Positional specificity of different transcription factor classes within enhancers

Significance

Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. The degree to which the arrangement of motif sites within regulatory elements determines their function remains unclear. Here, we show that the positional distribution of TF motif sites within nucleosome-depleted regions of DNA fall into six distinct classes. These patterns are highly consistent across cell types and bring together factors that have similar functional and binding properties. Furthermore, the position of motif sites appears to be related to their known functions. Our results suggest that TFs play distinct roles in forming a functional enhancer, facilitated by their position within a regulatory sequence.

Abstract

Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. TF binding occurs in nucleosome-depleted regions of DNA (NDRs), which generally encompass regions with lengths similar to those protected by nucleosomes. However, less is known about where within these regions specific TFs tend to be found. Here, we characterize the positional bias of inferred binding sites for 103 TFs within ∼500,000 NDRs across 47 cell types. We find that distinct classes of TFs display different binding preferences: Some tend to have binding sites toward the edges, some toward the center, and some at other positions within the NDR. These patterns are highly consistent across cell types, suggesting that they may reflect TF-specific intrinsic structural or functional characteristics. In particular, TF classes with binding sites at NDR edges are enriched for those known to interact with histones and chromatin remodelers, whereas TFs with central enrichment interact with other TFs and cofactors such as p300. Our results suggest distinct regiospecific binding patterns and functions of TF classes within enhancers.