OmnipathR 3.0.4
OmnipathR is an R package built to provide easy access to the data stored in the OmniPath webservice (Türei, Korcsmáros, and Saez-Rodriguez 2016):
The webservice implements a very simple REST style API. This package make requests by the HTTP protocol to retreive the data. Hence, fast Internet access is required for a proper use of OmnipathR.
OmnipathR can retrieve five different types of data:
Post-translational modifications (PTMs): It provides enzyme-substrate reactions in a very similar way to the aforementioned interactions. Some of the biological databases related to PTMs integrated in OmniPath are Phospho.ELM (Dinkel et al. 2010) and PhosphoSitePlus [Hornbeck et al. (2014)}.
Complexes: it provides access to a comprehensive database of more than 22000 protein complexes. This data comes from different resources such as: CORUM (Giurgiu et al. 2018) or Hu.map (Drew et al. 2017).
Annotations: it provides a large variety of data regarding different annotations about proteins and complexes. These data come from dozens of databases covering different topics such as: The Topology Data Bank of Transmembrane Proteins (TOPDB) (Dobson et al. 2014) or ExoCarta (Keerthikumar et al. 2016), a database collecting the proteins that were identified in exosomes in multiple organisms.
Intercell: it provides information on the roles in inter-cellular signaling. For instance. if a protein is a ligand, a receptor, an extracellular matrix (ECM) component, etc. The data does not come from original sources but combined from several databases by us. The source databases, such as CellPhoneDB (Vento-Tormo et al. 2018) or Receptome (Ben-Shlomo et al. 2003), are also referred for each reacord.
Figure ?? shows an overview of the resources featured in OmniPath. For more detailed information about the original data sources integrated in Omnipath, please visit:
{r, fig1, dpi=300, fig.width=10, fig.height=10, fig.cap="Overview of the resources featured in OmniPath. Causal resources (including activity-flow and enzyme-substrate resources) can provide direction (*) or sign and direction (+) of interactions.", echo=FALSE} library(knitr) knitr::include_graphics("../man/figures/page1_1.png")
Excluding the miRNA interactions, all interactions and PTMs are available for human, mouse and rat. The rodent data has been translated from human using the NCBI Homologene database. Many human proteins do not have known homolog in rodents, hence rodent datasets are smaller than their human counterparts.
In case you work with mouse omics data you might do better to translate your dataset to human (for example using the pypath.homology module, https://github.com/saezlab/pypath/) and use human interaction data.
First of all, you need a current version of R. OmnipathR is a freely available package deposited on Bioconductor and GitHub. You can install it by running the following commands on an R console:
if (!requireNamespace("BiocManager", quietly = TRUE))
install.packages("BiocManager")
BiocManager::install("OmnipathR")We also load here the required packages to run the code in this vignette.
library(OmnipathR)
library(tidyr)
library(dnet)
library(gprofiler2)In the following paragraphs, we provide some examples to describe how to use the OmnipathR package to retrieve different types of information from Omnipath webserver. In addition, we play around with the data aiming at obtaining some biological relevant information.
Noteworthy, the sections complexes, annotations and intercell are linked. We explore the annotations and roles in inter-cellular communications of the proteins involved in a given complex. This basic example shows the usefulness of integrating the information available in the different Omnipath resources.
Proteins interact among them and with other biological molecules to perform cellular functions. Proteins also participates in pathways, linked series of reactions occurring inter/intra cells to transform products or to transmit signals inducing specific cellular responses. Protein interactions are therefore a very valuable source of information to understand cellular functioning.
