The regulation of target genes by their transcription factors is complex and incompletely understood. Multiple signals involving core promoters, distal enhancers, epigenetic controls on chromatin accessibility, stochastic and cooperative binding on different times scales are all involved. Predictive modeling of these processes in fine detail and at scale is beyond our current capabilities.

We know, however, that gene regulation usually includes two gross features which, independently, are poor predictors, but which together have predictive power:

1) somewhat correlated gene expression of TF and target gene

2) actual or predicted DNA binding of the TF in regulatory DNA regions associated with the target gene

TReNa combines these two predictors to create (at minimum) “broad brush” or “low-resolution” gene regulatory predictions. inasmuch as TReNa may be used with a wide range of genomic, epigenetic and expression data “high resolution” predictions can be made as well. TReNa thus operates at many points along this continuum:

low-res mode: uses bulk mRNA data, generalized predictions of regulatory regions, computational matching of TF to DNA sequence in those regions

high-res mode: uses single cell RNA-seq, scATAC-seq or DNase regions, timecourse or well-discriminated environmental conditions, 3C, scChIP-seq, other recently emerging binding assays.

The low-resolution mode is useful when gene regulatory relationships are little known, or in which a coarse-grained result is adequate. A prime example of this is in the creation of genome scale regulatory models by aggregating thousands of low-res single-gene models.

The high-resolution mode can predict relationships which can approach mechanistic accuracy, and which justify attempts at laboratory validation.

TReNa is available as a Bioconductor package here.

Complementary to TReNa, igvR is an R package providing interactive connections to igv.js (the Integrative Genomics Viewer) running in a web browser, available here.

Key Project Personnel:

Cory FunkPaul ShannonNathan Price