Research Abstract

The majority of our genome is highly repetitive sequence derived from the activities of self-propagating retrotransposons. My research focuses on roles these mobile genetic elements play in human disease. Despite their enormous impact on genome composition over evolutionary time and across virtually all eukaryotic taxa, transposons are often presumed to be inert, non-functional ‘junk DNA’, and I am one of few physician-scientists bridging this area of fundamental biology with biomedical research.

Specific types of transposons are active in modern humans, and my lab was one of the first to develop strategies to map insertion sites of these elements in the human genome. Our observations underscored that transposons are major sources of genetic structural variation in human populations (Cell, 2010). Over the next decade, catalogs of commonly-occurring mobile element insertion alleles grew, and my group led efforts to identify those variants that may be relevant to disease risk by integrating information about these insertions with findings of genome wide association studies (GWAS) (PNAS, 2017). We found scores of Alu insertions on haplotypes associated with risk for developing diseases, including the most common form of childhood cancer, precursor B-cell acute lymphoblastic leukemia (ALL) and the common autoimmune disease of the central nervous system, multiple sclerosis (MS). My group has since developed experimental systems to show that inherited transposable element insertion alleles can affect gene expression and mRNA splicing (NAR, 2019), demonstrating molecular mechanisms for how transposons may impact phenotypes. Together, these avenues of investigation have shown that we each inherit a unique compliment of transposon insertions – thousands of LINE-1, Alu, SVA, and ERV alleles – and that a specific subset of these sequences potentially affects our likelihood to develop disease. I have authored related reviews in Cell (2012) and Nature Reviews Genetics (2019).

My laboratory has also had a long-standing interest in transposable element expression in human malignancies. Many cancers undergo epigenetic changes that permit the expression of otherwise silenced transposable elements. Here, we are best known for our research on Long INterspersed Element-1 (LINE-1, L1), the only protein-coding retrotransposon active in modern humans. We were the first to develop and commercialize a monoclonal antibody to detect the LINE-1-encoded RNA-binding protein, open reading frame 1 protein (ORF1p). Using this reagent, we showed that LINE-1 expression is a hallmark of human cancers, including many of the most lethal of these diseases – lung, prostate, breast, colon, pancreatic, and ovarian cancers (Am J Path, 2014). We are exploring whether ORF1p has utility as a marker for cancer detection. We have shown that ORF1p expression is an indicator of LINE-1 activity as a mobile genetic element, i.e., cancers that express ORF1p have somatically-acquired insertions of genomic LINE-1 sequences that distinguish tumor genomes from a patient’s constitutional genetic make-up. I have led collaborations to map acquired LINE-1 insertion sites in pancreatic (Nature Medicine, 2015) and ovarian cancers (PNAS, 2017) at Johns Hopkins School of Medicine, and I have participated in larger efforts to identify somatically-acquired insertions as part of the International Cancer Genome Consortium (Nature Genetics, 2020). Together, these studies have shown that LINE-1 expression is commonplace in human cancers, and that it contributes to genome instability. I recently authored a review on this topic for Nature Reviews Cancer (2017).

We are now devoting significant efforts to understand implications of LINE-1 expression for cancer cell biology. We have found that non-transformed cells undergo a p53-dependent growth arrest when LINE-1 expression is forced, and that LINE-1 can induce interferon responses similar to those elicited by viral infection. In vitro studies in my lab show that in cells that mutate p53 and other tumor suppressor genes, LINE-1 enhances the relative growth advantage gained by those mutations. Meanwhile, LINE-1 expression makes p53-deficient cells especially vulnerable to loss of replication-coupled DNA repair pathways, and DNA-damaging chemotherapies (Nature Structural and Molecular Biology, 2020). Together, these findings indicate that LINE-1 expression may promote cancerous transformation, and that in transformed cells, retrotransposition may conflict with DNA replication in a manner that can be exploited for cancer therapeutics. Ultimately, we aim to leverage this understanding of LINE-1 biology to inform approaches to cancer treatment.