NLM DIR Seminar Schedule

Abstract:

Millions of enhancers have been predicted in the human and mouse genomes based on enhancer-like signatures or massively parallel report assays (MPRAs). The number of experimentally validated in vivo enhancer-promoter pairs is, however, only in the dozens. How exactly tens of thousands of enhancers and active promoters in a cell organize into transcription regulatory loops remains unclear.
Using TF enrichment as an indicator of enhancer strength, we identified a portion of H3K27ac peaks as potentially strong enhancers and found a universal pattern of promoter and enhancer distribution that would not show if all the H3K27ac peaks are counted as enhancers: At actively transcribed regions of length of ~200-300kb, the numbers of active promoters and enhancers are inversely related. Super enhancers or enhancer clusters are associated with isolated active promoters, regardless of the gene’s cell-type specificity. As the number of nearby active promoters increases, the number of enhancers decreases. At regions where multiple active genes are closely located, there are few distant enhancers. With Hi-C analysis, we demonstrate that the interactions among the regulatory elements occur predominantly in clusters and multiway among linearly close elements . We propose a simple model of spatial organization of active promoters and enhancers: Gene transcriptions and regulations mainly occur at local active transcription hubs contributed dynamically by multiple elements from linearly close enhancers and/or active promoters. The model can be represented with a flower-shaped structure. Furthermore, local transcription hubs from distant parts of a chromosome can get into contact and form larger hubs, reflected as nodes in hierarchical TAD structures in Hi-C contact maps.