Cancer cells exhibit alterations in parameters of nuclear architecture that control cell fate and compromise control of cell growth. Our Program has established new biological paradigms by showing that gene regulatory factors integrate cell signaling at chromatin microenvironments ('subnuclear foci') and support epigenetic mechanisms through association with mitotic chromosomes. In collaboration with other Program Project investigators. Project 1 will now establish new dimensions in gene regulation by defining perturbations in architecturally linked regulatory mechanisms during interphase and mitosis in AML and breast cancer cells. Our central hypothesis is that (i) subnuclear targeting of transcription factors to gene regulatory foci during interphase and (ii) the association of transcription factors with their target genes in mitotic chromosomes are fundamental to the retention of biological states of normal and cancer cells. Therefore, we will use IF microscopy, biochemical, genomic and proteomic approaches (i) to characterize modifications in architectural epigenetics and molecular pathological consequences of expressing the translocation-related t(8;21) AML-ETO fusion protein (Aim 1), (ii) to analyze genes that are transcriptionally and spatially controlled by Runx2 in chromatin micro-environments ('subnuclear foci') during interphase in breast cancer cells (Aim 2), and (iii) to examine Runx2 mediated architectural epigenetics in breast cancer cells by characterization of Runx2 and cognate gene regulatory factors that associate with mitotic chromosomes (Aim 3). By investigating the functional role of Runx2 in establishing chromatin micro- environments ('subnuclear foci') during interphase and architectural epigenetics in cancer cells during mitosis, we will challenge traditional biochemical views of gene regulation by defining the pathological linkages between modifications in nuclear architecture and gene expression that are fundamental to the molecular etiology of tumorigenesis.

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Changes in the overall shape and structure ofthe nucleus are pathological hallmarks of cancer cells that are linked to cellular transformation. This study will use state-of-the-art methods to characterize how targeting of oncogenic transcription factors to specific subnuclear structures and mitotic chromosomes supports gene regulation as components of a novel epigenetic mechanism ('architectural epigenetics').

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-0)
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University of Vermont & St Agric College
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Barutcu, A Rasim; Hong, Deli; Lajoie, Bryan R et al. (2016) RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells. Biochim Biophys Acta 1859:1389-1397
Varela, Nelson; Aranguiz, Alejandra; Lizama, Carlos et al. (2016) Mitotic Inheritance of mRNA Facilitates Translational Activation of the Osteogenic-Lineage Commitment Factor Runx2 in Progeny of Osteoblastic Cells. J Cell Physiol 231:1001-14
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Barutcu, A Rasim; Lajoie, Bryan R; Fritz, Andrew J et al. (2016) SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells. Genome Res 26:1188-201
VanOudenhove, Jennifer J; Medina, Ricardo; Ghule, Prachi N et al. (2016) Transient RUNX1 Expression during Early Mesendodermal Differentiation of hESCs Promotes Epithelial to Mesenchymal Transition through TGFB2 Signaling. Stem Cell Reports 7:884-896
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Taipaleenmäki, Hanna; Farina, Nicholas H; van Wijnen, Andre J et al. (2016) Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget :
VanOudenhove, Jennifer J; Grandy, Rodrigo A; Ghule, Prachi N et al. (2016) Unique Regulatory Mechanisms for the Human Embryonic Stem Cell Cycle. J Cell Physiol :
Barutcu, A Rasim; Fritz, Andrew J; Zaidi, Sayyed K et al. (2016) C-ing the Genome: A Compendium of Chromosome Conformation Capture Methods to Study Higher-Order Chromatin Organization. J Cell Physiol 231:31-5
Wu, Qiong; Sharma, Soni; Cui, Hang et al. (2016) Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells. Oncotarget 7:27158-75

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