Functions of interspersed repeats Specific types of transposons are active in modern humans, and our 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 our 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). Our group has since developed experimental systems to show that inherited transposable element insertion alleles can affect gene expression and mRNA splicing, 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 have phenotypic effects. We have authored related reviews in Cell (2012) and Nature Reviews Genetics (2019).
Questions going forward: What is the landscape of transposon expression in diseased tissues? Do functional variants of transposon insertions modify disease risk or disease phenotypes?
LINE-1 expression and activity in cancer Our 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 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. We have led collaborations to map somatically-acquired LINE-1 insertion sites in pancreatic (Nature Medicine, 2015) and ovarian cancers (PNAS, 2017) and 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. We 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 our 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.
Questions going forward: Does LINE-1 expression promote malignant transformation? Can we leverage LINE-1 expression as a cancer therapeutic?