Organisation, ontogenetische Differenzierung und Evolution invertierter Stäbchen-Photorezeptorkerne
Biologie des Verhaltens und der Sinne
Evolution, Anthropologie
Zellbiologie
Zusammenfassung der Projektergebnisse
The cell nucleus is a remarkably well-organized organelle with membraneless but distinct compartments of various functions. The largest of the compartments - transcriptionally active euchromatin and transcriptionally inactive heterochromatin - are spatially segregated in such a way that the active genomic loci occupy the nuclear interior, whereas silent genomic loci are preferentially associated with the nuclear periphery. This rule is broken by rod photoreceptor cells of nocturnal mammals, in which the two major compartments have inverted nuclear positions. The position and dense compaction of heterochromatin in the nuclear center converts rod nuclei into microlenses focusing light and thus facilitating nocturnal vision. As often the case in biology, when a mutation helps to understand normal processes and structures, inverted nuclei have served as a tool to unravel general principles of conventional nuclear organization. In the last 10 years, we used this model to study important mechanisms driving genome folding within the cell nucleus. (i) We have discovered two major protein complexes tethering heterochromatin to the nuclear periphery, LBR-dependent and lamin A/C-dependent tethers. (ii) By studying rod cell nuclei of the mouse carrying a human artificial chromosome, we demonstrated autonomous behavior of small genomic segments and postulated that building of a functional nucleus is largely a self-organizing process based on mutual recognition of chromosome segments belonging to the major chromatin classes. (iii) Using both biological experiments and polymer modeling, we discovered what drives nuclear compartmentalization: we showed that attractions between heterochromatic regions are essential for the phase separation of the active and inactive genome in inverted and conventional nuclei. In addition, our work paved a new way for retinal optic studies and draw attention of those researchers who use mouse retina as a model for DNA-damage and studies of other regenerative processes: the unique structure of inverted nuclei necessitates a careful translation of results received on mouse photoreceptors to human photoreceptors with conventional nuclei.
Projektbezogene Publikationen (Auswahl)
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(2010). 3D-FISH on cultured cells combined with immunostaining. In Methods Mol Biol, pp. 117-126
Solovei, I., and Cremer, M.
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(2010). Differentiation and large scale spatial organization of the genome. Curr Opin Genet Dev 20, 562-569
Joffe, B., Leonhardt, H., and Solovei, I.
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(2010). Fluorescence in situ hybridization (FISH) on tissue cryosections. In Methods Mol Biol, pp. 71-82
Solovei, I.
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(2012). Reliable detection of epigenetic histone marks and nuclear proteins in tissue cryosections. Chromosome Res 20, 849-858
Eberhart, A., Kimura, H., Leonhardt, H., Joffe, B., and Solovei, I.
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(2013). Epigenetics of eu- and heterochromatin in inverted and conventional nuclei from mouse retina. Chromosome Res 21, 535-554
Eberhart, A., Feodorova, Y., Song, C., Wanner, G., Kiseleva, E., Furukawa, T., Kimura, H., Schotta, G., Leonhardt, H., Joffe, B., Solovei, I.
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(2013). LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152, 584-598
Solovei, I., Wang, A.S., Thanisch, K., Schmidt, C.S., Krebs, S., Zwerger, M., Cohen, T.V., Devys, D., Foisner, R., Peichl, L., Herrmann, H., Blum, H., Engelkamp, D., Stewart, C.L., Leonhardt, H., Joffe, B.
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(2014). Diurnality and Nocturnality in Primates: An Analysis from the Rod Photoreceptor Nuclei Perspective. Evol Biol 41, 1-11
Joffe, B., Peichl, L., Hendrickson, A., Leonhardt, H., and Solovei, I.
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(2014). DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution. Epigenetics Chromatin 7, 17
Song, C., Feodorova, Y., Guy, J., Peichl, L., Jost, K.L., Kimura, H., Cardoso, M.C., Bird, A., Leonhardt, H., Joffe, B., Solovei, I.
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(2015). Quick and reliable method for retina dissociation and separation of rod photoreceptor perikarya from adult mice. MethodsX 2, 39-46
Feodorova, Y., Koch, M., Bultman, S., Michalakis, S., and Solovei, I.
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(2016). How to rule the nucleus: divide et impera. Curr Opin Cell Biol 40, 47-59
Solovei, I., Thanisch, K., and Feodorova, Y.
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(2017). Nuclear envelope localization of LEMD2 is developmentally dynamic and lamin A/C dependent yet insufficient for heterochromatin tethering. Differentiation 94, 58-70
Thanisch, K., Song, C., Engelkamp, D., Koch, J., Wang, A., Hallberg, E., Foisner, R., Leonhardt, H., Stewart, C.L., Joffe, B., Solovei, I.
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(2017). Small chromosomal regions position themselves autonomously according to their chromatin class. Genome Res 27, 922-933
van de Werken, H.J.G., Haan, J.C., Feodorova, Y., Bijos, D., Weuts, A., Theunis, K., Holwerda, S.J.B., Meuleman, W., Pagie, L., Thanisch, K., Kumar, P., Leonhardt, H., Marynen, P., van Steensel, B., Voet, T., de Laat, W., Solovei, I., Joffe, B.
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(2019). Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 570, 395-399
Falk, M., Feodorova, Y., Naumova, N., Imakaev, M., Lajoie, B.R., Leonhardt, H., Joffe, B., Dekker, J., Fudenberg, G., Solovei, I., Mirny, L.
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(2019). Rod nuclear architecture determines contrast transmission of the retina and behavioral sensitivity in mice. Elife 8
Subramanian, K., Weigert, M., Borsch, O., Petzold, H., Garcia-Ulloa, A., Myers, E.W., Ader, M., Solovei, I., and Kreysing, M.
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(2020). Differences in the Response to DNA Double- Strand Breaks between Rod Photoreceptors of Rodents, Pigs, and Humans. Cells 9
Frohns, F., Frohns, A., Kramer, J., Meurer, K., Rohrer-Bley, C., Solovei, I., Hicks, D., Layer, P.G., and Lobrich, M.
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(2020). Viewing Nuclear Architecture through the Eyes of Nocturnal Mammals. Trends Cell Biol. 30, 276-289
Feodorova, Y., Falk, M., Mirny, L.A., and Solovei, I.
