also suggested functional links between REST and TRIM28 during neuronal development.

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“…A few web resources, including GEO (Barrett et al 2013), ArrayExpress (Kolesnikov et al 2015), GeneNetwork (Chesler et al 2004), and Bgee (Bastian et al 2008) amongst others, have created repositories of such expression data for curation, reuse, and integration. Several tools, such as GeneMANIA (Warde-Farley et al 2010), GIANT , SEEK (Zhu et al 2015), GeneFriends (van Dam et al 2015), WeGET (Szklarczyk et al 2016), COXPRESdb (Obayashi et al 2019), WGCNA (Langfelder and Horvath 2008), and CLIC , are able to assign putative new functions to genes by means of correlations or co-expression networks. At their core, these methods rely on the concept of guilt-byassociation -that transcripts or proteins exhibiting similar expression patterns tend to be functionally related (Eisen et al 1998).…”

Section: Introductionmentioning

confidence: 99%

“…The key polarity of interactions is often lost among gene products and linked modules (Warde-Farley et al 2010;Greene et al 2015;van Dam et al 2015;Zhu et al 2015;Li et al 2017). Gene set analyses, such as gene set enrichment analysis (GSEA) (Subramanian et al 2005), have been developed to identify processes or modules that are affected by certain genetic or environmental perturbations (Khatri et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Identifying gene function and module connections by the integration of multi-species expression compendia

Rukina

David

et al. 2019

Preprint

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The functions of many eukaryotic genes are still poorly understood. We developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First, Gene-Module Association Determination (G-MAD) allows the annotation of gene function. Second, Module-Module Association Determination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multi-species expression compendia-1,700 datasets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast-collected in this study. Unlike most existing bioinformatics tools, GeneBridge exploits both positive and negative gene/module-module associations. We constructed association networks, such as those bridging mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available at systems-genetics.org, to facilitate the identification of connections linking genes, modules, phenotypes, and diseases.

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Targeted exploration and analysis of large cross-platform human transcriptomic compendia

Cited by 145 publications

References 33 publications

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation

Identifying gene function and module connections by the integration of multi-species expression compendia

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