The Scacheri lab is broadly interested in the epigenome and the role of gene enhancer elements in normal development and human disease. Enhancer elements are fundamental to establishing and maintaining gene expression patterns during development and throughout adulthood. We are focused on leveraging the known role of enhancers in defining cell state to gain new insight into human development and the aberrant cellular states that drive human disease.  We utilize cutting edge genomic technologies for this work and are continually developing and applying new computational approaches to utilize these data to inform our understanding of biology. Current areas of focus include the following:



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.



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 has 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 Common Disease.


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.



A variety of genetic diseases are caused by mutations in genes encoding proteins that function at the level of chromatin. One such example is CHARGE syndrome, a congenital disorder characterized by a complex pattern of birth defects involving the eyes, ears, heart and other organs. The responsible gene is a chromatin remodeler called CHD7 (chromodomain helicase DNA binding protein 7). We discovered that CHD7 has dual roles as a transcriptional regulator in the nucleoplasm and the nucleolus. In the nucleoplasm, CHD7 binds to thousands of enhancer elements and regulates multiple genes that specify neural lineages and other cell types. In the nucleolus, CHD7 regulates ribosomal RNA levels, which are tightly coupled to cell proliferation rates. We are now combining mouse, zebrafish, and iPS-cell systems to further study the mechanism of CHD7 function during development and how the cellular deficiencies ultimately give rise to the multiple birth defects observed in CHARGE syndrome.