Abstract: When and why do individual cells in a population behave differently from the rest? Cancer is a disease replete with examples of single cells behaving badly—for instance, when treated with anti-cancer therapies, most cells die but a few rare cells remain and continue to grow despite treatment, presenting a major barrier to cure. Mostly, people think resistance is due to genetic differences in those rare cells, but we found that non-genetic differences can also lead to resistance. We will talk about tools we are developing to find these non-genetically distinct rare cell subpopulations both prospectively and retrospectively, thus allowing us to connect single cell profiles to phenotypic differences. We also describe recent efforts to manipulate these single cell behaviors. Together, these results might help us develop new quantitative approaches to the problem of therapy resistance in cancer, and may help answer outstanding conceptual questions in single cell biology in general.
Arjun Raj is Assistant Professor of Bioengineering at the University of Pennsylvania, He received his BA in Physics and Mathematics from the University of California, Berkeley and his PhD in Mathematics from New York University.
The goal of the Raj Lab is to develop a quantitative understanding of molecular underpinnings of cellular behavior and then use this knowledge to better human health. Their research combines new tools they have developed for single cell imaging with new genomic and computational methods to make highly accurate measurements of the molecular components underlying cellular function, focusing in particular on the behavior of single cells within an ensemble. Many of the measurement tools that they have developed also have applications in diagnostics for infectious disease and cancer. Also, their results provide a quantitative basis for synthetic biology. Areas of particular interest include cancer biology, long non-coding RNA, quantitative genetics, stem cell biology with applications to cartilage regeneration and diagnostics based on ultra-rapid viral detection.
Bartman, Caroline R, Hsu, Sarah C, Hsiung, Chris C-S, Raj, Arjun, Blobel, Gerd A: Enhancer regulation of transcriptional bursting parameters revealed by forced chromatin looping. Molecular cell 62(2): 237-247, 2016.
Symmons, Orsolya, Raj, Arjun: What’s Luck Got to Do with It: Single Cells, Multiple Fates, and Biological Nondeterminism. Molecular cell 62(5): 788-802, 2016.
Shaffer, Sydney M, Biaesch, Andrew G, Torborg, Stefan, Krepler, Clemens, Herlyn, Meenhard, Raj, Arjun: Abstract B32: Single-cell non-genetic heterogeneity confers drug resistance in melanoma. Cancer Research 76(3 Supplement): B32-B32, 2016.
Raj, Anil, Wang, Sidney H, Shim, Heejung, Harpak, Arbel, Li, Yang I, Engelmann, Brett, Stephens, Matthew, Gilad, Yoav, Pritchard, Jonathan K: Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. eLife 5: e13328, 2016.
Hsiung, Chris C-S, Bartman, Caroline, Huang, Peng, Ginart, Paul, Stonestrom, Aaron J, Keller, Cheryl A, Face, Carolyne, Jahn, Kristen S, Evans, Perry, Sankaranarayanan, Laavanya: A hyperactive transcriptional state marks genome reactivation at the mitosis-G1 transition. bioRxiv Page: 053678, 2016.
Ginart, Paul, Kalish, Jennifer M, Jiang, Connie L, Yu, Alice C, Bartolomei, Marisa S, Raj, Arjun: Visualizing allele-specific expression in single cells reveals epigenetic mosaicism in an H19 loss-of-imprinting mutant. Genes Dev 2(016): 567-78, 2016.
Dar, Roy D, Schaffer, Sydney M, Dey, Siddarth S, Foley, Jonathan E, Singh, Abhyudai, Razooky, Brandon S, Arkin, Adam P, Schafer, David V, Simpson, Michael L, Raj, Arjun: Transcriptional bursting explains the noise-versus-mean relationship in mRNA and protein levels. bioRxiv Page: 049528, 2016.
Cote, Allison J, McLeod, Claire M, Farrell, Megan J, McClanahan, Patrick D, Dunagin, Margaret C, Raj, Arjun, Mauck, Robert L: Single-cell differences in matrix gene expression do not predict matrix deposition. Nature communications 7, 2016.
Chen, Fei, Wassie, Asmamaw T, Cote, Allison J, Sinha, Anubhav, Alon, Shahar, Asano, Shoh, Daugharthy, Evan R, Chang, Jae-Byum, Marblestone, Adam, Church, George M: Nanoscale imaging of RNA with expansion microscopy. Nature methods 2016.
Burdick, Joshua, Walton, Travis, Preston, Elicia, Zacharias, Amanda, Raj, Arjun, Murray, John Isaac: Overlapping cell population expression profiling and regulatory inference in C. elegans. BMC genomics 17(1): 1, 2016.