Comprehensive assessment of differential ChIP-seq tools guides optimal algorithm selection

BACKGROUND: The analysis of chromatin binding patterns of proteins in different biological states is a main application of chromatin immunoprecipitation followed by sequencing (ChIP-seq). A large number of algorithms and computational tools for quantitative comparison of ChIP-seq datasets exist, but their performance is strongly dependent on the parameters of the biological system under investigation. Thus, a systematic assessment of available computational tools for differential ChIP-seq analysis is required to guide the optimal selection of analysis tools based on the present biological scenario. RESULTS: We created standardized reference datasets by in silico simulation and sub-sampling of genuine ChIP-seq data to represent different biological scenarios and binding profiles. Using these data, we evaluated the performance of 33 computational tools and approaches for differential ChIP-seq analysis. Tool performance was strongly dependent on peak size and shape as well as on the scenario of biological regulation. CONCLUSIONS: Our analysis provides unbiased guidelines for the optimized choice of software tools in differential ChIP-seq analysis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02686-y.