The first enhancer in an enhancer chain safeguards subsequent enhancer-promoter contacts from a distance

Wei Song,Roded Sharan,Ivan Ovcharenko

doi:10.1186/s13059-019-1808-y

Abstract

BackgroundRobustness and evolutionary stability of gene expression in the human genome are established by an array of redundant enhancers.ResultsUsing Hi-C data in multiple cell lines, we report a comprehensive map of promoters and active enhancers connected by chromatin contacts, spanning 9000 enhancer chains in 4 human cell lines associated with 2600 human genes. We find that the first enhancer in a chain that directly contacts the target promoter is commonly located at a greater genomic distance from the promoter than the second enhancer in a chain, 96 kb vs. 45 kb, respectively. The first enhancer also features higher similarity to the promoter in terms of tissue specificity and higher enrichment of loop factors, suggestive of a stable primary contact with the promoter. In contrast, a chain of enhancers which connects to the target promoter through a neutral DNA segment instead of an enhancer is associated with a significant decrease in target gene expression, suggesting an important role of the first enhancer in initiating transcription using the target promoter and bridging the promoter with other regulatory elements in the locus.ConclusionsThe widespread chained structure of gene enhancers in humans reveals that the primary, critical enhancer is distal, commonly located further away than other enhancers. This first, distal enhancer establishes contacts with multiple regulatory elements and safeguards a complex regulatory program of its target gene.

Highlights

Robustness and evolutionary stability of gene expression in the human genome are established by an array of redundant enhancers
Similar to the ribonucleic acid polymerase II (RNAPII)-associated chromatin interaction network [31], all enhancers and promoters were denoted as vertices, while the significant intra-chromosome Hi-C interactions among them were denoted as edges
The mitochondrial oxidase assembly protein 1 (OXA1) gene, which is related to mitochondrial adenosine triphosphate (ATP) synthase and whose mutations may cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect [33], is associated with the largest number of 87 enhancer chain (EC) (Additional file 1: Figure S3B and S3D)

Summary

Introduction

Robustness and evolutionary stability of gene expression in the human genome are established by an array of redundant enhancers. The genes and their associated regulatory elements in the human genome are not uniformly distributed [7, 8], such as gene deserts which contain no protein-coding sequences but harbor multiple distant. Three-dimensional (3D) chromatin conformation experiments, such as Hi-C, provide high-resolution contact information between mapped genomic regions across human tissues and cell lines, including the associations between enhancers and their target genes [18,19,20,21]. It has been found that the connections formed by promoters and their contacts are dynamic and tissue-specific [28, 29]. During different stages of macrophage development, the activator protein-1 (AP-1)-enriched dynamic loops form a multi-loop activation cluster to control tissue-specific transcription [30]. Current studies have not addressed (1) the organization of multiple enhancers in the 3D space and in the 1D genome, (2) the difference in genomic features between multiple interacting enhancers, (3) the biological function of a multi- enhancer regulatory program on gene expression, and (4) the genome-wide presence of multiple interacting enhancers that are not part of SEs

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Results

Discussion

Conclusion