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A computational framework for identifying the transcription factors involved in enhancer-promoter loop formation

ABSTRACT: The pairwise interaction between transcription factors (TFs) plays an important role in enhancer-promoter loop formation. Although thousands of TFs in the human genome have been found, only a few TF pairs have been demonstrated to be related to loop formation. It is still a challenge to determine which TF pairs could be involved in the enhancer-promoter regulation network. This work describes a computational framework to identify TF pairs in enhancer-promoter regulation. By integrating different levels of data derived from Promoter Capture Hi-C, chromatin immunoprecipitation sequencing (ChIP-seq) of histone marks, RNA-seq, protein-protein interaction (PPI), and TF motif, we identified 361 significant TF pairs and constructed a TF interaction network. From the network, we found several hub-TFs, which may have important roles in the regulation of long-range interactions. Our studies extended TF pairs identified in other experimental and computational approaches. These findings will help the further study of long-range interactions between enhancers and promoters. Graphical Abstract The communication between active enhancer and distal promoter is believed to be mediated by transcription factors (TFs). Liu et al. proposed a computational framework and identified 361 candidate TF pairs that drive enhancer-promoter interaction. Furthermore, they identified several hub-TFs, such as EP300 and MYC, by constructing a TF interaction network.

SUBMITTER: Liu L

PROVIDER: S-EPMC7779541 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Project description:Expression quantitative trait loci (eQTL) analysis is useful for identifying genetic variants correlated with gene expression, however, it cannot distinguish between causal and nearby non-functional variants. Because the majority of disease-associated SNPs are located in regulatory regions, they can impact allele-specific binding (ASB) of transcription factors and result in differential expression of the target gene alleles. In this study, our aim was to identify functional single-nucleotide polymorphisms (SNPs) that alter transcriptional regulation and thus, potentially impact cellular function. Here, we present regSNPs-ASB, a generalized linear model-based approach to identify regulatory SNPs that are located in transcription factor binding sites. The input for this model includes ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing) raw read counts from heterozygous loci, where differential transposase-cleavage patterns between two alleles indicate preferential transcription factor binding to one of the alleles. Using regSNPs-ASB, we identified 53 regulatory SNPs in human MCF-7 breast cancer cells and 125 regulatory SNPs in human mesenchymal stem cells (MSC). By integrating the regSNPs-ASB output with RNA-seq experimental data and publicly available chromatin interaction data from MCF-7 cells, we found that these 53 regulatory SNPs were associated with 74 potential target genes and that 32 (43%) of these genes showed significant allele-specific expression. By comparing all of the MCF-7 and MSC regulatory SNPs to the eQTLs in the Genome-Tissue Expression (GTEx) Project database, we found that 30% (16/53) of the regulatory SNPs in MCF-7 and 43% (52/122) of the regulatory SNPs in MSC were also in eQTL regions. The enrichment of regulatory SNPs in eQTLs indicated that many of them are likely responsible for allelic differences in gene expression (chi-square test, p-value < 0.01). In summary, we conclude that regSNPs-ASB is a useful tool for identifying causal variants from ATAC-seq data. This new computational tool will enable efficient prioritization of genetic variants identified as eQTL for further studies to validate their causal regulatory function. Ultimately, identifying causal genetic variants will further our understanding of the underlying molecular mechanisms of disease and the eventual development of potential therapeutic targets.

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A computational framework for identifying the transcription factors involved in enhancer-promoter loop formation

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