The development of cancer is closely associated with the accumulation of not only oncogene and tumor suppressor mutations but also epigenetic changes that alter chromatin structure and lead to dysregulated gene expression. Using colon cancer as a model, we previously showed that signature epigenetic alterations at gene enhancer elements underlie altered gene expression programs in cancer, indicating that enhancers are critical drivers of malignant transformation. We call these Variant Enhancer Loci, or VELs (Figure 1). This work has opened the door for new avenues of investigation including exploiting the enhancer alterations as biomarkers for early disease detection and as therapeutic targets for selectively killing tumor cells without harming normal cells. We are also investigating the role of VELs in the spreading of tumor cells from one organ to another or metastasis, and whether we can leverage our knowledge of VELs toward the development of first in class targeted anti-metastatic therapies.
Figure 1. Variant Enhancer Loci (VELs)
Figure 1: The top depicts a normal colon, where the gene on the left associated with the enhancer histone mark (H3K4me1 – green balls) is turned on, and the gene on the right not associated with the enhancer mark is turned off. In colon cancer, the gene on the left has lost the enhancer mark and is turned off while the gene on the right has gained the mark and is turned on. VELs shared among multiple individual tumors constitute a signature of colon cancer. The genes associated with common VELs are reproducibly dysregulated across multiple colon tumors from patients (depicted in the heatmap), and drive a specific transcriptional program to promote colon carcinogenesis.
HERITABLE RISK FOR COMMON DISEASE
Collectively, common diseases comprise some of the most clinically pressing health-related problems, including heart disease, diabetes, multiple sclerosis, arthritis, mental illness, and cancer. In the last decade, DNA variants (SNPs) associated with genetic susceptibility to these and many other common diseases have been identified through genome wide association studies (GWAS). Most of the discovered SNPs are localized outside genes, in non-coding regions of the genome. Our lab, as well as others, have shown that most of the SNPs lie in cell type-specific gene enhancer elements. The enhancer-SNPs presumably confer disease risk by influencing expression of their target genes, but mechanistic understanding of how this occurs is far from complete. In an effort to fill the knowledge gap, our team recently showed that the common disease variants often lie within clusters of enhancer elements, also referred to as super enhancers and stretch enhancers by others. SNPs distributed across multiple enhancers within the cluster collude to impact target gene expression. Thus, contrary to popular belief, there is not necessarily one causal SNP within a given GWAS locus that influences expression of the target gene and confers the risk to disease. We call this the “Multiple Enhancer Variant” (MEV) hypothesis (Figure 2). We are now utilizing murine-based approaches and biochemical analyses of chromatin architecture to study the relationship between MEVs and missing heritability in GWAS, and determine whether knowledge of the target genes and the effect of MEVs on transcription can be utilized for preventative or therapeutic measures for common diseases.
Figure 2. Multiple Enhancer Variants in
Figure 2. Drawing illustrates the concept of multiple enhancer variants impacting expression of a gene. The dimmer switches represent a cluster of three individual enhancer elements arranged in cis. These function cooperatively to regulate the level of a given gene, represented by the light bulb. DNA variants that predispose to common diseases often lie within enhancer clusters, and cooperatively impact expression of target genes by altering the individual enhancer set points.
HIGHLIGHTED RECENT PAPERS
Morton AR, DA Nergiz, Faber ZJ, MacLeod G, Bartels CF, Piazza MS, Allan KC, Mack SC, Wang X, Gimple RC, Wu Q, Rubin, BRP, Shetty S, Angers, S, Dirks PB, Sallari RC, Lupien M, Rich JN, Scacheri PC. Cell, 2019.
Bayles I, Krajewska M, Saiakhova A, Morrow J, Pontius WD, Bartels C, Lu J, Faber ZJ, Fedorov Y, Hong ES, Karnuta JM, Rubin B, Adams D, George RE, Scacheri PC. JCI, 2019.
Hung S, Saiakhova A, Faber Z, Bartels CF, Neu D, Bayles I, Ojo E, Hong ES, Pontius WD, Morton AR, Liu R, Kalady M, Wald DN, Markowitz S, Scacheri PC. eLife, 2019.