The aim of our laboratory is to understand how genomes are organized in vivo and how this organization contributes to genome function in health and disease. We have made significant progress in several areas: We have extended our earlier efforts to develop imaging methods to visualize genome function in living cells. In particular, we have developed an experimental system which allows us for the first time to visualize the behavior of broken DNA regions in living cells. We have used this system to probe the mechanism by which cancer chromosome translocations occur in intact cells. We have also continued our ongoing work on exploring the spatial organization of the genome in the interphase cell nucleus. We have developed novel software tools to analyze spatial genome positioning and we have applied it to the analysis of genome organization differences in normal and cancer cells. We are applying these methods to the development of novel cancer diagnosis strategies. Finally, we are exploring the molecular mechanisms of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS), in particular as a means to uncover the process of aging-related tumor formation. We are exploring the mechanism by which higher order genome organization is lost in HGPS patient cells and we are investigating the molecular basis for the organismal defects in HGPS patients and during normal aging. We are also using HGPS to explore the molecular mechanisms of aging-associated cancer formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010309-13
Application #
8348971
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2011
Total Cost
$2,412,816
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Pegoraro, Gianluca; Misteli, Tom (2017) High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease. Trends Genet 33:604-615
Shachar, Sigal; Misteli, Tom (2017) Causes and consequences of nuclear gene positioning. J Cell Sci 130:1501-1508
Finn, Elizabeth H; Pegoraro, Gianluca; Shachar, Sigal et al. (2017) Comparative analysis of 2D and 3D distance measurements to study spatial genome organization. Methods 123:47-55
Torres, Cristina Morales; Biran, Alva; Burney, Matthew J et al. (2016) The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 353:
Bustin, Michael; Misteli, Tom (2016) Nongenetic functions of the genome. Science 352:aad6933
Finn, Elizabeth H; Misteli, Tom; Shachar, Sigal (2016) Painting a Clearer Picture of Chromatin. Dev Cell 36:356-7
Meaburn, Karen J; Agunloye, Olufunmilayo; Devine, Michelle et al. (2016) Tissue-of-origin-specific gene repositioning in breast and prostate cancer. Histochem Cell Biol 145:433-46
Gordon, Leslie B; Kieran, Mark W; Kleinman, Monica E et al. (2016) The decision-making process and criteria in selecting candidate drugs for progeria clinical trials. EMBO Mol Med 8:685-7
Ji, Xiong; Dadon, Daniel B; Powell, Benjamin E et al. (2016) 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell 18:262-75
Kubben, Nard; Brimacombe, Kyle R; Donegan, Megan et al. (2016) A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds. Methods 96:46-58

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