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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Serebryannyy, Leonid; Misteli, Tom (2018) Protein sequestration at the nuclear periphery as a potential regulatory mechanism in premature aging. J Cell Biol 217:21-37
Baranes-Bachar, Keren; Levy-Barda, Adva; Oehler, Judith et al. (2018) The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. Mol Cell 69:866-878.e7
Kubben, Nard; Misteli, Tom (2017) Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 18:595-609
DeBoy, Emily; Puttaraju, Madaiah; Jailwala, Parthav et al. (2017) Identification of novel RNA isoforms of LMNA. Nucleus 8:573-582
Larson, Daniel R; Misteli, Tom (2017) The genome-seeing it clearly now. Science 357:354-355
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
Pegoraro, Gianluca; Misteli, Tom (2017) High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease. Trends Genet 33:604-615
Gudla, Prabhakar R; Nakayama, Koh; Pegoraro, Gianluca et al. (2017) SpotLearn: Convolutional Neural Network for Detection of Fluorescence In Situ Hybridization (FISH) Signals in High-Throughput Imaging Approaches. Cold Spring Harb Symp Quant Biol 82:57-70
Finn, Elizabeth H; Misteli, Tom (2017) Genome Architecture from a Different Angle. Dev Cell 41:3-4

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