We study how the DNA in a nucleus organizes itself in order to understand how cells make decisions.
The chromosomes that make up the human genome, if put together and stretched end to end, would be about three meters long. All of that DNA has to fold and wrap and coil itself to fit into each cell’s nucleus without any tangles, which could be disastrous when a cell divides. But this folding process isn’t as simple as finding a way of packing everything neatly into the smallest possible space because where genes wind up within the nucleus can change their activity. A genome that’s organized “wrong” is a hallmark of cancer.
Previously, I used fluorescence imaging to map how chromosomes folded in thousands of different cells. I found that not just every cell, but in fact every chromosome, folded itself a little bit differently. This means there are a lot of “right” ways to fold a genome. But I also saw some interesting patterns: some folded shapes were more common in some cell types, and some regions within the cell were more variable. My work led me to hypothesize that variability itself might be a feature of how the genome works, rather than unfortunate noise hiding true signals.
My lab expands on this hypothesis in two ways: first, we’re examining how cell-to-cell variability in genome organization changes during development and disease. Second, we’re working to understand how variability in genome organization is controlled by the cell.
The myriad different cell types in metazoans are a demonstration that a single genome can give rise to many different phenotypes. The processes of differentiation and the disorder found in diseases such as cancer and neurodegeneration show that individual cells can move fluidly from one state to another in response to environmental cues or genetic injury; this fluidity requires underlying variability. I found high levels of intrinsic variation in one important epigenetic feature, genome organization.
My lab is working to 1) identify the mechanistic sources of variability in genome organization, 2) measure and map it in developmental and disease models, and 3) clarify its molecular functional consequences.
Determine the mechanisms controlling variability in genome organization
A wide range of mechanisms have been shown to drive genome organization, most prominently a combination of three factors: loop extrusion by cohesin to anchors created by the chromatin architectural protein CTCF, chromatin compartments formed by self-association of heterochromatin, and the active reorganization driven by the cell cycle. Furthermore, many of these mechanisms -- along with genome organization -- are disordered in cancer. This leads to the hypothesis that genome organizational variability might be a global feature of cancer cells with many different etiologies. A mechanistic dissection of how the factors controlling genome architecture also contribute to plasticity and variability therein will yield insights into basic principles of how cells function. A more thorough understanding of how these mechanisms are altered in cancer may help us better understand that disease as well.
Investigating the cell-type specificity of variability in genome organization
Many studies have shown cell-type-specific genome organization on a population level. I observed in my own work that cell-type-specific associations can be marked by a change in mean distance or change in variability within the population. However, many of the mechanisms likely to affect variability in genome organization on a global level (such as length of the cell cycle, expression and targeting of chromatin factors, and overall transcriptional output) are cell-type-specific as well. I will thoroughly test the hypothesis that variability in genome organization is cell-type-specific using Hi-C and imaging in in vitro and in vivo models of development.
Determine the functional role of variability in genome organization
My ultimate goal is to determine how genome organization, and particularly variability therein, determines cellular functions. To directly address this question, it will be essential to specifically alter genome organization without inducing pleiotropic effects. A better understanding of the mechanisms controlling genome organization will present the tools necessary to do these studies, and a combination of in vitro and in vivo studies should shed light on this question.
B.Sc., University of Chicago, 2004-2008
Ph.D., Stanford University, 2008-2014
Postdoctoral fellow, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 2015-2022
Honors and Awards
2010-2014 Stanford Graduate Fellowship in Science and Engineering (Smith Fellow)
2016, 2017 NIH Fellows Award for Research Excellence
2019 CCR Excellence in Postdoctoral Research Training Award
Joined OMRF scientific staff in 2022
Nakayama, K., Shachar, S., Finn, E.H., Sato, H., Hirakawa, A., and Misteli, T. Large-scale mapping of positional changes of hypoxia-responsive genes upon activation. Mol Biol Cell. 2022. PMID: 35476603
Finn, E.H., Pegoraro, G., Brandão, H.B., Valton, A.L., Oomen, M., Mirny, L., Dekker, J., and Misteli, T. Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization. Cell. 176(6):1502-1515. 2019. PMID: 30799036, PMCID: PMC6408223.
Finn, E.H., Pegoraro, G., Shachar, S., and Misteli, T. Comparative Analysis of 2D and 3D Distance Measurements to Study Spatial Genome Organization. Methods. 123:47-55. 2017. PMID: 28179124, PMCID: PMC5522766.
Finn, E.H., Smith, C.L., Rodriguez, J., Sidow, A., and Baker, J.C. Maternal Bias and Escape From X Chromosome Imprinting in the Midgestation Mouse Placenta. Dev Biol. 390(1): 80-92. 2014. PMID: 24594094, PMCID: PMC4045483.