We here download the original OmniPath human interactions (Türei, Korcsmáros, and Saez-Rodriguez 2016). To do so, we first check the different source databases and select some of them. Then, we print some of the downloaded interactions (“+” means activation, “-” means inhibition and “?” means undirected interactions or inconclusive data).
## We check some of the different interaction databases
get_interaction_resources()## [1] "ABS" "ACSN"
## [3] "ACSN_SignaLink3" "ARACNe-GTEx_DoRothEA"
## [5] "ARN" "Adhesome"
## [7] "AlzPathway" "BEL-Large-Corpus_ProtMapper"
## [9] "Baccin2019" "BioGRID"
## [11] "BioGRID_ICELLNET" "CA1"
## [13] "CancerCellMap" "CellChatDB"
## [15] "CellChatDB-cofactors" "CellPhoneDB"
## [17] "CellPhoneDB_ICELLNET" "CellTalkDB"
## [19] "DEPOD" "DIP"
## [21] "DLRP_talklr" "DOMINO"
## [23] "DeathDomain" "Dinarello2013_ICELLNET"
## [25] "DoRothEA" "DoRothEA-reviews_DoRothEA"
## [27] "ELM" "EMBRACE"
## [29] "ENCODE-distal" "ENCODE-proximal"
## [31] "ENCODE_tf-mirna" "FANTOM4_DoRothEA"
## [33] "Fantom5_LRdb" "GO-lig-rec_ICELLNET"
## [35] "Guide2Pharma" "Guide2Pharma_CellPhoneDB"
## [37] "Guide2Pharma_ICELLNET" "Guide2Pharma_LRdb"
## [39] "Guide2Pharma_talklr" "HOCOMOCO_DoRothEA"
## [41] "HPMR" "HPMR_ICELLNET"
## [43] "HPMR_LRdb" "HPMR_talklr"
## [45] "HPRD" "HPRD-phos"
## [47] "HPRD_KEA" "HPRD_LRdb"
## [49] "HPRD_MIMP" "HPRD_talklr"
## [51] "HTRIdb" "HTRIdb_DoRothEA"
## [53] "HuRI" "I2D_CellPhoneDB"
## [55] "ICELLNET" "IMEx_CellPhoneDB"
## [57] "InnateDB" "InnateDB-All_CellPhoneDB"
## [59] "InnateDB_CellPhoneDB" "InnateDB_ICELLNET"
## [61] "InnateDB_SignaLink3" "IntAct"
## [63] "IntAct_CellPhoneDB" "IntAct_DoRothEA"
## [65] "JASPAR_DoRothEA" "KEA"
## [67] "KEGG-MEDICUS" "Kinexus_KEA"
## [69] "Kirouac2010" "Kirouac2010_ICELLNET"
## [71] "LMPID" "LRdb"
## [73] "Li2012" "Lit-BM-17"
## [75] "LncRNADisease" "MIMP"
## [77] "MINT_CellPhoneDB" "MPPI"
## [79] "Macrophage" "Macrophage_ICELLNET"
## [81] "MatrixDB" "MatrixDB_CellPhoneDB"
## [83] "NCI-PID_ProtMapper" "NFIRegulomeDB_DoRothEA"
## [85] "NRF2ome" "NetPath"
## [87] "NetworKIN_KEA" "ORegAnno"
## [89] "ORegAnno_DoRothEA" "PAZAR"
## [91] "PAZAR_DoRothEA" "PhosphoNetworks"
## [93] "PhosphoPoint" "PhosphoSite"
## [95] "PhosphoSite_KEA" "PhosphoSite_MIMP"
## [97] "PhosphoSite_ProtMapper" "PhosphoSite_noref"
## [99] "ProtMapper" "REACH_ProtMapper"
## [101] "RLIMS-P_ProtMapper" "Ramilowski2015"
## [103] "Ramilowski2015_Baccin2019" "Ramilowski2015_ICELLNET"
## [105] "ReMap_DoRothEA" "Reactome_ICELLNET"
## [107] "Reactome_LRdb" "Reactome_ProtMapper"
## [109] "Reactome_SignaLink3" "RegNetwork_DoRothEA"
## [111] "SIGNOR" "SIGNOR_ICELLNET"
## [113] "SIGNOR_ProtMapper" "SPIKE"
## [115] "SPIKE_ICELLNET" "STRING_ICELLNET"
## [117] "STRING_talklr" "SignaLink3"
## [119] "SignaLink3_ICELLNET" "Sparser_ProtMapper"
## [121] "TCRcuration_SignaLink3" "TFactS_DoRothEA"
## [123] "TFe_DoRothEA" "TRED_DoRothEA"
## [125] "TRIP" "TRRD_DoRothEA"
## [127] "TRRUST_DoRothEA" "TransmiR"
## [129] "UniProt_CellPhoneDB" "UniProt_LRdb"
## [131] "Wang" "Wojtowicz2020"
## [133] "connectomeDB2020" "dbPTM"
## [135] "iPTMnet" "iTALK"
## [137] "lncrnadb" "miR2Disease"
## [139] "miRDeathDB" "miRTarBase"
## [141] "miRecords" "ncRDeathDB"
## [143] "phosphoELM" "phosphoELM_KEA"
## [145] "phosphoELM_MIMP" "talklr"## The interactions are stored into a data frame.
interactions <-
import_omnipath_interactions(resources=c("SignaLink3","PhosphoSite",
"SIGNOR"))
## We visualize the first interactions in the data frame.
print_interactions(head(interactions))## # A tibble: 6 × 5
## source interaction target n_resources n_references
## <chr> <chr> <chr> <int> <chr>
## 1 RACK1 (P63244) ==( - )==> TRPM6 (Q9BX84) 2 SIGNOR:18258429;TRIP:18…
## 2 PRKG1 (Q13976) ==( - )==> TRPC6 (Q9Y210) 4 PhosphoSite:19961855;Ph…
## 3 SRC (P12931) ==( + )==> TRPV1 (Q8NER1) 5 PhosphoSite:16319926;Pr…
## 4 PRKG1 (Q13976) ==( - )==> TRPC3 (Q13507) 8 HPRD:14983059;KEA:14983…
## 5 TRPM7 (Q96QT4) ==( + )==> ANXA1 (P04083) 10 HPRD-phos:15485879;HPRD…
## 6 PTPN1 (P18031) ==( - )==> TRPV6 (Q9H1D0) 6 DEPOD:15894168;DEPOD:17…Protein-protein interactions are usually converted into networks. Describing protein interactions as networks not only provides a convenient format for visualization, but also allows applying graph theory methods to mine the biological information they contain.
