In sigven/oncoEnrichR: Cancer-dedicated gene set interpretation

Regulatory interactions

Using data from the OmniPath/DoRothEA gene set resource, we are here interrogating previously established transcription factor (TF) - target interactions for members of the query set. TF-target interactions in DoRothEA have been established according to different lines of evidence, i.e. i) literature-curated resources ii) ChIP-seq peaks iii) TF binding site motifs iv) gene expression-inferred interactions.
In DoRothEA, each interaction is assigned a confidence level based on the amount of supporting evidence, ranging from A (highest confidence) to D (lowest confidence):
A - Supported by all four lines of evidence, manually curated by experts in specific reviews, or supported both in at least two curated resources are considered to be highly reliable
B-D - Curated and/or ChIP-seq interactions with different levels of additional evidence
E - Used for interactions that are uniquely supported by computational predictions (not included in oncoEnrichR)
Here, we show regulatory interactions related to the queryset along three different axes:

i) interactions for which both regulatory gene and regulatory target are found in the queryset ii) interactions for which only the regulatory gene is found in the queryset iii) interactions for which only the regulatory target is found in the queryset - Interactions are ranked according to confidence, visualized in varying shades of blue (from low-confident interactions to high-confident interactions ).

We interrogate interactions in the query set for two separate collections of regulatory interactions in DoRothEA:

regulatory interactions inferred with gene expression from GTex (global set),
regulatory interactions inferred with gene expression from TCGA (cancer-focused set)

reg_interactions <- list()
active_tab <- list()
for(cl in c('global','pancancer')){
  reg_interactions[[cl]] <- list()
  active_tab[[cl]] <- list()

  reg_interactions[[cl]][['tf_target']] <- data.frame()
  reg_interactions[[cl]][['tf_only']] <- data.frame()
  reg_interactions[[cl]][['target_only']] <- data.frame()

  active_tab[[cl]][['tf_target']] <- F
  active_tab[[cl]][['tf_only']] <- F
  active_tab[[cl]][['target_only']] <- F

  if(NROW(onc_enrich_report[['data']][['regulatory']][['interactions']][[cl]]) > 0){
    reg_interactions[[cl]][['tf_target']] <- 
      onc_enrich_report[['data']][['regulatory']][['interactions']][[cl]] |>
      dplyr::filter(stringr::str_detect(queryset_overlap,"TF_TARGET_")) |>
      dplyr::select(-c(regulator_cancer_max_rank,
                       target_cancer_max_rank)) |>
      head(2500)

    if(NROW(reg_interactions[[cl]][['tf_target']]) > 0){
      active_tab[[cl]][['tf_target']] <- T
    }

    reg_interactions[[cl]][['tf_only']] <- 
      onc_enrich_report[['data']][['regulatory']][['interactions']][[cl]] |>
      dplyr::filter(stringr::str_detect(queryset_overlap,"^(TF_(A|B|C|D))$")) |>
      dplyr::select(-c(regulator_cancer_max_rank,
                       target_cancer_max_rank)) |>
      head(2500)

    if(NROW(reg_interactions[[cl]][['tf_only']]) > 0 & 
       active_tab[[cl]][['tf_target']] == F){
      active_tab[[cl]][['tf_only']] <- T
    }

    reg_interactions[[cl]][['target_only']] <- 
      onc_enrich_report[['data']][['regulatory']][['interactions']][[cl]] |>
      dplyr::filter(stringr::str_detect(queryset_overlap,"^(TARGET_(A|B|C|D))$")) |>
      dplyr::select(-c(regulator_cancer_max_rank,
                       target_cancer_max_rank)) |>
      head(2500)

    if(NROW(reg_interactions[[cl]][['target_only']]) > 0 & 
       active_tab[[cl]][['tf_target']] == F &
       active_tab[[cl]][['tf_only']] == F){
      active_tab[[cl]][['target_only']] <- T
    }
  }
}

for(cl in c('global','pancancer')){
  if(active_tab[[cl]][['tf_target']] == F & 
     active_tab[[cl]][['tf_only']] == F & 
     active_tab[[cl]][['target_only']] == F){
    active_tab[[cl]][['tf_target']] <- T
  }
}

DoRothEA - global set {.tabset}

if(active_tab[['global']][['tf_target']] == T){
  cat("")
  cat("##### Regulatory gene and target {.active}")
  cat("")
}else{
  cat("")
  cat("##### Regulatory gene and target")
  cat("")
}

tf_target_sd <- 
  crosstalk::SharedData$new(reg_interactions[['global']][['tf_target']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", tf_target_sd, ~regulator)
  ),
  list(
    crosstalk::filter_select("target_gene", "Target", tf_target_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", tf_target_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  tf_target_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  ) |>
  DT::formatStyle(
    'regulator', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["tf_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["tf_colors"]]
    )
  ) |>
  DT::formatStyle(
    'target', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["target_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["target_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - global set) for which <b>BOTH</b> the regulatory gene and the target are part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

if(active_tab[['global']][['tf_only']] == T){
  cat("")
  cat("##### Regulatory gene only {.active}")
  cat("")
}else{
  cat("")
  cat("##### Regulatory gene only")
  cat("")
}

tf_only_sd <- 
  crosstalk::SharedData$new(reg_interactions[['global']][['tf_only']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", tf_only_sd, ~regulator)
  ),
  list(
    crosstalk::filter_select("target_gene", "Target", tf_only_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", tf_only_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  tf_only_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  ) |>
  DT::formatStyle(
    'regulator', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["tf_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["tf_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - global set) for which <b>ONLY</b> the regulatory gene is part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

if(active_tab[['global']][['target_only']] == T){
  cat("")
  cat("##### Target only {.active}")
  cat("")
}else{
  cat("")
  cat("##### Target only")
  cat("")
}

target_only_sd <- 
  crosstalk::SharedData$new(reg_interactions[['global']][['target_only']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", target_only_sd, ~regulator)
  ),
  list(
    crosstalk::filter_select("target_gene", "Target", target_only_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", target_only_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  target_only_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  )  |>
  DT::formatStyle(
    'target', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["target_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["target_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - global set) for which <b>ONLY</b> the regulatory target is part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

