Sequence and chromatin determinants of transcription factor binding and the establishment of cell type-specific binding patterns

Transcription factors (TFs) selectively bind distinct sets of sites in different cell types. Such cell type-specific binding specificity is expected to result from interplay between the TF's intrinsic sequence preferences, cooperative interactions with other regulatory proteins, and cell type-specific chromatin landscapes. Cell type-specific TF binding events are highly correlated with patterns of chromatin accessibility and active histone modifications in the same cell type. However, since concurrent chromatin may itself be a consequence of TF binding, chromatin landscapes measured prior to TF activation provide more useful insights into how cell type-specific TF binding events became established in the first place. Here, we review the various sequence and chromatin determinants of cell type-specific TF binding specificity. We identify the current challenges and opportunities associated with computational approaches to characterizing, imputing, and predicting cell type-specific TF binding patterns. We further focus on studies that characterize TF binding in dynamic regulatory settings, and we discuss how these studies are leading to a more complex and nuanced understanding of dynamic protein-DNA binding activities. We propose that TF binding activities at individual sites can be viewed along a two-dimensional continuum of local sequence and chromatin context. Under this view, cell type-specific TF binding activities may result from either strongly favorable sequence features or strongly favorable chromatin context. •TF-DNA binding is determined by intrinsic sequence preferences and cell-specific chromatin interactions.•Cell type-specific TF-DNA binding patterns can be imputed using chromatin features from the same cell type.•It’s more challenging to predict how a TF will interact with the preexisting chromatin if introduced into a new cell type.· TF binding at individual sites can be viewed along a two-dimensional continuum of local sequence and chromatin context.