We convert here our set of interactions to a network/graph (igraphobject). Then, we apply two very common approaches to extract information from a biological network:
print_path\_es and
print_path\_vs display very similar results, but the first one takes as an
input an edge sequence and the second one a node sequence.## We transform the interactions data frame into a graph
OPI_g <- interaction_graph(interactions = interactions)
## Find and print shortest paths on the directed network between proteins
## of interest:
print_path_es(shortest_paths(OPI_g,from = "TYRO3",to = "STAT3",
output = 'epath')$epath[[1]],OPI_g)## source interaction target n_resources
## 1 TYRO3 (Q06418) ==( + )==> GRB2 (P62993) 2
## 2 GRB2 (P62993) ==( + )==> EGFR (P00533) 11
## 3 EGFR (P00533) ==( + )==> STAT3 (P40763) 12
## n_references
## 1 SIGNOR:17306385
## 2 DIP:1322798;DOMINO:12577067;DOMINO:16273093;DOMINO:16729043;HPRD:11726515;HPRD:12577067;HPRD:1322798;HPRD:14679214;HPRD:16799092;HPRD:7518560;HPRD:7527043;HPRD:8662998;HPRD:8810325;HPRD:8887653;InnateDB:16799092;IntAct:10229072;IntAct:11896612;IntAct:14679214;IntAct:16273093;IntAct:16729043;IntAct:21278786;IntAct:23799367;IntAct:24658140;IntAct:27059931;IntAct:7518560;IntAct:7527043;IntAct:8887653;IntAct:8940013;IntAct:9020117;LMPID:7518560;LMPID:8491186;Lit-BM-17:10026169;Lit-BM-17:10085134;Lit-BM-17:10229072;Lit-BM-17:10595738;Lit-BM-17:11370743;Lit-BM-17:11408594;Lit-BM-17:11896612;Lit-BM-17:11960376;Lit-BM-17:12577067;Lit-BM-17:1322798;Lit-BM-17:14679214;Lit-BM-17:15657067;Lit-BM-17:16273093;Lit-BM-17:16729043;Lit-BM-17:16799092;Lit-BM-17:17242169;Lit-BM-17:17971399;Lit-BM-17:18271526;Lit-BM-17:19289468;Lit-BM-17:19531499;Lit-BM-17:19836242;Lit-BM-17:20124286;Lit-BM-17:21596750;Lit-BM-17:21706016;Lit-BM-17:23178716;Lit-BM-17:23799367;Lit-BM-17:23956138;Lit-BM-17:24189400;Lit-BM-17:24658140;Lit-BM-17:24797263;Lit-BM-17:25402006;Lit-BM-17:27059931;Lit-BM-17:7506413;Lit-BM-17:7510700;Lit-BM-17:7518560;Lit-BM-17:7527043;Lit-BM-17:7592693;Lit-BM-17:7650032;Lit-BM-17:8647858;Lit-BM-17:8662998;Lit-BM-17:8810340;Lit-BM-17:8887653;Lit-BM-17:8940013;Lit-BM-17:9020117;Lit-BM-17:9050991;Lit-BM-17:9416834;Lit-BM-17:9886492;NetPath:12577067;NetPath:17991782;NetPath:19509291;NetPath:19531499;NetPath:9544989;SIGNOR:11726515;SPIKE:11084343;SPIKE:12648464;SPIKE:16713569;SPIKE:7518560;SPIKE:8887653
## 3 BioGRID:18258752;BioGRID:20145033;CancerCellMap:12070153;HPRD:12873986;InnateDB:12873986;InnateDB:14963038;InnateDB:15284024;InnateDB:15950906;IntAct:14966128;IntAct:24135280;IntAct:24658140;IntAct:25241761;Lit-BM-17:10358079;Lit-BM-17:14966128;Lit-BM-17:15284024;Lit-BM-17:15485908;Lit-BM-17:15657067;Lit-BM-17:15950906;Lit-BM-17:18258752;Lit-BM-17:21573184;Lit-BM-17:23956138;Lit-BM-17:24135280;Lit-BM-17:24189400;Lit-BM-17:24658140;Lit-BM-17:25241761;Lit-BM-17:25402006;Lit-BM-17:9756944;NetPath:20032199;ProtMapper:15951569;ProtMapper:23894143;SIGNOR:14967450;SIGNOR:22693070;SPIKE:15950906## Find and print all shortest paths between proteins of interest:
print_path_vs(all_shortest_paths(OPI_g,from = "DYRK2",
to = "MAPKAPK2")$res,OPI_g)## Pathway 1: DYRK2 -> TBK1 -> AKT3 -> PEA15 -> MAPK3 -> MAPKAPK2## Pathway 2: DYRK2 -> TBK1 -> AKT2 -> PEA15 -> MAPK3 -> MAPKAPK2## Pathway 3: DYRK2 -> TBK1 -> AKT1 -> PEA15 -> MAPK3 -> MAPKAPK2## Pathway 4: DYRK2 -> TBK1 -> AKT3 -> PPP1CA -> MAPK3 -> MAPKAPK2## Pathway 5: DYRK2 -> TBK1 -> AKT2 -> PPP1CA -> MAPK3 -> MAPKAPK2## Pathway 6: DYRK2 -> TBK1 -> AKT1 -> PPP1CA -> MAPK3 -> MAPKAPK2## Pathway 7: DYRK2 -> TP53 -> RPS6KA5 -> CDC25A -> MAPK3 -> MAPKAPK2## Pathway 8: DYRK2 -> TP53 -> RPS6KA4 -> CDC25A -> MAPK3 -> MAPKAPK2## Pathway 9: DYRK2 -> TP53 -> RPS6KA3 -> CDC25A -> MAPK3 -> MAPKAPK2## Pathway 10: DYRK2 -> TP53 -> RPS6KA2 -> CDC25A -> MAPK3 -> MAPKAPK2## Pathway 11: DYRK2 -> TP53 -> RPS6KA1 -> CDC25A -> MAPK3 -> MAPKAPK2## Pathway 12: DYRK2 -> TBK1 -> AKT3 -> PEA15 -> MAPK1 -> MAPKAPK2## Pathway 13: DYRK2 -> TBK1 -> AKT2 -> PEA15 -> MAPK1 -> MAPKAPK2## Pathway 14: DYRK2 -> TBK1 -> AKT1 -> PEA15 -> MAPK1 -> MAPKAPK2## Pathway 15: DYRK2 -> TBK1 -> AKT3 -> PPP1CA -> MAPK1 -> MAPKAPK2## Pathway 16: DYRK2 -> TBK1 -> AKT2 -> PPP1CA -> MAPK1 -> MAPKAPK2## Pathway 17: DYRK2 -> TBK1 -> AKT1 -> PPP1CA -> MAPK1 -> MAPKAPK2## Pathway 18: DYRK2 -> TP53 -> RPS6KA3 -> DAPK1 -> MAPK1 -> MAPKAPK2## Pathway 19: DYRK2 -> TP53 -> RPS6KA5 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 20: DYRK2 -> TP53 -> RPS6KA4 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 21: DYRK2 -> TP53 -> RPS6KA3 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 22: DYRK2 -> TP53 -> RPS6KA2 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 23: DYRK2 -> TP53 -> RPS6KA1 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 24: DYRK2 -> TBK1 -> AKT3 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 25: DYRK2 -> TBK1 -> AKT2 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 26: DYRK2 -> TBK1 -> AKT1 -> GSK3B -> MAPK14 -> MAPKAPK2## Pathway 27: DYRK2 -> TBK1 -> AKT3 -> MAP2K4 -> MAPK14 -> MAPKAPK2## Pathway 28: DYRK2 -> TBK1 -> AKT2 -> MAP2K4 -> MAPK14 -> MAPKAPK2## Pathway 29: DYRK2 -> TBK1 -> AKT1 -> MAP2K4 -> MAPK14 -> MAPKAPK2## Pathway 30: DYRK2 -> TBK1 -> AKT3 -> MAP3K5 -> MAPK14 -> MAPKAPK2## Pathway 31: DYRK2 -> TBK1 -> AKT2 -> MAP3K5 -> MAPK14 -> MAPKAPK2## Pathway 32: DYRK2 -> TBK1 -> AKT1 -> MAP3K5 -> MAPK14 -> MAPKAPK2## We apply a clustering algorithm (Louvain) to group proteins in
