Associate Professor of Oncological Sciences and Adjunct Associate Professor of Biomedical Engineering
Transcription Factors, Gene Regulation, Cancer, Genomics, CRISPR
Transcription factors orchestrate complex patterns of gene expression by interacting with specific loci throughout the genome. 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 use and develop experimental methods that take advantage of next-generation sequencing to create high-resolution maps of gene regulatory events. We also utilize cutting edge computational approaches to take full advantage of these rich genomics datasets.
Consequences of 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 enhancers that are inappropriately active in cancer
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 discovering enhancers, and the associated transcription factors, that contribute to the gene expression changes that occur 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. This information could be valuable in the development of more specific estrogen-related therapies.
Engineering gene expression
Gene expression patterns have been associated with a number of different clinical outcomes. However, it is unclear if these correlated gene expression differences are causally responsible for clinical phenotypes. To analyze the phenotypic impact of gene expression differences, 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.
References (Selected Publications)
- Rodriguez AC, Vahrenkamp JM, Berrett KC, Clark KA, Guillen KP, Scherer SD, Yang CH, Welm BE, Janat-Amsbury MM, Graves BJ, Gertz J (2020). ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells. Cancer Research. Mar 15;80(6):1234-1245.
- Vahrenkamp JM, Szczotka K, Dodson MK, Jarboe EA, Soisson AP, Gertz J (2019). FFPEcap-seq: a method for sequencing capped RNAs in formalin-fixed paraffin-embedded samples. Genome Research. Nov;29(11):1826-1835.
- Ginley-Hidinger M, Carleton JB, Rodriguez AC, Berrett KC, Gertz J (2019). Sufficiency analysis of estrogen responsive enhancers using synthetic activators. Life Sci Alliance. 2019 Oct;2(5).
- Blanchard Z, Vahrenkamp JM, Berrett KC, Arnesen S, Gertz J (2018). Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer. Genome Research. Sep;29(9):1429-1441. PMCID: PMC6724674
Vahrenkamp JM, Yang CH, Rodriguez AC, Almomen A, Berrett KC, Trujillo AN, Guillen KP, Welm BE, Jarboe EA, Janat-Amsbury MM, Gertz J (2018). Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor alpha In Endometrial Cancer. Cell Rep, 22(11), 2995-3005.
Layer RM, Pedersen BS, DiSera T, Marth GT, Gertz J, Quinlan AR (2018). GIGGLE: a search engine for large-scale integrated genome analysis. Nat Methods, 15(2), 123-126.
Carleton JB, Berrett KC, Gertz J (2017). Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor alpha-Bound Enhancers. Cell Syst, 5(4), 333-344.e5.
DAmato NC, Gordon MA, Babbs B, Spoelstra NS, Carson Butterfield KT, Torkko KC, Phan VT, Barton VN, Rogers TJ, Sartorius CA, Elias A, Gertz J, Jacobsen BM, Richer JK (2016). Cooperative Dynamics of AR and ER Activity in Breast Cancer. Mol Cancer Res, 14(11), 1054-1067.
Savic D, Roberts BS, Carleton JB, Partridge EC, White MA, Cohen BA, Cooper GM, Gertz J, Myers RM (2015). Promoter-distal RNA polymerase II binding discriminates active from inactive CCAAT/ enhancer-binding protein beta binding sites. Genome Res, 25(12), 1791-800.
Gertz J, Savic D, Varley KE, Partridge EC, Safi A, Jain P, Cooper GM, Reddy TE, Crawford GE, Myers RM (2013). Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol Cell, 52(1), 25-36.
Gertz J, Reddy TE, Varley KE, Garabedian MJ, Myers RM (2012). Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res, 22(11), 2153-62.
Gertz J, Varley KE, Reddy TE, Bowling KM, Pauli F, Parker SL, Kucera KS, Willard HF, Myers RM (2011). Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet, 7(8), e1002228.
Gertz J, Siggia ED, Cohen BA (2009). Analysis of combinatorial cis-regulation in synthetic and genomic promoters. Nature, 457(7226), 215-8.