The long-range interaction landscape of gene promoters

By Amartya Sanyal, B. Lajoie, Gaurav Jain, Job Dekker. Nature, 2012

1,488 citations recorded by the source corpus.

The vast non-coding portion of the human genome is full of functional elements and disease-causing regulatory variants. The principles defining the relationships between these elements and distal target genes remain unknown. Promoters and distal elements can engage in looping interactions that have been implicated in gene regulation. Here we have applied chromosome conformation capture carbon copy (5C) to interrogate comprehensively interactions between transcription start sites (TSSs) and distal elements in 1% of the human genome representing the ENCODE pilot project regions. 5C maps were generated for GM12878, K562 and HeLa-S3 cells and results were integrated with data from the ENCODE consortium. In each cell line we discovered >1,000 long-range interactions between promoters and distal sites that include elements resembling enhancers, promoters and CTCF-bound sites. We observed significant correlations between gene expression, promoter–enhancer interactions and the presence of enhancer RNAs. Long-range interactions show marked asymmetry with a bias for interactions with elements located ∼120 kilobases upstream of the TSS. Long-range interactions are often not blocked by sites bound by CTCF and cohesin, indicating that many of these sites do not demarcate physically insulated gene domains. Furthermore, only ∼7% of looping interactions are with the nearest gene, indicating that genomic proximity is not a simple predictor for long-range interactions. Finally, promoters and distal elements are engaged in multiple long-range interactions to form complex networks. Our results start to place genes and regulatory elements in three-dimensional context, revealing their functional relationships.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f1846682fef3edbc9192fdd3a3dc0fe4b1c3c2ba

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Citations in the corpus

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes (2013, positive): “Most of these interactions occur within a distance of 50 kb of the enhancer, although many can occur at greater distances up to several megabases (Sanyal et al., 2012).”
New developments on the Encyclopedia of DNA Elements (ENCODE) data portal (2019, methodology): “The EN-CODE consortium has generated data from a set of Hi-C, ChIA-PET and 5C experiments that characterize the three-dimensional chromatin organization in different cells and tissues (5,25–29).”
Activation of proto-oncogenes by disruption of chromosome neighborhoods (2015, methodology): “5C was performed as described (55) with the following changes.”
Beyond GWASs: illuminating the dark road from association to function. (2013, background): “5, indicating that genetic variants located in cis-regulatory elements might influence transactivation of multiple promoters and therefore directly affect the expression of more than one gene.(68) Indeed, our unpublished data indicate that the variants responsible for the association at the 11q13 br”
CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data (2015, methodology): “We also found that promoter-interacting fragments were strongly enriched for CTCF binding sites, as previously reported [9, 21].”
Transcriptional enhancers: from properties to genome-wide predictions (2014, background): “Indeed, 3C-based methods predict frequent contacts both between many regions on single chromosomes and across chromosomes 107,109,112 .”
Mapping nucleosome resolution chromosome folding in yeast by Micro-C (2015, neutral): “, 2004), enhancer-promoter loops (Sanyal et al., 2012), ‘‘topologically associating domains’’/‘‘chromosomally interacting domains’’ (TADs/CIDs) (Dixon et al.”
A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. (2014, background): “…18 kbCTSPhysically Interact A hallmark of distal enhancer elements is their engagement in chromatin loops physically contacting with promoters to induce transcription factor assembly and polymerase II recruitment (Deng et al., 2012; Sanyal et al., 2012; Thurman et al., 2012; Tolhuis et al., 2002).”