## our network. We apply here Louvain which is fast but can only run
## on undirected graphs. Other clustering algorithms can deal with
## directed networks but with longer computational times,
## such as cluster_edge_betweenness. These cluster methods are directly
## available in the igraph package.
OPI_g_undirected <- as.undirected(OPI_g, mode=c("mutual"))
OPI_g_undirected <- simplify(OPI_g_undirected)
cl_results <- cluster_fast_greedy(OPI_g_undirected)
## We extract the cluster where a protein of interest is contained
cluster_id <- cl_results$membership[which(cl_results$names == "ERBB2")]
module_graph <- induced_subgraph(OPI_g_undirected,
V(OPI_g)$name[which(cl_results$membership == cluster_id)]){r fig2, fig.width=10, fig.height=5, dpi=300, echo = FALSE, fig.cap="ERBB2 associated cluser. Subnetwork extracted from the interactions graph representing the cluster where we can find the gene *ERBB2* (yellow node)"} ## We print that cluster with its interactions. par(mar=c(0.1,0.1,0.1,0.1)) plot(module_graph, vertex.label.color="black",vertex.frame.color="#ffffff", vertex.size= 15, edge.curved=.2, vertex.color = ifelse(igraph::V(module_graph)$name == "ERBB2","yellow", "#00CCFF"), edge.color="blue",edge.width=0.8)
We used above the interactions from the dataset described in the original OmniPath publication (Türei, Korcsmáros, and Saez-Rodriguez 2016). In this section, we provide examples on how to retry and deal with interactions from the remaining datasets. The same functions can been applied to every interaction dataset.
In the first example, we are going to get the interactions from the pathwayextra dataset, which contains activity flow interactions without literature reference. We are going to focus on the mouse interactions for a given gene in this particular case.
## We query and store the interactions into a dataframe
interactions <-
import_pathwayextra_interactions(resources=c("BioGRID","STRING"),
organism = 10090)## Warning in omnipath_check_param(param): The following resources are not
## available: STRING. Check the resource names for spelling mistakes.## We select all the interactions in which Amfr gene is involved
interactions_Amfr <- dplyr::filter(interactions, source_genesymbol == "Amfr" |
target_genesymbol == "Amfr")
## We print these interactions:
print_interactions(interactions_Amfr)## # A tibble: 1 × 5
## source interaction target n_resources n_references
## <chr> <chr> <chr> <int> <chr>
## 1 Amfr (Q9R049) ==( + )==> Vcp (Q01853) 6 BioGRID:16987818;BioGRID:1…Next, we download the interactions from the kinaseextra dataset, which contains enzyme-substrate interactions without literature reference. We are going to focus on rat reactions targeting a particular gene.
## We query and store the interactions into a dataframe
interactions <-
import_kinaseextra_interactions(resources=c("PhosphoPoint",
"PhosphoSite"), organism = 10116)
## We select the interactions in which Dpysl2 gene is a target
interactions_TargetDpysl2 <- dplyr::filter(interactions,
target_genesymbol == "Dpysl2")
## We print these interactions:
print_interactions(interactions_TargetDpysl2)## # A tibble: 5 × 5
## source interaction target n_resources n_references
## <chr> <chr> <chr> <int> <chr>
## 1 Fer (P09760) ==( ? )==> Dpysl2 (P47942) 2 PhosphoSite:29396402;P…
## 2 Cdk5 (Q03114) ==( + )==> Dpysl2 (P47942) 5 PhosphoSite:15652488;P…
## 3 Rock1 (Q63644) ==( ? )==> Dpysl2 (P47942) 6 HPRD:10818093;HPRD:124…
## 4 Gsk3b (P18266) ==(+/-)==> Dpysl2 (P47942) 11 HPRD-phos:15652488;HPR…
## 5 Rock2 (Q62868) ==( + )==> Dpysl2 (P47942) 10 CA1:10818093;KEA:10818…In the following example we are going to work with the ligrecextra dataset, which contains ligand-receptor interactions without literature reference. Our goal is to find the potential receptors associated to a given ligand, CDH1 (Figure ??).
