The effect of non-coding DNA variations on P53 and cMYC competitive inhibition at cis-overlapping motifs

Abstract

Non-coding DNA variations play a critical role in increasing the risk for development of common complex diseases, and account for the majority of SNPs highly associated with cancer. However, it remains a challenge to identify etiologic variants and to predict their pathological effects on target gene expression for clinical purposes. Cis-overlapping motifs (COMs) are elements of enhancer regions that impact gene expression by enabling competitive binding and switching between transcription factors. Mutations within COMs are especially important when the involved transcription factors have opposing effects on gene regulation, like P53 tumor suppressor and cMYC proto-oncogene. In this study, genome-wide analysis of ChIP-seq data from human cancer and mouse embryonic cells identified a significant number of putative regulatory elements with signals for both P53 and cMYC. Each co-occupied element contains, on average, two COMs, and one common SNP every two COMs. Gene ontology of predicted target genes for COMs showed that the majority are involved in DNA damage, apoptosis, cell cycle regulation, and RNA processing. EMSA results showed that both cMYC and P53 bind to cis-overlapping motifs within a ChIP-seq co-occupied region in Chr12. In vitro functional analysis of selected co-occupied elements verified enhancer activity, and also showed that the occurrence of SNPs within three COMs significantly altered enhancer activity. We identified a list of COM-associated functional SNPs that are in close proximity to SNPs associated with common diseases in large population studies. These results suggest a potential molecular mechanism to identify etiologic regulatory mutations associated with common diseases.

Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci

“…We prioritized cis-overlapping motifs (CisOMs) including those of cMYC proto-oncogene (cMYC) and tumor suppressor p53 (TP53) that show competitive binding at many loci (44) because CisOMs provide one of the mechanisms of metastability (Fig. 3E) and also those that may have consequences for human disease (table S5).…”

p53 and RAD9, the DNA Damage Response, and Regulation of Transcription Networks

“…Cis-overlapping motifs specific to different transcription factors can influence p53 binding. For example, there are sites in the genome where p53 and c-MYC binding motifs share sequences, so competition for binding and gene transactivation is clearly an issue (72). This is important biologically, as p53 is a tumor suppressor and c-MYC is an oncogene.…”

Identification of Disease Risk DNA Variations is Shaping the Future of Precision Health

“…To emphasize the importance of gene regulation, genome-wide association studies (GWAS) of human common diseases demonstrate that ~10% of the disease-related single nucleotide polymorphisms (SNPs) are located in amino acid coding sequences, whereas around 90% of the disease-associated SNPs fall outside of protein coding regions [2,3,9]. Identification of pathological DNA variants is critical for early diagnosis and better prognosis of genetic diseases in high-risk individuals and also for developing targeted therapies in patients with existing genetic disorders [9,10]. Research has been previously directed towards DNA variations located within coding sequences because of their direct effect on the function of the corresponding gene/protein product.…”

“…Based on evolutionary studies as well as omics and GWAS data, understanding the underlying mechanism by which noncoding DNA variations alter gene function and identification of differentially expressed genes is critical for identifying genetic factors that increase the risk for common complex diseases [10]. Furthermore, developing computational modeling for predicting the impact of genetic and epigenetic factors on disease prognosis and severity will pave the way for the implementation of precision health strategies focusing on prevention and targeted therapy rather than a ‘one pill fits all’ approach [8,9].…”