The inappropriate expression of genes is a common defect across different types of cancer. Transcription factors (TF), which orchestrate gene expression patterns by interacting with specific loci throughout the genome, play a key role in the growth and development of tumors. Our research goal is to understand how transcription factors choose their genomic binding sites, how binding events lead to gene expression changes, and how the actions of transcription factors are altered in cancer. To determine the roles that transcription factors play in gene regulation, we develop and apply experimental methods that take advantage of next-generation sequencing to create high-resolution maps of gene regulatory networks. We also utilize and create computational approaches to take full advantage of these rich genomic datasets.
Transcription Factor Mutations in Cancer
The widespread adoption of exome and whole genome sequencing has led to a rapidly expanding catalog of disease-associated mutations; however, the molecular consequences of most identified genetic defects are unclear. Many of these alterations found in cancer involve transcription factors and could have dramatic effects on gene expression. To study the gene regulation impact of transcription factor mutations, we are using genome editing to introduce particular mutations into human cell lines. By analyzing gene expression and transcription factor binding in these cell lines, we aim to understand the direct consequences of transcription factor mutations on gene regulation.
Identification of Cancer-Associated Enhancers
The gene expression signature that a tumor exhibits can be informative for both prognosis and in determining treatments. While gene expression changes can be clinically useful, it is not clear which genomic loci are responsible for the altered gene regulation. We are interested in using genomics to discover enhancers, and the associated transcription factors, that contribute to the gene expression changes observed during cancer progression. Finding enhancers that are inappropriately active in cancer will shed light on important gene regulation events that take place in tumors and could lead to better prognostic and diagnostic tests.
Tissue-Specific Estrogen Signaling
While estrogen signaling plays a critical role in the growth and treatment of breast cancers, estrogens exert diverse physiological effects on many different tissues in both men and women. The wide reaching impact of estrogens underlies the many side effects that estrogen-related therapies can cause. Estrogens act primarily through activation of the transcription factors estrogen receptor α and estrogen receptor β. By studying genomic binding of estrogen receptor α as well as gene expression responses to estrogens, we hope to gain insight into why estrogen receptor α chooses distinct binding sites and impacts different target genes in different tissues and tumor types.
Engineering Gene Expression
Transcription factors orchestrate complex patterns of gene expression by interacting with specific loci throughout the genome. We are developing synthetic transcription factors that can be engineered to bind to any location in the genome and simultaneously change the expression of hundreds genes. The ability to alter gene expression on a large scale will shed light on how gene expression levels lead to cellular phenotypes. We are particularly interested in how gene expression changes lead to proliferation, migration, and drug sensitivity.