## We query and store the interactions into a dataframe
interactions <- import_ligrecextra_interactions(resources=c("iTALK",
"Baccin2019"), organism=9606)
## Receptors of the CDH1 ligand.
interactions_ADM2 <- dplyr::filter(interactions, source_genesymbol == "ADM2")
## We transform the interactions data frame into a graph
OPI_g <- interaction_graph(interactions = interactions_ADM2)
## We induce a network with these genes
Induced_Network <- dNetInduce(g=OPI_g,
nodes_query=as.character( V(OPI_g)$name), knn=0,
remove.loops=FALSE, largest.comp=FALSE){r fig3, dpi=300, echo = FALSE, fig.cap="Ligand-receptor interactions for the ADM2 ligand."} ## We print the induced network par(mar=c(0.1,0.1,0.1,0.1)) plot(Induced_Network, vertex.label.color="black", vertex.frame.color="#ffffff",vertex.size= 20, edge.curved=.2, vertex.color = ifelse(igraph::V(Induced_Network)$name %in% c("ADM2"), "yellow","#00CCFF"), edge.color="blue",edge.width=0.8)
Another very interesting interaction dataset also available in OmniPath is DoRothEA (Garcia-Alonso et al. 2019). It contains transcription factor (TF)-target interactions with confidence score, ranging from A-E, being A the most confident interactions. In the code chunk shown below, we select and print the most confident interactions for a given TF.
## We query and store the interactions into a dataframe
interactions <- import_dorothea_interactions(
resources=c("DoRothEA"),
dorothea_levels = 'A',
organism=9606
)
## We select the most confident interactions for a given TF and we print
## the interactions to check the way it regulates its different targets
interactions_A_GLI1 <- dplyr::filter(interactions, dorothea_level=="A",
source_genesymbol == "GLI1")
print_interactions(interactions_A_GLI1)## # A tibble: 7 × 5
## source interaction target n_resources n_references
## <chr> <chr> <chr> <int> <chr>
## 1 GLI1 (P08151) ==( + )==> PTCH1 (Q13635) 1 0
## 2 GLI1 (P08151) ==( + )==> BCL2 (P10415) 0 0
## 3 GLI1 (P08151) ==( + )==> CCND2 (P30279) 0 0
## 4 GLI1 (P08151) ==( - )==> EGR2 (P11161) 0 0
## 5 GLI1 (P08151) ==( + )==> IGFBP6 (P24592) 0 0
## 6 GLI1 (P08151) ==( + )==> SFRP1 (Q8N474) 0 0
## 7 GLI1 (P08151) ==( - )==> SLIT2 (O94813) 0 0The last dataset describing interactions is mirnatarget. It stores miRNA-mRNA and TF-miRNA interactions. These interactions are only available for human so far. We next select the miRNA interacting with the TF selected in the previous code chunk, GLI1. The main function of miRNAs seems to be related with gene regulation. It is therefore interesting to see how some miRNA can regulate the expression of a TF which in turn regulates the expression of other genes. Figure ?? shows a schematic network of the miRNA targeting GLI1 and the genes regulated by this TF.
## We query and store the interactions into a dataframe
interactions <-
import_mirnatarget_interactions(resources=c("miRTarBase","miRecords"))
## We select the interactions where a miRNA is interacting with the TF
## used in the previous code chunk and we print these interactions.
interactions_miRNA_GLI1 <-
dplyr::filter(interactions, target_genesymbol == "GLI1")
print_interactions(interactions_miRNA_GLI1)## # A tibble: 5 × 5
## source interaction target n_resources n_references
## <chr> <chr> <chr> <int> <chr>
## 1 hsa-miR-133b (MIMAT0000770) ==( ? )==> GLI1 (P08151) 1 miRTarBase:…
## 2 hsa-miR-202 (MIMAT0002811) ==( ? )==> GLI1 (P08151) 1 miRTarBase:…
## 3 hsa-miR-324-5p (MIMAT0000761) ==( ? )==> GLI1 (P08151) 3 miRTarBase:…
## 4 hsa-miR-125b (MIMAT0000423) ==( ? )==> GLI1 (P08151) 2 miRTarBase:…
## 5 hsa-miR-326 (MIMAT0000756) ==( ? )==> GLI1 (P08151) 2 miRTarBase:…## We transform the previous selections to graphs (igraph objects)
OPI_g_1 <-interaction_graph(interactions = interactions_A_GLI1)
OPI_g_2 <-interaction_graph(interactions = interactions_miRNA_GLI1){r fig4, dpi=300, echo = FALSE, fig.cap="miRNA-TF-target network. Schematic network of the miRNA (red square nodes) targeting \textit{GLI1} (yellow node) and the genes regulated by this TF (blue round nodes)."} ## We print the union of both previous graphs par(mar=c(0.1,0.1,0.1,0.1)) plot(OPI_g_1 %u% OPI_g_2, vertex.label.color="black", vertex.frame.color="#ffffff",vertex.size= 20, edge.curved=.25, vertex.color = ifelse(grepl("miR",igraph::V(OPI_g_1 %u% OPI_g_2)$name), "red",ifelse(igraph::V(OPI_g_1 %u% OPI_g_2)$name == "GLI1", "yellow","#00CCFF")), edge.color="blue", vertex.shape = ifelse(grepl("miR",igraph::V(OPI_g_1 %u% OPI_g_2)$name), "vrectangle","circle"),edge.width=0.8)
Another query type available is PTMs which provides enzyme-substrate reactions in a very similar way to the aforementioned interactions. PTMs refer generally to enzymatic modification of proteins after their synthesis in the ribosomes. PTMs can be highly context-specific and they play a main role in the activation/inhibition of biological pathways.
In the next code chunk, we download the PTMs for human. We first check the different available source databases, even though we do not perform any filter. Then, we select and print the reactions involving a specific enzyme-substrate pair. Those reactions lack information about activation or inhibition. To obtain that information, we match the data with OmniPath interactions. Finally, we show that it is also possible to build a graph using this information, and to retrieve PTMs from mouse or rat.
