In the loop: promoter–enhancer interactions and bioinformatics

Abstract

Enhancer–promoter regulation is a fundamental mechanism underlying differential transcriptional regulation. Spatial chromatin organization brings remote enhancers in contact with target promoters in cis to regulate gene expression. There is considerable evidence for promoter–enhancer interactions (PEIs). In the recent years, genome-wide analyses have identified signatures and mapped novel enhancers; however, being able to precisely identify their target gene(s) requires massive biological and bioinformatics efforts. In this review, we give a short overview of the chromatin landscape and transcriptional regulation. We discuss some key concepts and problems related to chromatin interaction detection technologies, and emerging knowledge from genome-wide chromatin interaction data sets. Then, we critically review different types of bioinformatics analysis methods and tools related to representation and visualization of PEI data, raw data processing and PEI prediction. Lastly, we provide specific examples of how PEIs have been used to elucidate a functional role of non-coding single-nucleotide polymorphisms. The topic is at the forefront of epigenetic research, and by highlighting some future bioinformatics challenges in the field, this review provides a comprehensive background for future PEI studies.

Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region

“…The observed reduction in CTCF occupancy at 11.2516 (Figure C), accompanied by loss of the 11.2516 interactions with the promoters as shown by 4C‐seq (Figure D), upon deletion of intron 6 is supportive of this role. These data are consistent with the reported mechanisms of looping of enhancers to target promoters at other loci . In summary, the removal of key CREs from chr11p13 did not add clarity to our understanding of its functional genomics.…”

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

“…They increase its affinity to RNAP II, thereby promoting transcriptional initiation/elongation . Such interactions result in the formation of chromatin loops, (for review, see References 9 and 21‐24) which makes enhancers located remote from their target genes along the linear DNA a particularly challenging target for topographical analyses in the context of the 3D and 4D (space and time) organization in the nucleus.…”

iRegNet3D: three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations

“…Since increasing evidence has emerged for distal enhancers coming into close proximity with promoters via a looping mechanism [50–53] and their interaction is fundamental to the control of transcriptional activity [54], we sought to explore how chromatin interactions might be related to the phenotypic impact of non-coding mutations using iRegNet3D. We classified each pair of non-coding mutations as ‘in the same anchor’ ( n  = 3480), ‘across interacting regions’ ( n  = 166), ‘across non-interacting regions of the same chromosome’ ( n  = 3164) or ‘on different chromosomes’ ( n  = 1,128,161) using published 3D chromatin interactome data [26].…”