MARADONER: Motif Activity Response Analysis Done Right

Inferring the activities of transcription factors from high-throughput transcriptomic or open chromatin profiling, such as RNA-/CAGE-/ATAC-Seq, is a long-standing challenge in systems biology. Identification of highly active master regulators enables mechanistic interpretation of differential gene expression, chromatin state changes, or perturbation responses across conditions, cell types, and diseases. Here, we describe MARADONER, a statistical framework and its software implementation for motif activity response analysis (MARA), utilizing the sequence-level features obtained with pattern matching (motif scanning) of individual promoters and promoter- or gene-level activity or expression estimates. Compared to the classic MARA, MARADONER (MARA-done-right) employs an unbiased variance parameter estimation and a bias-adjusted likelihood estimation of fixed effects, thereby enhancing goodness-of-fit and the accuracy of activity estimation. Further, MARADONER is capable of accounting for heteroscedasticity of motif scores and activity estimates.