## We check the different PTMs databases
get_enzsub_resources()## [1] "BEL-Large-Corpus_ProtMapper" "DEPOD"
## [3] "HPRD" "HPRD_MIMP"
## [5] "KEA" "Li2012"
## [7] "MIMP" "NCI-PID_ProtMapper"
## [9] "PhosphoNetworks" "PhosphoSite"
## [11] "PhosphoSite_MIMP" "PhosphoSite_ProtMapper"
## [13] "ProtMapper" "REACH_ProtMapper"
## [15] "RLIMS-P_ProtMapper" "Reactome_ProtMapper"
## [17] "SIGNOR" "SIGNOR_ProtMapper"
## [19] "Sparser_ProtMapper" "dbPTM"
## [21] "phosphoELM" "phosphoELM_MIMP"## We query and store the enzyme-PTM interactions into a dataframe.
## No filtering by databases in this case.
enzsub <- import_omnipath_enzsub()
## We can select and print the reactions between a specific kinase and
## a specific substrate
print_interactions(dplyr::filter(
enzsub,
enzyme_genesymbol == "MAP2K1",
substrate_genesymbol == "MAPK3"
))## Warning: Unknown or uninitialised column: `is_stimulation`.## # A tibble: 6 × 5
## enzyme interaction substrate modification n_resources
## <chr> <chr> <chr> <chr> <int>
## 1 MAP2K1 (Q02750) ====> MAPK3_T202 (P27361) phosphorylation 8
## 2 MAP2K1 (Q02750) ====> MAPK3_Y204 (P27361) phosphorylation 8
## 3 MAP2K1 (Q02750) ====> MAPK3_Y210 (P27361) phosphorylation 2
## 4 MAP2K1 (Q02750) ====> MAPK3_T207 (P27361) phosphorylation 2
## 5 MAP2K1 (Q02750) ====> MAPK3_T80 (P27361) phosphorylation 1
## 6 MAP2K1 (Q02750) ====> MAPK3_Y222 (P27361) phosphorylation 1## In the previous results, we can see that enzyme-PTM relationships do not
## contain sign (activation/inhibition). We can generate this information
## based on the protein-protein OmniPath interaction dataset.
interactions <- import_omnipath_interactions()
enzsub <- get_signed_ptms(enzsub, interactions)
## We select again the same kinase and substrate. Now we have information
## about inhibition or activation when we print the enzyme-PTM relationships
print_interactions(dplyr::filter(enzsub,enzyme_genesymbol=="MAP2K1",
substrate_genesymbol=="MAPK3"))## enzyme interaction substrate modification n_resources
## 5 MAP2K1 (Q02750) ==( + )==> MAPK3_T202 (P27361) phosphorylation 8
## 1 MAP2K1 (Q02750) ==( + )==> MAPK3_Y204 (P27361) phosphorylation 8
## 2 MAP2K1 (Q02750) ==( + )==> MAPK3_T207 (P27361) phosphorylation 2
## 3 MAP2K1 (Q02750) ==( + )==> MAPK3_Y210 (P27361) phosphorylation 2
## 4 MAP2K1 (Q02750) ==( + )==> MAPK3_Y222 (P27361) phosphorylation 1
## 6 MAP2K1 (Q02750) ==( + )==> MAPK3_T80 (P27361) phosphorylation 1## We can also transform the enzyme-PTM relationships into a graph.
enzsub_g <- enzsub_graph(enzsub = enzsub)
## We download PTMs for mouse
enzsub <- import_omnipath_enzsub(
resources = c("PhosphoSite", "SIGNOR"),
organism = 10090
)Some studies indicate that around 80% of the human proteins operate in complexes, and many proteins belong to several different complexes (Berggård, Linse, and James 2007). These complexes play critical roles in a large variety of biological processes. Some well-known examples are the proteasome and the ribosome. Thus, the description of the full set of protein complexes functioning in cells is essential to improve our understanding of biological processes.
The complexes query provides access to more than 20000 protein complexes. This comprehensive database has been created by integrating different resources. We now download these molecular complexes filtering by some of the source databases. We check the complexes where a couple of specific genes participate. First, we look for the complexes where any of these two genes participate. We then identify the complex where these two genes are jointly involved. Finally, we perform an enrichment analysis with the genes taking part in that complex. You should keep an eye on this complex since it will be used again in the forthcoming sections.
## We check the different complexes databases
get_complex_resources()## [1] "CFinder" "CORUM" "CellChatDB" "CellPhoneDB"