DoRothEA - cancer-focused set {.tabset}

if(active_tab[['pancancer']][['tf_target']] == T){
  cat("")
  cat("##### Regulatory gene and target {.active}")
  cat("")
}else{
  cat("")
  cat("##### Regulatory gene and target")
  cat("")
}

tf_target_pancancer_sd <- 
  crosstalk::SharedData$new(reg_interactions[['pancancer']][['tf_target']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", tf_target_pancancer_sd, ~regulator),
    crosstalk::filter_select("mode_of_regulation", "Mode of regulation", tf_target_pancancer_sd, ~mode_of_regulation)

  ),
  list(
    crosstalk::filter_select("target_gene", "Target", tf_target_pancancer_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", tf_target_pancancer_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  tf_target_pancancer_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  ) |>
  DT::formatStyle(
    'regulator', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["tf_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["tf_colors"]]
    )
  ) |>
  DT::formatStyle(
    'target', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["target_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["target_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - cancer-focused set) for which <b>BOTH</b> the regulatory gene and the target are part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

if(active_tab[['pancancer']][['tf_only']] == T){
  cat("")
  cat("##### Regulatory gene only {.active}")
  cat("")
}else{
  cat("")
  cat("##### Regulatory gene only")
  cat("")
}

tf_only_pancancer_sd <- 
  crosstalk::SharedData$new(reg_interactions[['pancancer']][['tf_only']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", tf_only_pancancer_sd, ~regulator),
    crosstalk::filter_select("mode_of_regulation", "Mode of regulation", tf_only_pancancer_sd, ~mode_of_regulation)
  ),
  list(
    crosstalk::filter_select("target_gene", "Target", tf_only_pancancer_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", tf_only_pancancer_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  tf_only_pancancer_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  ) |>
  DT::formatStyle(
    'regulator', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["tf_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["tf_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - cancer- focused set) for which <b>ONLY</b> the regulatory gene is part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

if(active_tab[['pancancer']][['target_only']] == T){
  cat("")
  cat("##### Target only {.active}")
  cat("")
}else{
  cat("")
  cat("##### Target only")
  cat("")
}

target_only_pancancer_sd <- 
  crosstalk::SharedData$new(reg_interactions[['pancancer']][['target_only']])

crosstalk::bscols(
  list(
    crosstalk::filter_select("transcription_regulator", "Regulator", target_only_pancancer_sd, ~regulator),
        crosstalk::filter_select("mode_of_regulation", "Mode of regulation", target_only_pancancer_sd, ~mode_of_regulation)

  ),
  list(
    crosstalk::filter_select("target_gene", "Target", target_only_pancancer_sd, ~target),
    crosstalk::filter_select("confidence_level", "Confidence level (interaction)", target_only_pancancer_sd, ~confidence_level)
  )
)

htmltools::br()

DT::datatable(
  target_only_pancancer_sd, 
  escape = F, 
  extensions=c("Buttons","Responsive"), 
  width = "100%",
  style = 'bootstrap',
  rownames = F,
  options=list(buttons = c('csv','excel'),
               pageLength = 10,
               bPaginate = T,
               dom = 'Bfrtip')
  )  |>
  DT::formatStyle(
    'target', 
    'queryset_overlap',
    color = "white",
    backgroundColor = DT::styleEqual(
      onc_enrich_report[["config"]][["regulatory"]][["target_levels"]],
      onc_enrich_report[["config"]][["regulatory"]][["target_colors"]]
    )
  )

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> genes in the queryset are involved in regulatory interactions (DoRothEA - cancer-focused set) for which <b>ONLY</b> the regulatory target is part of the queryset.&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

Key regulatory network interactions

Visualization of known regulatory interactions (DoRothEA - cancer-focused set) where both regulator and target are found in the query set
Edge length between nodes reflects confidence level of regulatory interaction (shorter lengths - higher confidence)
Edge color between nodes indicates mode of regulation ( Stimulation vs. Repression )

regulatory_nodes <- onc_enrich_report[['data']][['regulatory']][['network']][['nodes']]
regulatory_edges <- onc_enrich_report[['data']][['regulatory']][['network']][['edges']]

visNetwork::visNetwork(regulatory_nodes, regulatory_edges) |> 
  visNetwork::visInteraction(multiselect=TRUE, tooltipDelay=300) |>
  visNetwork::visLegend()
  #visNetwork::visIgraphLayout(layout="layout_nicely")

cat('\n <ul><li>  <i> <span style="font-size: 105%; padding: 3px; background-color:#989898; color:white">&nbsp;&nbsp;<b>NO</b> pair of genes in the queryset are involved in regulatory interactions (<b>as reported in DoRothEA - cancer-focused set</b>)&nbsp;&nbsp; </span></i></li></ul>',sep='\n')
cat('\n')
cat('<br><br>')

{.unlisted .unnumbered .toc-ignore}

Citation Note : If you use the output of the Regulatory interactions module of oncoEnrichR in your research, please cite the following resources and tools: