MOtif aNAlysis with Lisa European Bioconductor Meeting 2019 Dania - PowerPoint PPT Presentation

mo monaLi Lisa MOtif aNAlysis with Lisa European Bioconductor Meeting 2019 Dania Machlab Lukas Burger Michael Stadler Friedrich Miescher Institute for Biomedical Research

Background and Motivation Co-binding Chromatin remodeling Use monaLisa to: • Identify Enriched motifs Blocking repositioning • Select motifs explaining observed changes Architectural role Francois Spitz & Eileen E. M. Furlong (2012) Nature Reviews Genetics

Background and Motivation Genome Enhancer Gene A ATAC-seq Condition 1 RNA-seq Condition 1 ATAC-seq Condition 2 RNA-seq Condition 2 Predicted TFBS

Identify Enriched Motifs density of promoters delta methylation enrichment (log2) FDR ( − log10) CTCF CTCFL RARAvar2 Rarbvar2 KLF4 Percent G+C 100 Klf1 80 Klf12 60 40 E2F7 20 BHLHE41 0 log2 enrichment KLF13 2 ZEB1 1 0 ERG − 1 ETS1 − 2 FDR ETV5 10 ELK3 8 6 ETV1 4 ETV4 2 0 FEV FLI1 ERF ETV3 ID4 KLF14 SP4 enrichment (log2) FDR (-log10)

Select Motifs using Stability Selection Randomized lasso stability selection weakness Lasso Randomized Lasso Lasso with parameter Stability Selection Stability Selection Cross Validation observed logFC predicted TFBS regularization parameter Y X perform ~ regularized regression large 𝜇 s mall 𝜇 true signal noise Meinshausen & Bühlmann (2010) Journal of the Royal Statistical Society

Select Motifs Explaining Observed Changes in Accessibility NFATC1 TEAD2 TEAD3 NKX2 − 8 Nkx2 − 5(var.2) NFIC Pear. Cor. KLF5 1 0.5 0 GATA3 − 0.5 − 1 Gata1 GATA1::TAL1 HNF1A Nr2f6 Hnf4a NFATC1 TEAD2 TEAD3 NKX2 − 8 Nkx2 − 5(var.2) NFIC KLF5 GATA3 Gata1 GATA1::TAL1 HNF1A Nr2f6 Hnf4a selection probability 0.0 0.2 0.4 0.6 0.8 1.0 glmnet::glmnet and stabs::stabsel used

Summary and Outlook • We can identify TFs enriched in regions of interest that display certain log-fold changes • We can select TFs that are likely to explain the observed log-fold changes using stability selection • We can be use any fold-change defined on regions of interest (ATAC-seq, methylation, expression, ChIP-seq …) to select motifs explaining the observed logFC • We want to look at motif enrichment without using existing databases (unbiased view) • Enriched k-mers, grouping them, aligning them to predict the motif • Submit to Bioconductor • https://github.com/fmicompbio/monaLisa