Our program project is a thematically and operationally integrated multidisciplinary approach to experimentally address components of nuclear organization that are functionally linked to modified transcriptional control in transformed and tumor cells. Our working hypothesis is that parameters of nuclear architecture support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, genes and regulatory complexes as dynamic, three-dimensional microenvironments within the nucleus. In a highly collaborative setting, this program project has been instrumental in establishing paradigm-shifting insights into: 1) mitotic retention of transcription factors at gene loci for epigenetic control of cell fate;2) requirements for fidelity of nuclear organization to support integration of regulatory pathways and networks;3) relationships of chromatin structure and remodeling to mammary epithelial cell morphology;4) obligatory nuclear structure-function relations in leukemia and breast cancer;and 5) contributions of regulatory protein subnuclear targeting for control of osteolysis by metastatic breast tumors. In the renewal application we will functionally define novel dimensions to regulatory mechanisms that relate nuclear structure to gene expression and to changes in nuclear architecture to aberrant growth of tumor cells. Our emphasis will be on impaired subnuclear organization and assembly of regulatory machinery in nuclear microenvironments of metastatic breast cancer and leukemia cells in which biological control is compromised. Cellular, molecular, biochemical, in vivo genetic, microscopic, genomic and proteomic strategies will be pursued to address mechanisms mediating nuclear structure-gene expression interrelationships. The program focuses on: subnuclear targeting and architectural epigenetics in cancer cells (Project 1);linkage of chromatin remodeling-mediated gene regulation with parameters of nuclear organization and breast tumorigenesis (Project 2);and organization of transcriptional complexes in nuclear microenvironments to mediate metastatic bone disease (Project 3).

Public Health Relevance

The program will link molecular mechanisms by which nuclear structure ensures fidelity of biological control and deregulation of parameters of nuclear architecture to disease progression in cancer. We will define novel components of nuclear organization that can be targeted for innovative cancer therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-0 (O1))
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Knowlton, John R
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University of Vermont & St Agric College
Schools of Medicine
United States
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Nickerson, Jeffrey A; Wu, Qiong; Imbalzano, Anthony N (2017) Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming. Front Oncol 7:49
Wu, Qiong; Lian, Jane B; Stein, Janet L et al. (2017) The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics 9:919-931
Dobson, Jason R; Hong, Deli; Barutcu, A Rasim et al. (2017) Identifying Nuclear Matrix-Attached DNA Across the Genome. J Cell Physiol 232:1295-1305
VanOudenhove, Jennifer J; Grandy, Rodrigo A; Ghule, Prachi N et al. (2017) Unique Regulatory Mechanisms for the Human Embryonic Stem Cell Cycle. J Cell Physiol 232:1254-1257
VanOudenhove, Jennifer J; Medina, Ricardo; Ghule, Prachi N et al. (2017) Precocious Phenotypic Transcription-Factor Expression During Early Development. J Cell Biochem 118:953-958
Underwood, Jean M; Becker, Klaus A; Stein, Gary S et al. (2017) The Ultrastructural Signature of Human Embryonic Stem Cells. J Cell Biochem 118:764-774
Zaidi, Sayyed K; Perez, Andrew W; White, Elizabeth S et al. (2017) An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells. Oncotarget 8:39994-40005
Farina, Nicholas H; Ramsey, Jon E; Cuke, Melissa E et al. (2017) Development of a predictive miRNA signature for breast cancer risk among high-risk women. Oncotarget 8:112170-112183
Barutcu, A Rasim; Lian, Jane B; Stein, Janet L et al. (2017) The connection between BRG1, CTCF and topoisomerases at TAD boundaries. Nucleus 8:150-155
Zaidi, Sayyed K; Frietze, Seth E; Gordon, Jonathan A et al. (2017) Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer. Mol Cell Biol 37:

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