ORCID Profile
0000-0001-7046-1257
Current Organisation
University of Bern
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Publisher: Informa UK Limited
Date: 03-04-2017
Publisher: Cold Spring Harbor Laboratory
Date: 2010
Abstract: Chromatin is nonrandomly distributed in nuclear space, yet the functional significance of this remains unclear. Here, we make use of transgenes carrying developmentally regulated promoters to study subnuclear gene positioning during the development of Caenorhabditis elegans. We found that small transgenes (copy number ≤50) are randomly distributed in early embryonic nuclei, independent of promoter activity. However, in differentiated tissues, these same transgenes occupied specific subnuclear positions: When promoters are repressed, transgenes are found at the nuclear periphery, whereas active, developmentally regulated promoters are enriched in the nuclear core. The absence of specific transgene positioning in embryonic nuclei does not reflect an absence of proteins that mediate perinuclear sequestration: Embryonic nuclei are able to sequester much larger transgene arrays (copy number 300-500) at the periphery. This size-dependent peripheral positioning of gene arrays in early embryos correlates with the accumulation of heterochromatic marks (H3K9me3 and H3K27me3) on large arrays. Interestingly, depletion of nuclear lamina components caused release of arrays from the nuclear envelope and interfered with their efficient silencing. Our results suggest that developmentally silenced chromatin binds the nuclear lamina in a manner correlated with the deposition of heterochromatic marks. Peripheral sequestration of chromatin may, in turn, support the maintenance of silencing.
Publisher: Cold Spring Harbor Laboratory
Date: 15-04-2010
DOI: 10.1101/GAD.559610
Abstract: To understand whether the spatial organization of the genome reflects the cell's differentiated state, we examined whether genes assume specific subnuclear positions during Caenorhabditis elegans development. Monitoring the radial position of developmentally controlled promoters in embryos and larval tissues, we found that small integrated arrays bearing three different tissue-specific promoters have no preferential position in nuclei of undifferentiated embryos. However, in differentiated cells, they shifted stably toward the nuclear lumen when activated, or to the nuclear envelope when silent. In contrast, large integrated arrays bearing the same promoters became heterochromatic and nuclear envelope-bound in embryos. Tissue-specific activation of promoters in these large arrays in larvae overrode the perinuclear anchorage. For transgenes that carry both active and inactive promoters, the inward shift of the active promoter was dominant. Finally, induction of master regulator HLH-1 prematurely induced internalization of a muscle-specific promoter array in embryos. Fluorescence in situ hybridization confirmed analogous results for the endogenous endoderm-determining gene pha-4 . We propose that, in differentiated cells, subnuclear organization arises from the selective positioning of active and inactive developmentally regulated promoters. We characterize two forces that lead to tissue-specific subnuclear organization of the worm genome: large repeat-induced heterochromatin, which associates with the nuclear envelope like repressed genes in differentiated cells, and tissue-specific promoters that shift inward in a dominant fashion over silent promoters, when they are activated.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.CUB.2011.08.030
Abstract: In worms, as in other organisms, many tissue-specific promoters are sequestered at the nuclear periphery when repressed and shift inward when activated. It has remained unresolved, however, whether the association of facultative heterochromatin with the nuclear periphery, or its release, has functional relevance for cell or tissue integrity. Using ablation of the unique lamin gene in C. elegans, we show that lamin is necessary for the perinuclear positioning of heterochromatin. We then express at low levels in otherwise wild-type worms a lamin carrying a point mutation, Y59C, which in humans is linked to an autosomal-dominant form of Emery-Dreifuss muscular dystrophy. Using embryos and differentiated tissues, we track the subnuclear position of integrated heterochromatic arrays and their expression. In LMN-1 Y59C-expressing worms, we see abnormal retention at the nuclear envelope of a gene array bearing a muscle-specific promoter. This correlates with impaired activation of the array-borne myo-3 promoter and altered expression of a number of muscle-specific genes. However, an equivalent array carrying the intestine-specific pha-4 promoter is expressed normally and shifts inward when activated in gut cells of LMN-1 Y59C worms. Remarkably, adult LMN-1 Y59C animals have selectively perturbed body muscle ultrastructure and reduced muscle function. Lamin helps sequester heterochromatin at the nuclear envelope, and wild-type lamin permits promoter release following tissue-specific activation. A disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction in LMN-1 Y59C worms phenocopies Emery-Dreifuss muscular dystrophy.
Location: Switzerland
No related grants have been discovered for Benjamin Towbin.