## [5] "Compleat" "ComplexPortal" "Guide2Pharma" "HPMR"
## [9] "Havugimana2012" "ICELLNET" "KEGG-MEDICUS" "NetworkBlast"
## [13] "PDB" "SIGNOR" "Signor" "hu.MAP"
## [17] "hu.MAP2"## We query and store complexes from some sources into a dataframe.
complexes <- import_omnipath_complexes(resources=c("CORUM", "hu.MAP"))
## We check all the molecular complexes where a set of genes participate
query_genes <- c("WRN","PARP1")
## Complexes where any of the input genes participate
complexes_query_genes_any <- unique(get_complex_genes(complexes,query_genes,
total_match=FALSE))
## We print the components of the different selected components
head(complexes_query_genes_any$components_genesymbols,6)## [1] "NCAPD2_NCAPG_NCAPH_PARP1_SMC2_SMC4_XRCC1"
## [2] "CCNA2_CDK2_LIG1_PARP1_POLA1_POLD1_POLE_RFC1_RFC2_RPA1_RPA2_RPA3_TOP1"
## [3] "CCNA2_CCNB1_CDK1_PARP1_POLA1_POLD1_POLE_RFC1_RFC2_RPA1_RPA2_RPA3_TOP1"
## [4] "MRE11_PARP1_RAD50_TERF2_TERF2IP_XRCC5_XRCC6"
## [5] "TERF2_WRN"
## [6] "CALR_DHX30_H2AFX_HIST3H2BB_HSPA5_NPM1_PARP1"## Complexes where all the input genes participate jointly
complexes_query_genes_join <- unique(get_complex_genes(complexes,query_genes,
total_match=TRUE))
## We print the components of the different selected components
complexes_query_genes_join$components_genesymbols## [1] "PARP1_WRN_XRCC5_XRCC6"genes_complex <-
unlist(strsplit(complexes_query_genes_join$components_genesymbols, "_"))
## We can perform an enrichment analyses with the genes in the complex
EnrichmentResults <- gost(genes_complex, significant = TRUE,
user_threshold = 0.001, correction_method = c("fdr"),
sources=c("GO:BP","GO:CC","GO:MF"))
## We show the most significant results
EnrichmentResults$result %>%
dplyr::select(term_id, source, term_name,p_value) %>%
dplyr::top_n(5,-p_value)## term_id source term_name p_value
## 1 GO:0010332 GO:BP response to gamma radiation 4.819842e-08
## 2 GO:0032508 GO:BP DNA duplex unwinding 3.143404e-07
## 3 GO:0032392 GO:BP DNA geometric change 3.143404e-07
## 4 GO:0010212 GO:BP response to ionizing radiation 6.780115e-07
## 5 GO:0000781 GO:CC chromosome, telomeric region 3.221331e-07Biological annotations are statements, usually traceable and curated, about the different features of a biological entity. At the genetic level, annotations describe the biological function, the subcellular situation, the DNA location and many other related properties of a particular gene or its gene products.
The annotations query provides a large variety of data about proteins and complexes. These data come from dozens of databases and each kind of annotation record contains different fields. Because of this, here we have a record_id field which is unique within the records of each database. Each row contains one key value pair and you need to use the record_id to connect the related key-value pairs (see examples below).
Now, we focus in the annotations of the complex studied in the previous section. We first inspect the different available databases in the omnipath webserver. Then, we download the annotations for our complex itself as a biological entity. We find annotations related to the nucleus and transcriptional control, which is in agreement with the enrichment analysis results of its individual components.
## We check the different annotation databases
get_annotation_resources()## [1] "Adhesome" "Almen2009" "Baccin2019"
## [4] "CORUM_Funcat" "CORUM_GO" "CSPA"
## [7] "CSPA_celltype" "CancerGeneCensus" "CancerSEA"
## [10] "CellCellInteractions" "CellChatDB" "CellChatDB_complex"
## [13] "CellPhoneDB" "CellPhoneDB_complex" "CellTalkDB"
## [16] "ComPPI" "DGIdb" "DisGeNet"
## [19] "EMBRACE" "Exocarta" "GO_Intercell"
## [22] "GPCRdb" "Guide2Pharma" "HGNC"
## [25] "HPA_secretome" "HPA_subcellular" "HPA_tissue"
## [28] "HPMR" "HPMR_complex" "HumanCellMap"
## [31] "ICELLNET" "ICELLNET_complex" "IntOGen"
## [34] "Integrins" "KEGG-PC" "Kirouac2010"
## [37] "LOCATE" "LRdb" "MCAM"
## [40] "MSigDB" "Matrisome" "MatrixDB"
## [43] "Membranome" "NetPath" "OPM"
## [46] "Phobius" "Phosphatome" "Ramilowski2015"
## [49] "Ramilowski_location" "SIGNOR" "SignaLink_function"
## [52] "SignaLink_pathway" "Surfaceome" "TCDB"
## [55] "TFcensus" "TopDB" "UniProt_family"
## [58] "UniProt_keyword" "UniProt_location" "UniProt_tissue"
## [61] "UniProt_topology" "Vesiclepedia" "Zhong2015"
## [64] "connectomeDB2020" "iTALK" "kinase.com"
## [67] "talklr"## We can further investigate the features of the complex selected
## in the previous section.
## We first get the annotations of the complex itself:
annotations <- import_omnipath_annotations(proteins=paste0("COMPLEX:",
complexes_query_genes_join$components_genesymbols))
head(dplyr::select(annotations,source,label,value),10)## # A tibble: 10 × 3
## source label value
## <chr> <chr> <chr>
## 1 LOCATE location nucleus
## 2 LOCATE location nucleolus
## 3 UniProt_location location Nucleus
## 4 CancerSEA state DNA repair
## 5 MSigDB collection reactome_pathways
## 6 MSigDB geneset REACTOME_DNA_REPAIR
## 7 MSigDB collection chemical_and_genetic_perturbations
## 8 MSigDB geneset PUJANA_CHEK2_PCC_NETWORK
## 9 MSigDB collection chemical_and_genetic_perturbations
## 10 MSigDB geneset KAUFFMANN_DNA_REPAIR_GENESAfterwards, we explore the annotations of the individual components of the complex in some databases. We check the pathways where these proteins are involved. Once again, we also find many nucleus related annotations when checking their cellular location.
