A high-resolution map of the three-dimensional chromatin interactome in human cells

Abstract

A large number of cis-regulatory sequences have been annotated in the human genome1,2, but defining their target genes remains a challenge3. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C) based techniques4. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here, we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C)5. We determined over one million long-range chromatin interactions at 5–10kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter-enhancer contacts upon TNF-α signaling in these cells. Unexpectedly, we found that TNF-α responsive enhancers are already in contact with their target promoters prior to signaling. Such pre-existing chromatin looping, which also exists in other cell types with different extra-cellular signaling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is rather stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.

Long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region upregulating the allele-specific MYC expression in HeLa cells

“…6). In supporting our notion, several studies have showed that distal regulatory elements can interact with not only their target genes but also other elements, and the formation of intricate three‐dimensional patterns involves genes and their regulatory elements hundreds of kb distant from each other in linear relationship 24, 25, 26…”

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).…”

“…These assays directly identify genomic loci that are in sufficiently close proximity in living cells to be cross‐linked 117. Several versions of 3C such as 4Cseq, ChIA‐PET,112 5C111 HiChIP118 and Hi‐C113 allow for mapping of chromatin interactions on a whole genome level. Recently, to improve the resolution and sensitivity of Hi‐C assays, in situ protocols have been developed.…”

EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types

“…For example, the combination of H3K4me1 and H3K27ac is a widely used mark for enhancers (Cotney et al, 2012;Heintzman et al, 2009); (vii) The DNA sequences of enhancers could also be transcribed and these transcribed enhancer RNAs (eRNAs) are an indicator of active enhancers (Andersson et al, 2014); (viii) Approaches to determine the threedimensional conformation of chromosomes (e.g. 5C and ChIA-PET, Capture-C) are able to provide enhancer-promoter interactions (Fullwood et al, 2009;Jin et al, 2013).…”