Project 3 seeks to uncover the connection between higher-order chromatin structure and gene regulation mechanisms relevant to cancer. Cellular differentiation is linked to silencing of broad groups of genes, often with accompanying formation of "facultative heterochromatin", a more-compact (more-folded) state of chromatin. Intrinsically preferred higher order structures may be explicitly encoded in genomic DNA sequence. 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. Answering these questions depends on development of technologies for physical analyses of nuclear and chromatin structure, and then on application of them to cancer model systems. 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. Physical tools to be used include chemically sensitive and high-resolution electron microscopy methods from materials science, including use of protein-specific nanoparticle labeling techniques to image chromatin domains;non-imaging light-scattering techniques sensitive to variations and textures in chromatin domains in live cells at submicron length scales;single-molecule, single-chromosome, and single-genome micromanipulation studies of chromatin folding;and high-resolution mass spectroscopy for detection of post translational modifications of chromatin proteins. Data will be used in construction of quantitative models of how sequence features are correlated with and control higher-order chromatin structure and how that control is modified in cancerous cells, and understanding of how spatially correlated patterns of global repression impact cell cycle dynamics. The result will be illumination ofthe existence and modes of transfer of a high-level layer of information, partially genetic and partially epigenetic, involved in switching of chromatin structure and gene expression during development of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA143869-05
Application #
8549139
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$254,827
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Oyer, J A; Huang, X; Zheng, Y et al. (2014) Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 28:198-201
Ezponda, Teresa; Licht, Jonathan D (2014) Molecular pathways: deregulation of histone h3 lysine 27 methylation in cancer-different paths, same destination. Clin Cancer Res 20:5001-8
Banigan, Edward J; Marko, John F (2014) Torque correlation length and stochastic twist dynamics of DNA. Phys Rev E Stat Nonlin Soft Matter Phys 89:062706
Damania, Dhwanil; Subramanian, Hariharan; Backman, Vadim et al. (2014) Network signatures of nuclear and cytoplasmic density alterations in a model of pre and postmetastatic colorectal cancer. J Biomed Opt 19:16016
Jones, Daniel L; Brewster, Robert C; Phillips, Rob (2014) Promoter architecture dictates cell-to-cell variability in gene expression. Science 346:1533-6
Duncan, Mark T; Shin, Seungjin; Wu, Jia J et al. (2014) Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocytic and erythroid differentiation. Biotechnol Bioeng 111:2082-94
Xi, Liqun; Brogaard, Kristin; Zhang, Qingyang et al. (2014) A locally convoluted cluster model for nucleosome positioning signals in chemical map. J Am Stat Assoc 109:48-62
Brewster, Robert C; Weinert, Franz M; Garcia, Hernan G et al. (2014) The transcription factor titration effect dictates level of gene expression. Cell 156:1312-23
Wu, L; Runkle, C; Jin, H-J et al. (2014) CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor. Oncogene 33:504-13
Bhattacharyya, Sucharita; Yu, Houqing; Mim, Carsten et al. (2014) Regulated protein turnover: snapshots of the proteasome in action. Nat Rev Mol Cell Biol 15:122-33

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