Poster Sessions

BIOINFO-21

Valer Gotea

V. Gotea, A. Visel, L.A. Pennacchio, I. Ovcharenko

Homotypic Clusters of Transcription Factor Binding Sites Are a Key Component of Human Promoters and Enhancers

Cis-regulatory modules (CRMs) consist of multiple transcription factor binding sites (TFBSs). Homotypic clusters of TFBSs (HCTs), in which multiple binding sites for the same transcription factor (TF) co-occur, has been found to be associated with CRMs in invertebrates, but their presence and function has remained largely unknown in mammals. We used binding motifs for a set of 273 TFs to map the HCT locations in the human genome, where we found them spanning nearly 2% of its sequence, and with their constituent TFBSs subject to functional constraint. We also found that HCTs map to experimentally defined binding location of corresponding TFs, are enriched in promoters (4-fold enrichment, P<2e-16), and in regions bound by the enhancer-associated p300 protein (3.3-fold enrichment, P<2e-100). Additionally, nearly half of 487 experimentally verified enhancers (25-fold enrichment, P<8e-102) contain HCTs. We validated the enhancer activity of two predicted HCTs in transgenic mouse assays. In summary, this is the first study to describe the abundance of HCTs in the human genome and their important contribution to proximal and distant regulatory elements.