We are interested in how genetic and epigenetic alterations of regulatory DNA elements drive cancer.
Cancer is driven by genetic and epigenetic changes to the DNA. We now know quite well how genetic alterations of genes drive cancer, thanks to extensive mapping efforts. However, we still know very little about the extent and function of genetic and epigenetic alterations at regulatory regions away from genes.
Other than expanding our understanding of gene regulation and dysregulation in cancer, we aim to leverage this knowledge to predict novel therapeutic targets for the development of new drugs, and develop models to predict patient outcome to help guiding treatment plans for cancer patients.
Our scientific approach combines epigenetic profiling, development of computational models and algorithms, and experimental validation. We combine cutting edge experimental techniques with developing new machine learning algorithms and big-data analytical approaches.
We study how genetic and epigenetic alterations of regulatory DNA elements cause cancer or contribute to the disease. We focus on two types of regulatory DNA elements: enhancers (regulating transcription), and CTCF binding sites (regulating chromosomal topology, i.e. the folding of the chromosome in 3D).
Epigenetic topological alterations in cancer
We have previously demonstrated that aberrant DNA methylation of CTCF binding sites in IDH-mutant glioma perturbs chromosomal topology . Normally our chromosomes are divided to multiple topological domains which allow frequent interaction within each domain, but limit interactions across domain boundaries. We demonstrated that in IDH-mutant gliomas, CTCF binding sites at boundaries get methylated, lose CTCF binding, disrupt insulation between adjacent topological domains, and allow aberrant interactions between genes and enhancers. Specifically, this allows activation of the PDGFRA oncogene that cause the cells to become tumorigenic. This groundbreaking model demonstrates that epigenetic and topologic alterations can drive cancer, while highlighting the importance of regulatory DNA alterations.
We are extending this framework to additional types of cancer and of topologic disruptions to test the interplay between metabolism, epigenetics, topology and gene regulation, and how it is dysregulated across different types of cancer.
Genetic dysregulation of DNA regulatory elements in cancer
We develop systematic approaches to integrate genetic, epigenetic, topologic and transcriptional information to study how genetic alterations affect the function of regulatory DNA elements. For example, we have recently uncovered how genetic translocations alter the targets of enhancers to rewire the gene regulatory network into a positive feedback loop . We are now working to extend such approaches to comprehensive analysis of functional regulatory DNA alterations across cancer.
 Insulator dysfunction and oncogene activation in IDH mutant gliomas. Flavahan WA*, Drier Y*, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Nature, 2016. Link
 An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, Carey CD, Rodig SJ, Sholl LM, Afrogheh AH, Faquin WC, Queimado L, Qi J, Wick MJ, El-Naggar AK, Bradner JE, Moskaluk CA, Aster JC, Knoechel B, Bernstein BE. Nature Genetics, 2016. Link
 Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma. Ryan RJ*, Drier Y*, Whitton H, Cotton MJ, Kaur J, Issner R, Gillespie S, Epstein CB, Nardi V, Sohani AR, Hochberg EP, Bernstein BE. Cancer Discovery, 2015. Link
 Pathway-based personalized analysis of cancer. Drier Y, Sheffer M, Domany E. PNAS, 2013. Link
 Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability. Drier Y, Lawrence MS, Carter SL, Stewart C, Gabriel SB, Lander ES, Meyerson M, Beroukhim R, Getz G. Genome Research, 2013. Link
 The genomic complexity of primary human prostate cancer. Berger MF*, Lawrence MS*, Demichelis F*, Drier Y*, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA. Nature, 2011. Link