NLM IRP Seminar Schedule

Abstract:

Enhancers and promoters are classically considered to be bound by a small set of TFs in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract dozens and hundreds of TFs with seemingly no detectable correlation between TF ChIP-seq peaks and the presence of the DNA-binding motifs. In this study, we used a set of 1,003 TF ChIP-seq datasets in HepG2, K562, and H1 cells to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We established that the HOT loci form at the promoter and enhancer regions, and the density of mapped TF ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. HOT loci evolve under the extremes of strong negative sequence conservation and are 50 times more conserved than the coding DNA. They form the foundation of human super-enhancers. Sequence-based accurate classification of HOT loci using deep learning suggested that their formation is driven by the sequence features. We observed that HOT loci are enriched in 3D chromatin hubs and disease-causal variants. We report an abundance of HOT loci in the human genome thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.