The authors have used a clever genetic screen to identify “Cheater mutations” in genes that confer the ability of cells to behave in a non-cooperative fashion in a tissue context. These cheater cells could for example, outgrow surrounding cells as aberrant clones, and thereby derail a tightly regulated process of differentiation that is pivotal in development. A very nice bioinformatic rendering of the data revealed that an axis of regulatory genes that are under the influence of topoisomerase I and p53 (and a few others) seem particularly critical in maintaining the choreography of development and regulatory cooperation. This is a rather fascinating and novel finding, since it underscores the importance of genomic DNA topology in maintaining orderly developmental cues, cell-cell cooperation and communication. Mutations in topo I, which would affect the superhelical structure of domains in chromatin, appear to derail embryonic development. Clearly topoisomerases are pivotal in metazoans and are a foundation in gene control. It appears that titration of DNA supercoiling during development, embryogenesis and differentiation is required and topoisomerase I, a non-sequence dependent breakage/resealing enzyme, sets the stage.
Article Source: Science
Safeguards for Cell Cooperation in Mouse Embryogenesis Shown by Genome-Wide Cheater Screen
Ensuring cooperation among formerly autonomous cells has been a central challenge in the evolution of multicellular organisms. One solution is monoclonality, but this option still leaves room for exploitative behavior, as it does not eliminate genetic and epigenetic variability. We therefore hypothesized that embryonic development must be protected by robust regulatory mechanisms that prevent aberrant clones from superseding wild-type cells. Using a genome-wide screen in murine induced pluripotent stem cells, we identified a network of genes (centered on p53, topoisomerase 1, and olfactory receptors) whose down-regulation caused the cells to replace wild-type cells in vitro and in the mouse embryo—without perturbing normal development. These genes thus appear to fulfill an unexpected role in fostering cell cooperation.
Science 27 September 2013: Vol. 341 no. 6153 pp. 1511-1514DOI:10.1126/science.1241628