Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation

Abstract

Summary Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intra-genic, extra-genic and inter-genic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated non-coding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into the transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells.

Mapping enhancer and promoter interactions

“…Of these interactions, 2 373 involved enhancer-promoter interactions. Interestingly, a substantial number of the detected interactions, 3 669, were distal promoter-promoter interactions, a finding consistent with results using RNA Polymerase II to detect interactions [11]. The remaining 478 interactions were reported to be enhancer-enhancer interactions.…”

“…As enhancers can be highly cell type specific [2,3], having interaction maps in additional cell types and conditions will be a valuable resource. Such interaction maps would likely yield insights into the dynamics of gene regulation and into the mechanisms by which individual distal regulatory variants act to confer disease risk [11]. Genomics has been largely centered on a one-dimensional representation of the genome, but this work by Chepelev et al [12] and recent work by others represent important steps towards mapping and understanding the higher dimensional nature of the genome.…”

“…One study used RNA Polymerase II [11] and the study by Chepelev et al [12], published in Cell Research used histones with the H3K4me2 modification. H3K4me2 was strategically selected as the histone modification because of its general association with both promoter and enhancer regions [13].…”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…It has been suggested that the ratio between H3K4me3 and H3K4me1 indicates the tendency of the region to act as either a promoter or an enhancer (74). To classify the differential regions as enhancers or promoters, we used a published dataset, which includes both H3K4me3 and H3K4me1 ChIP-seq data of mouse embryonic stem cells (75).…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…Hence, DNA looping facilitates gene network formation as a single enhancer may interact with more than one promoter, and a single promoter may be contacted by more than one enhancer. Many of these interactions occur in a tissue‐specific manner and appear to be the major determinants of cell type‐specific responses 111, 113, 114, 115. Critically, many enhancers do not interact with the nearest active gene but contact gene promoters many hundreds to thousands of kilobases away through long‐range DNA looping (modelled for T cells in Figure 8).…”