Cell Fate and Nuclear Organization - Prof. Peter Meister

Meister laboratory website

Our body is composed of billions of cells, each of them achieving a specialized task. For example, our flat skin cells ensure protection from external physical and chemical aggressions whereas our rod-like photoreceptor cells in the eye allow light to be sensed in our environment. Despite this variability in structure and function, almost all cells in our body have exactly the same genome, the DNA sequence where our genetic information is stored. As an analogy, one could think of the genome as the hard disk of a computer, where every program for each cell type is stored but in each cell only one of these programs is executed.

Our body is composed of billions of cells, each of them achieving a specialized task. For example, our flat skin cells ensure protection from external physical and chemical aggressions whereas our rod-like photoreceptor cells in the eye allow light to be sensed in our environment. Despite this variability in structure and function, almost all cells in our body have exactly the same genome, the DNA sequence where our genetic information is stored. As an analogy, one could think of the genome as the hard disk of a computer, where every program for each cell type is stored but in each cell only one of these programs is executed.
The genome is physically separated from the rest of the cell within a specialized organelle, the nucleus. A high level of compaction is achieved: our genome is 2 meters long but stored in a ball of a diameter of 5 micrometers (the nucleus). This would correspond to a very thin wire the length of the distance from Zürich to Geneva stored within a basketball. The compaction of this wire is, however, neither homogenous nor constant: some regions of the genome are very densely wrapped while others are looser. This compaction level along the wire, as well as the spatial distribution of the genome (where a given segment of the wire is located inside the nuclear ball) is unique to each cell type and setup when cells acquire a specialized function. Moreover, problems in structural components of the nucleus have been shown to be causal in a number of diseases. These point to the importance of the organization of the genome in space inside the nucleus. What we aim to discover is.

The link between the execution of a given program and the subnuclear 3D localization of the individual genes – lines of codes – that achieve that program; the rules that govern gene localization.
What holds the different parts of the wire at defined places inside the nucleus.
The effect of changing the localization of individual genes and/or parts of the wire on the program and function of the cell.

 

The organism which is used for these studies is the roundworm C. elegans. This simple animal is found in our gardens on rotting fruits, its fast life cycle (3 days) makes it an ideal laboratory model. It is one of the best-known organisms in which individual different cells achieve specialized tasks (as the skin or photoreceptor cells). Since much of the machinery involved in organizing the genome in 3 dimensions is evolutionarily conserved, the knowledge gained in the roundworm will improve our understanding of the gene expression program also in more complex animals like humans where such studies are not yet possible. The characterization of what is responsible for nuclear organization will also shed light on the mechanisms that underlie induced changes in these expression programs. This knowledge will improve our comprehension of cancer appearance, where cells change their function and begin to divide anarchically. It will also help us understand how cells can revert to non-specialized states, an emerging field full of therapeutic promises..

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2014

Sharma, Rahul; Jost, Daniel; Kind, Jop; Gómez-Saldivar, Georgina; van Steensel, Bas; Askjaer, Peter; Vaillant, Cédric; Meister, Pierre (2014). Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans. Genes & development, 28(23), pp. 2591-2596. Cold Spring Harbor Laboratory Press 10.1101/gad.248864.114

Bou Dib, Peter; Gnägi, Bettina; Daly, Fiona; Sabado, Virginie; Tas, Damla; Glauser, Dominique A; Meister, Pierre; Nagoshi, Emi (2014). A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress. PLoS genetics, 10(10), e1004718. Public Library of Science 10.1371/journal.pgen.1004718

Askjaer, Peter; Galy, Vincent; Meister, Peter (2014). Modern tools to study nuclear pore complexes and nucleocytoplasmic transport in Caenorhabditis elegans. Methods in cell biology, 122, pp. 277-310. Academic Press 10.1016/B978-0-12-417160-2.00013-8

Askjaer, Peter; Ercan, Sevinç; Meister, Peter (2014). Modern techniques for the analysis of chromatin and nuclear organization in C. elegans. WormBook : the online review of C. elegans biology, pp. 1-35. wormbook.org. 10.1895/wormbook.1.169.1

2013

Sharma, Rahul; Meister, Pierre (2013). Nuclear organization in the nematode C. elegans. Current opinion in cell biology, 25(3), pp. 395-402. Elsevier 10.1016/j.ceb.2013.02.002

Meister, Pierre; Taddei, Angela (2013). Building silent compartments at the nuclear periphery: a recurrent theme. Current opinion in genetics & development, 23(2), pp. 96-103. Elsevier 10.1016/j.gde.2012.12.001

Rohner, Sabine; Kalck, Veronique; Wang, Xuefei; Ikegami, Kohta; Lieb, Jason D.; Gasser, Susan M.; Meister, Peter; Meister, Pierre (2013). Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans. Journal of cell biology, 200(5), pp. 589-604. Rockefeller Institute Press 10.1083/jcb.201207024

Lanctôt, Christian; Meister, Pierre (2013). Microscopic analysis of chromatin localization and dynamics in C. elegans. In: Shav-Tal, Yaron (ed.) Imaging Gene Expression. Methods in Molecular Biology: Vol. 1042 (pp. 153-172). New York: Humana Press 10.1007/978-1-62703-526-2_11

2012

Towbin, B.D.; Gonzalez-Aguilera, C.; Sack, R.; Gaidatzis, D.; Kalck, V.; Meister, Peter; Askjaer, P.; Gasser, S.M. (2012). Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery. Cell, 150(5), pp. 934-947. Cambridge, Mass.: Cell Press 10.1016/j.cell.2012.06.051

2011

Meister, Peter; Schott, S.; Bedet, C.; Xiao, Y.; Rohner, S.; Bodennec, S.; Hudry, B.; Molin, L.; Solari, F.; Gasser, S.M.; Palladino, F. (2011). Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism. Genome biology, 12(12), R123. London: BioMed Central Ltd. 10.1186/gb-2011-12-12-r123

Mattout, A.; Pike, B.L.; Towbin, B.D.; Bank, E.M.; Gonzalez-Sandoval, A.; Stalder, M.B.; Meister, Peter; Gruenbaum, Y.; Gasser, S.M. (2011). An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity. Current Biology, 21(19), pp. 1603-1614. Cambridge, Mass.: Cell Press 10.1016/j.cub.2011.08.030

Meister, P.; Mango, S.E.; Gasser, S.M. (2011). Locking the genome: nuclear organization and cell fate. Current opinion in genetics & development, 21(2), pp. 167-174. Amsterdam: Elsevier 10.1016/j.gde.2011.01.023

Gehlen, L.R.; Nagai, S.; Shimada, K.; Meister, P.; Taddei, A.; Gasser, S.M. (2011). Nuclear geometry and rapid mitosis ensure asymmetric episome segregation in yeast. Current Biology, 21(1), pp. 25-33. Cambridge, Mass.: Cell Press 10.1016/j.cub.2010.12.016