Tissue specific analysis of chromatin state reveals predictive signatures of enhancer activity during embryonic development. BiTS-ChIP

Chromatin modifications are associated with many aspects of gene expression, yet their role in cell type specific changes during embryonic development remains elusive. Here we present a new in vivo method to assess chromatin modifications, Polymerase and transcription factor occupancy in a cell type specific manner in a multicellular context. BiTS-ChIP is based on FACS sorting covalently cross-linked nuclei, which preserves nuclear context, yielding cell type specific chromatin with high specificity and sensitivity. Applying BiTS-ChIP, we directly assessed the relationship between chromatin marks on developmental enhancers and their temporal and spatial activity during Drosophila mesoderm development. Our results revealed multiple chromatin states that are linked to enhancers in an active and inactive state. Using a Bayesian Network, we demonstrate that combined chromatin signatures are sufficient to predict spatio-temporal enhancer activity de novo. The model revealed that RNA Polymerase is highly predictive for the precise timing of enhancer activity, and is recruited in the vicinity of transcription factor binding. This study provides a powerful method to obtain cell-type specific insights into transcriptional regulation and is broadly applicable to other organisms.