DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

My group focuses on several areas in systems and synthetic biology. We are trying to understand how groups of molecules and cells function together to generate spatial and temporal organization. At the same time, we are developing design principles to create complex biological systems. Some of the current research areas are summarized below. See our web site for more details and additional references. 1) Genome organization. Our studies of nuclear organization concern the spatial and temporal relationships between genes and other nuclear structures and their functional significance. It has become increasingly clear that the organization of genes within the nucleus plays an important role in cell identity and epigenetics. Recent work from our lab has included a genome-wide study of nuclear organization and generating a high-resolution map of gene location. In doing so, we made discoveries concerning the relationship between gene activation and repression. Current interests in the lab include studying the dynamic nature of the genome under different growth states and different cell types, throughout the cell cycle and in response to drugs in development as anti-cancer therapeutics. We also study the dynamics of post-transcriptional regulation and its relationship to the organization of the genome in response to drugs and diseases. 2) Pathways in Disease. Many signaling pathways employ spatial organization as a key part of their response to environmental stimuli. For example, the movement of key proteins in and out of the nucleus is often one of the downstream steps in signal response. We have taken advantage of this spatial organization to screen for small molecules and genes that affect signaling pathways and therapeutic targets. Currently, we are building on these findings to gain a more quantitative picture of how tumor cells respond to certain drugs. We employ a combination of high-resolution microscopy, genome association technology, modeling and cell-based screens. 3) Designing biological systems. Our goal is to both enhance our understanding of the principles of natural biological design, and to develop tools and concepts for designing artificial organisms. In the long term, we hope to develop principles for building novel cells that act as sensors, memory devices, bio-computers, or energy producers, and to build novel subsystems such as proteins with designed properties. Current projects use the advanced operating system afforded by eukaryotes to create artificial proteins with therapeutic value, a cellular oscillator that could lead to pulsatile drug delivery, a cell division counter for analysis of aging, and manipulation/creation of metabolic pathways to produce bio-hydrogen as an economical energy source. These experiments use a combination of theoretical and experimental approaches.

Publications

• Drubin DA, Way JC, Silver PA.Designing biological systems.Genes Dev 2007 Feb 1;21(3):242-54.
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• Moore MJ, Schwartzfarb EM, Silver PA, Yu MC.Differential recruitment of the splicing machinery during transcription predicts genome-wide patterns of mRNA splicing.Mol Cell 2006 Dec 28;24(6):903-15.
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• Yu MC, Lamming DW, Eskin JA, Sinclair DA, Silver PA.The role of protein arginine methylation in the formation of silent chromatin.Genes Dev 2006 Dec 1;20(23):3249-54.
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• Tsankov AM, Brown CR, Yu MC, Win MZ, Silver PA, Casolari JM.Communication between levels of transcriptional control improves robustness and adaptivity.Mol Syst Biol 2006;2:65.
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• Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M.Genome-wide analysis of estrogen receptor binding sites.Nat G
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• Auld KL, Brown CR, Casolari JM, Komili S, Silver PA.Genomic association of the proteasome demonstrates overlapping gene regulatory activity with transcription factor substrates.Mol Cell 2006 Mar 17;21(6):861-71.
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• Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, Fox EA, Silver PA, Brown M.Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA
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• Casolari JM, Brown CR, Komili S, West J, Hieronymus H, Silver PA.Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization.Cell 2004 May 14;117(4):427-39.
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• Kau TR, Way JC, Silver PA.Nuclear transport and cancer: from mechanism to intervention.Nat Rev Cancer 2004 Feb;4(2):106-17.
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• Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA.A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells.Cancer Ce
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• Hieronymus H, Silver PA.Genome-wide analysis of RNA-protein interactions illustrates specificity of the mRNA export machinery.Nat Genet 2003 Feb;33(2):155-61.
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