Northwestern University Physical Sciences-Oncology Center
Northwestern University, Chicago, IL
Center Summary:
Northwestern University Physical Sciences-Oncology Center's (NU PS-OC) main focus is to probe the molecular basis of information flow within malignant cells. This center’s studies will highlight diverse characteristics of gene expression and storage. Moreover, these investigators postulate that in the cancerous state, the epigenome is significantly mutated. By merging experimental molecular and cellular biology with the physical sciences, these investigators will examine the regulation and expression of genes. In addition, they will explore the three-dimensional organization of the genome and the higher order chromatin structure using leading-edge physical techniques. Insight into chromatin structure modifications in malignant cells has the potential to expedite the development of tools for the early diagnosis of cancer. These investigators will also provide a foundation of basic understanding for how normal gene expression is calibrated and for how the epigenome as well as the proteosome are regulated. A clear understanding of these basic molecular functions should generate novel targets for cancer therapy.
| Website: http://www.psoc.northwestern.edu/ |
| Collaborators: |
California Institute of Technology
Children's Memorial Hospital
University of Chicago
University of Illinois-Urbana
Weizmann Institute |
Project 1 – Information Encoded in the Sequence-Dependent Mechanics of DNA
Project Leader: Robert B. Phillips (California Institute of Technology)
Show/Hide Details
Project 1 investigates a novel kind of genetic information that is encoded directly in the genomic DNA sequence, through the sequence-dependent mechanical properties of DNA itself. This information is superimposed directly on top of protein coding and regulatory signals that were previously recognized, and is based on the sequence-dependent mechanical properties of the DNA itself. Project 1 combines theoretical and experimental approaches to develop a predictive mechanistic understanding of these fundamentally important sequence-dependent mechanics of DNA.
Project 2 – DNA Sequence-Encoded Nucleosome Positioning, and Gene Regulation
Project Leader: Jonathan Licht (Northwestern)
Show/Hide Details
In simple eukaryotes, the genomic DNA sequence explicitly encodes the majority of the in vivo nucleosome organization and thereby regulates the competition of nucleosomes and gene regulatory proteins, facilitating many specific chromosome functions; however, in higher organisms, the extent to which the genomic sequence encodes nucleosome locations has been questioned and is not known. Moreover, higher organisms have differing nucleosome concentrations in differing cell types, with unclear ramifications for nucleosome positioning and chromosome function. This project will obtain needed data and develop quantitative predictive models for nucleosome locations, chromatin superstructures, nucleosome-factor competition, and gene expression levels, in development and cancer, using mouse and human cell line systems.
Project 3 – DNA Information and Organization at Supranucleosomal Scales: Chromatin Folding and Higher Order Structure, Heterochromatin and Domain-Wide Repression
Project Leader: John F. Marko (Northwestern)
Show/Hide Details
Project 3 seeks to uncover the connection between higher-order chromatin structure and gene regulation mechanisms relevant to cancer. An important effect of higher-order structure may be that origins of replication can be defined and regulated by chromatin structure, rather than by specific DNA sequence elements; changes in higher order structure in chromatin may appear in precancerous tissue, suggesting a hypothesis that optical detection of the “field effect” used in cancer diagnosis may follow from measurement of amounts and distribution of heterochromatin. This will allow understanding the basic chromosome organization changes associated with turning on malignancy, and then lead to use of those changes in establishment of new diagnostic tools.
Project 4 – Dynamic Nucleosome Signatures in Epigenetic Memory and Cancer Development
Project Leader: William L. Kath (Northwestern)
Show/Hide Details
Increasing evidence indicates that cancer results not only from changes in genetic information, but also from changes in epigenetic information, and recent theoretical analyses of epigenetic regulation in a model organism (yeast) show that ideas from the dynamical systems field may explain the stability of epigenetic states and the dynamics of spontaneous changes between them. This project will experimentally define the epigenetic changes resulting from the action of (1) a mutant kinase JAK2V617F, a causative factor in myeloproliferative disease; (2) a defined set of oncogenes that transform normal human cells to cancer cells (T antigen, ras, shRNA PP2a, telomerase); and (3) the changes in state of the MLH1 promoter that accompany gene silencing associated with promoter methylation, and reactivation that is induced by 5-aza-2'-deoxycytidine and is associated with DNA demethylation. We will use this information to develop quantitative predictive models of epigenetic inheritance and switching in these systems, based on a dynamical systems framework.
Project 5 – Encoding and Interpreting Information at the Protein Level
Project Leader: Andreas T. Matouschek (Northwestern)
Show/Hide Details
The protein’s (genetically encoded) amino acid sequence specifies not only the protein’s structure, but also its lifetime through hidden degradation signals encoded in the sequence, and degradation rates balance gene expression rates and thus represent the second half of the equation that determines the active concentration of proteins. In the same way that aberrant gene expression is linked to cancer, so too is aberrant protein processing or degradation. This project will decode the sequence signals that shape the proteome and will determine the mechanical and chemical principles underlying these mechanisms.
