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.
| Serebryannyy, Leonid A; Yemelyanov, Alex; Gottardi, Cara J et al. (2017) Nuclear ?-catenin mediates the DNA damage response via ?-catenin and nuclear actin. J Cell Sci 130:1717-1729 |
| Shah, M Y; Martinez-Garcia, E; Phillip, J M et al. (2016) MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene 35:5905-5915 |
| Voong, Lilien N; Xi, Liqun; Sebeson, Amy C et al. (2016) Insights into Nucleosome Organization in Mouse Embryonic Stem Cells through Chemical Mapping. Cell 167:1555-1570.e15 |
| Serebryannyy, Leonid A; Cruz, Christina M; de Lanerolle, Primal (2016) A Role for Nuclear Actin in HDAC 1 and 2 Regulation. Sci Rep 6:28460 |
| Hill, Steven M; Heiser, Laura M; Cokelaer, Thomas et al. (2016) Inferring causal molecular networks: empirical assessment through a community-based effort. Nat Methods 13:310-8 |
| Zhao, Baobing; Mei, Yang; Schipma, Matthew J et al. (2016) Nuclear Condensation during Mouse Erythropoiesis Requires Caspase-3-Mediated Nuclear Opening. Dev Cell 36:498-510 |
| Serebryannyy, Leonid A; Parilla, Megan; Annibale, Paolo et al. (2016) Persistent nuclear actin filaments inhibit transcription by RNA polymerase II. J Cell Sci 129:3412-25 |
| Chuang, Yishan; Hung, Michelle E; Cangelose, Brianne K et al. (2016) Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli. Innate Immun 22:647-657 |
| Kreamer, Naomi N; Phillips, Rob; Newman, Dianne K et al. (2015) Predicting the impact of promoter variability on regulatory outputs. Sci Rep 5:18238 |
| Mulligan, Peter J; Chen, Yi-Ju; Phillips, Rob et al. (2015) Interplay of Protein Binding Interactions, DNA Mechanics, and Entropy in DNA Looping Kinetics. Biophys J 109:618-29 |
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