Then, we explore some annotations of its individual components. Pathways where the proteins belong:
annotations <- import_omnipath_annotations(
proteins = genes_complex,
resources = "NetPath"
)
dplyr::select(annotations, genesymbol, value)## # A tibble: 7 × 2
## genesymbol value
## <chr> <chr>
## 1 PARP1 Corticotropin-releasing hormone (CRH)
## 2 PARP1 TNF-related weak inducer of apoptosis (TWEAK)
## 3 PARP1 Oncostatin-M (OSM)
## 4 PARP1 Androgen receptor (AR)
## 5 PARP1 Tumor necrosis factor (TNF) alpha
## 6 XRCC5 Androgen receptor (AR)
## 7 XRCC6 Androgen receptor (AR)Subcellular localization of our proteins:
annotations <-import_omnipath_annotations(
proteins = genes_complex,
resources = "ComPPI"
)Since we have same record_id for some results of our query, we spread these records across columns:
tidyr::spread(annotations, label, value) %>%
dplyr::arrange(desc(score)) %>%
dplyr::top_n(10, score)## # A tibble: 11 × 7
## uniprot genesymbol entity_type source record_id location score
## <chr> <chr> <chr> <chr> <dbl> <chr> <chr>
## 1 P12956 XRCC6 protein ComPPI 2857 nucleus 0.999999976291…
## 2 P09874 PARP1 protein ComPPI 11110 nucleus 0.999999887104
## 3 Q14191 WRN protein ComPPI 16012 nucleus 0.9999996544
## 4 P13010 XRCC5 protein ComPPI 13276 nucleus 0.99999868288
## 5 P13010 XRCC5 protein ComPPI 13275 membrane 0.972
## 6 P12956 XRCC6 protein ComPPI 2860 cytosol 0.958
## 7 P13010 XRCC5 protein ComPPI 13277 cytosol 0.958
## 8 Q14191 WRN protein ComPPI 16011 cytosol 0.94
## 9 P12956 XRCC6 protein ComPPI 2858 membrane 0.860000000000…
## 10 P12956 XRCC6 protein ComPPI 2859 extracellular 0.860000000000…
## 11 P13010 XRCC5 protein ComPPI 13274 extracellular 0.860000000000…The way above, we more or less reconstituted the data as it is in the
original resource. The same can be done much easier by passing the
wide = TRUE parameter to import_omnipath_annotations. In this case,
if the data contains more than one resources, a list of data frames
will be returned.
signaling_pathways <- import_omnipath_annotations(
resources = 'SignaLink_pathway',
wide = TRUE
)Cells perceive cues from their microenvironment and neighboring cells, and respond accordingly to ensure proper activities and coordination between them. The ensemble of these communication process is called inter-cellular signaling (intercell).
Intercell query provides information about the roles of proteins in inter-cellular signaling (e.g. if a protein is a ligand, a receptor, an extracellular matrix (ECM) component, etc.) This query type is very similar to annotations. However, intercell data does not come from original sources, but combined from several databases by us into categories (we also refer to the original sources).
We first inspect the different categories available in the OmniPath webserver. Then, we focus again in our previously selected complex and we check its the location of its individual components in the inter-cellular context. We can however see that the components of this particular complex are intracellular.
## We check some of the different intercell categories
get_intercell_generic_categories()## [1] "transmembrane" "transmembrane_predicted"
## [3] "peripheral" "plasma_membrane"
## [5] "plasma_membrane_transmembrane" "plasma_membrane_regulator"
## [7] "plasma_membrane_peripheral" "secreted"
## [9] "cell_surface" "ecm"
## [11] "ligand" "receptor"
## [13] "secreted_enzyme" "secreted_peptidase"
## [15] "extracellular" "intracellular"
## [17] "receptor_regulator" "secreted_receptor"
## [19] "sparc_ecm_regulator" "ecm_regulator"
## [21] "ligand_regulator" "cell_surface_ligand"
## [23] "cell_adhesion" "matrix_adhesion"
## [25] "adhesion" "matrix_adhesion_regulator"
## [27] "cell_surface_enzyme" "cell_surface_peptidase"
## [29] "secreted_enyzme" "extracellular_peptidase"
## [31] "secreted_peptidase_inhibitor" "transporter"
## [33] "ion_channel" "ion_channel_regulator"
## [35] "gap_junction" "tight_junction"
## [37] "adherens_junction" "desmosome"
## [39] "intracellular_intercellular_related"## We import the intercell data into a dataframe
intercell <- import_omnipath_intercell(scope = 'generic',
aspect = 'locational')
## We check the intercell annotations for the individual components of
## our previous complex. We filter our data to print it in a good format
dplyr::filter(intercell,genesymbol %in% genes_complex) %>%
dplyr::distinct(genesymbol, parent, .keep_all = TRUE) %>%
dplyr::select(category, genesymbol, parent) %>%
dplyr::arrange(genesymbol)## # A tibble: 4 × 3
## category genesymbol parent
## <chr> <chr> <chr>
## 1 intracellular PARP1 intracellular
## 2 intracellular WRN intracellular
## 3 intracellular XRCC5 intracellular
## 4 intracellular XRCC6 intracellularThe import_intercell_network function creates the most complete network,
including many interactions which are false positives in the context of
interacellular communication. It is highly recommended to apply some
quality filtering on this network. The high_confidence parameter performs
a quiet stringent filtering:
icn <- import_intercell_network(high_confidence = TRUE)Using the function filter_intercell_network instead, you have much more
flexibility to adjust the stringency of the filtering to the needs of your
analysis. See the full list of options in the docs of the function.
icn <-
import_intercell_network() %>%
filter_intercell_network(
min_curation_effort = 1,
consensus_percentile = 33
)## We close graphical connections
while (!is.null(dev.list())) dev.off()OmnipathR provides access to the wealth of data stored in the OmniPath webservice http://omnipathdb.org/ from the R enviroment. In addition, it contains some utility functions for visualization, filtering and analysis. The main strength of OmnipathR is the straightforward transformation of the different OmniPath data into commonly used R objects, such as dataframes and graphs. Consequently, it allows an easy integration of the different types of data and a gateway to the vast number of R packages dedicated to the analysis and representaiton of biological data. We highlighted these abilities in some of the examples detailed in previous sections of this document.
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## [5] tidyr_1.1.3 ggraph_2.0.5 igraph_1.2.6 OmnipathR_3.0.4
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## [85] ggforce_0.3.3 tidygraph_1.2.0 later_1.3.0
## [88] viridisLite_0.4.0 tibble_3.1.3 ellipsis_0.3.2Ben-Shlomo, I., S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh. 2003. “Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.” Science Signaling 2003 (187): re9–re9. https://doi.org/10.1126/stke.2003.187.re9.
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