Core 1 - The Deep Sequencing Core
Core Leader: Peter Kopp (Northwestern University)
The Deep Sequencing Core provides massively parallel DNA sequencing services using an ABI SOLiD (v3) instrument. A second parallel sequencing instrument, suitable for paired ends sequencing, will also be used. Experiments supported by this technology includes genomewide nucleosome mapping, mapping bound transcription factors genome-wide using chromatin-immunoprecipitation / sequencing (ChIP-seq), and gene expression profiling (RNA-seq).
Core 2 - The Bioinformatics Core
Core Leader: Ji-Ping Wang (Northwestern University)
The Bioinformatics Core provides advice and assistance in the analysis of genome-wide DNA sequence and microarray data, and in integrating different kinds of such data together to test hypotheses about genome structure and function. The mission of the Bioinformatics Core is to provide strong and timely bioinformatic support for all of the NU-PSOC projects by developing novel bioinformatic approaches and tools for the biological problems encountered in the Center's research. Operating within this broad framework, the Core will pursue two main goals: to promote and catalyze interdisciplinary research by providing a platform for interaction between computational scientists and biologists or cancer researchers; and to create training opportunities for postdoctoral fellows or graduate students.
Thomas V. O'Halloran, Ph.D.
Dr. O'Halloran is widely known for his interdisciplinary research program, which involves chemical synthesis, analytical chemistry, biochemistry, molecular biology and cell biology. In his role as Director of the Chemistry of Life Processes Institute, Professor O'Halloran administers and leads teams of interdisciplinary biomedical researchers. The Institute brings together researchers from the fields of chemistry, biology, physics, engineering, medicine, proteomics, nanobiotechnology, molecular therapeutics and biological molecular imaging. He also serves as the Associate Director for the Basic Sciences Research Division of the Robert H. Lurie Comprehensive Cancer Institute.
Dr. O'Halloran is the Morrison Professor in the Department of Chemistry and in the Department of Molecular Biosciences at Northwestern. His research interests focus on biological chemistry of inorganic elements and novel agents for treatment of infectious diseases and cancer.
Jonathan Licht, M.D.
Dr. Licht is the Johanna Dobe Professor of Medicine, Chief, Division of Hematology/Oncology and Associate Director for Clinical Sciences of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Licht received his M.D. from Columbia University and trained in medical oncology and molecular biology at the Dana-Farber Cancer Institute. From 1991-2006 he served on the faculty at the Mount Sinai School of Medicine in the Departments of Medicine and Molecular Biology, where he rose to the rank of Professor and Associate Dean for Cancer Programs. Dr. Licht’s laboratory studies aberrant transcriptional repression as a cause of hematological malignancy, including acute promyelocytic leukemia and multiple myeloma, and is exploring multiple strategies to reverse this repression. Dr. Licht, formerly a Leukemia Society Scholar, and recipient of a Buroughs Wellcome Clinical Scientist Award in Translational Research is currently the Principal Investigator of a Leukemia and Lymphoma Society Specialized Center of Excellence grant, studying epigenetic mechanisms in hematological malignancy. Dr. Licht is a Senior Editor of Clinical Cancer Research and serves on the editorial boards of Cancer Research and Oncogene. Dr. Licht served as a Councilor of the American Society for Clinical Investigation a member of the Association of American Physicians.
Jonathan Widom, Ph.D.
Jonathan Widom was born, in Ithaca, NY, 1955. He received his B.A. in Chemistry from Cornell University in 1977, and his Ph.D. in Biochemistry (with Professor Robert L. Baldwin) from Stanford University in 1982. He was a Jane Coffin Childs Postdoctoral Fellow with Sir Aaron Klug at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, from 1983–1985. In 1985 he joined the faculty of the University of Illinois at Urbana-Champaign, as Assistant Professor of Physical Chemistry, with appointments in the Departments of Chemistry, Biochemistry, Biophysics, and the Beckman Institute. In 1991, he moved to Northwestern University, where he is now William Deering Professor in the Department of Biochemistry, Molecular Biology, and Cell Biology (BMBCB) and the Department of Chemistry. At Northwestern University, he has served as Director of the Molecular Biophysics Training Program, Director of the Center for Structural Biology, Chairman of the BMBCB Department (two terms), and is the founding and present Director of the Keck Biophysics Facility. He has been a Member of the High Table at King's College, Cambridge, a Searle Scholar, a Presidential Young Investigator, and a Visiting Professor at Rockefeller University and at the University of Rome "La Sapienza". His research investigates the biophysical chemistry of DNA and protein-DNA complexes, with a focus in the area of chromosome structure and gene regulation. His work on the genomic code for nucleosome positioning has attracted special attention, with feature stories in The New York Times and many scientific journals.
