A Proteome-Scale Map of the Human Interactome Network

Rolland, Thomas; Taşan, Murat; Charloteaux, Benoît; Pevzner, Samuel; Zhong, Quan; Sahni, Nidhi; Yi, S. Stephen; Lemmens, Irma; Fontanillo, Celia; Mosca, Roberto; Kamburov, Atanas; Ghiassian, Susan Dina; Yang, Xinping; Ghamsari, Lila; Balcha, Dawit; Begg, Bridget E.; Braun, Pascal; Brehme, Marc; Broly, Martin; Carvunis, Anne‐Ruxandra; Convery-Zupan, Dan; Corominas, Roser; Coulombe-Huntington, Jasmin; Dann, Elizabeth; Dreze, Matija; Dricot, Amélie; Fan, Changyu; Franzosa, Eric A.; Gebreab, Fana; Gutierrez, Bryan J.; Hardy, Madeleine F.; Jin, Mike; Kang, Shuli; Kiros, Ruth; Lin, Guan Ning; Luck, Katja; MacWilliams, Andrew; Menche, Jörg; Murray, Ryan R.; Palagi, Alexandre; Poulin, Matthew M.; Rambout, Xavier; Rasla, John; Reichert, Patrick; Romero, Viviana; Ruyssinck, Elien; Sahalie, Julie M.; Scholz, Annemarie; Shah, Akash; Sharma, Amitabh; Shen, Yun; Spirohn, Kerstin; Tam, Stanley; Tejeda, Alexander O.; Trigg, Shelly A.; Twizere, Jean-Claude; Vega, Kerwin; Walsh, Jennifer; Cusick, Michael E.; Xia, Yu; Barabási, Albert‐László; Iakoucheva, Lilia M.; Aloy, Patrick; Rivas, Javier De Las; Tavernier, Jan; Calderwood, Michael A.; Hill, David E.; Hao, Tong; Roth, Frederick P.; Vidal, Marc

doi:10.1016/j.cell.2014.10.050

Cited by 1,290 publications

(1,308 citation statements)

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“…We found that the transeGenes in this hotspot are enriched for platelet degranulation (Table S8). Moreover, analyzing 25 cis-eGenes having binary interactions identified in a systematic screen for protein-protein interactions (PPI), 30 we found that 15 of them are hub genes in the PPI network ( Figure S3, p < 0.001 for randomly selecting 25 proteins in a PPI network), suggesting that cis-eGenes linked to trans-eQTLs play a central regulatory role in critical biological pathways through their mediation effects on trans-eGenes.…”

Section: Figure 2 Mediation Mechanisms Of Eqtlsmentioning

confidence: 96%

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

Yao

Joehanes

Johnson

et al. 2017

The American Journal of Human Genetics

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106

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Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10 À7 ); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-transeGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the transeGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

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Section: Figure 2 Mediation Mechanisms Of Eqtlsmentioning

confidence: 96%

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

Yao

Joehanes

Johnson

et al. 2017

The American Journal of Human Genetics

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106

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“…In a recent study, approximately two‐thirds of disease‐causing variants were found to impact at least one protein interaction (Sahni et al , 2015). Although only a minority of human protein interactions have been mapped (Rolland et al , 2014), already 40% of human genes have at least one interaction partner detectable by yeast two‐hybrid assay in a recent screen (Rolland et al , 2014). Taking the union of available assays, we estimate that 57% of known disease‐associated genes (Dataset EV2) already have an assay that is potentially amenable to DMS.…”

Section: Resultsmentioning

confidence: 99%

A framework for exhaustively mapping functional missense variants

Weile

Sun

Coté

et al. 2017

Molecular Systems Biology

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172

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Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin‐like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.

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“…Although we focused our attention on mRNA decay, our results suggest that ERG proteins might achieve control of gene expression by orchestrating multiple processes between transcription and decay. In addition, we have recently found 15 TFs among the RBPMS partners in our proteome-scale human interactome (GO: sequence-specific DNA binding) 47 . Therefore, a wide range of TFs and RBPs may actually collaborate in coupling transcriptional and post-transcriptional processes and machineries through the formation of highly versatile functional platforms.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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nature structural & molecular biology advance online publication a r t i c l e sAlthough undisputable evidence has clearly demonstrated that the nuclear steps of mRNA processing are mechanistically linked to transcription, a conceptual evolution in gene regulation has come with the realization that transcription might also be functionally connected to more remote processes occurring in the cytoplasm, such as mRNA decay 1,2 . Cytoplasmic mRNA decay is initiated by deadenylation, a rate-limiting event during which the poly(A) tail of the transcript is trimmed off by the CCR4-NOT complex, the main deadenylation machinery in eukaryotes 3 . The degradation of specific mRNAs, a key process in the regulation of eukaryotic gene expression, is achieved through the recruitment of the CCR4-NOT complex by sequence-specific RNA-binding proteins (RBPs) or by the microRNA machinery 3,4 . Poly(A)-shortened mRNAs, along with factors involved in the deadenylation, decapping and mRNA-degradation machineries, accumulate in microscopic mRNA-protein complex (mRNP) aggregates called processing bodies (PBs) 5 .The idea of coupling between mRNA synthesis and degradation has recently emerged. Genome-wide expression studies in yeast have shown that mRNA synthesis and decay are mechanistically and functionally coordinated, thus supporting the existence of common molecular effectors [6][7][8][9] . In particular, the CCR4-NOT deadenylation complex was first described as a transcriptional regulator and has been implicated in initiation and elongation by RNA polymerase II 10,11 . More surprisingly, it has also been shown that degradation of yeast mRNAs is determined by cis-acting sequence elements in promoters 12,13 . These findings have led to the concept of mRNA imprinting, in which sequence-specific DNA-binding factors might orchestrate mRNA synthesis and decay. This decay would occur via loading of factors regulating cytoplasmic mRNA degradation onto the transcribing mRNA 14 . However, the identity of these DNA-binding mRNA coordinators is still obscure, and it remains to be tested whether such coupling between transcription and decay also exists in higher eukaryotes. E26 (Ets) proteins, a family of 28 helix-loop-helix transcription factors (TFs) in metazoans, are characterized by a highly conserved DNA-binding ETS domain 15 . Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay. We demonstrate that ERG triggers degradation of mRNAs connected to Aurora signaling by recruiting RBPs and the CCR4-NOT deadenylation complex and that this activity is important fo...

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A Proteome-Scale Map of the Human Interactome Network

Cited by 1,290 publications

References 57 publications

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

A framework for exhaustively mapping functional missense variants

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

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