Genome-wide map of regulatory interactions in the human genome

Abstract

Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional chromatin structure and revealed how the distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type-specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions, while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus.

The second decade of 3C technologies: detailed insights into nuclear organization

“…How these loops relate to promoter-promoter contacts and enhancer hubs that have been observed by ChIA-PET studies against RNA polymerase II (Pol II) or enhancer-associated p300 Kuznetsova et al 2015) remains to be determined. Using a modified ChIA-PET protocol optimized for long reads and monitoring both CTCF and Pol II interaction networks, "CTCF/ cohesin foci" were described that also accumulate the transcriptional machinery (Heidari et al 2014;Tang et al 2015). In agreement, Hi-C also demonstrated that not only architectural loops but also gene-centered regulatory chromatin loops involve CTCF (Rao et al 2014).…”

The ubiquitous transcription factor CTCF promotes lineage-specific epigenomic remodeling and establishment of transcriptional networks driving cell differentiation

“…This is accomplished through specification of unique transcriptomes, a process that heavily relies on usage of cell type-specific enhancers. 1,2 Enhancer activation can be achieved through sequential TF recruitment to the chromatin following initial binding of pioneer TFs or involve a concomitant and cooperative binding of multiple TFs. [3][4][5] Cooperative binding may involve assisted loading where TF binding to close or overlapping motifs may facilitate each other's binding because of the very dynamic nature of TF-chromatin interactions.…”

Quantitative biology: from genes, cells to networks

“…In the first talk of this section, Dr. Michael Q. Zhang discussed the role of chromatin interactions and epigenetic regulations in mammalian development and differentiation by reviewing what we learnt through ENCODE and Epigenome Roadman projects [18]. Dr. Zhang also presented their recent progress in epigenomic analysis of multi-lineage differentiation of human embryonic stem cells, as well as in building a global chromatin map of regulatory interactions in the human genome.…”