Untersuchungen epigenetischer Eigenschaften des chromosomalen Elements Fab7 und der beteiligten Mechanismen in Drosophila melanogaster

In der Fruchtfliege Drosophila melanogaster sind zwei Gruppen von Genen identifiziert worden, die das segmentspezifische Expressionsmuster entwicklungsrele-vanter Regulationsfaktoren aufrechterhalten. Die Genprodukte der trithorax-Gruppe (trxG) wirken als positive Regulatoren und erhalten die Expression der Zielgene, während die Produkte der Polycomb-Gruppe (PcG) als negative Regulatoren dienen und reprimierende Funktionen ausüben. Die Produkte beider Genklassen wirken als Gedächtnisträger und „frieren“ den Expressionszustand ihrer Zielgene ein, indem sie an sogenannte „Cellular Memory Modules“ (CMMs) binden. Diese DNA Elemente sind am Umschaltungen der Zielgene vom reprimierten in den aktivierten Expressionszustand maßgeblich beteiligt. Um die Vorgänge während der Umschaltung des CMM zu klären, wurde untersucht, ob an diesem Prozess Transkription durch das CMM selbst beteiligt ist. Hierfür nutzte man Fliegen, deren transgenes Fab7-CMM anhand des dualen Gal4 Systems vom reprimierten Grundzustand in den aktivierten Zustand umgeschaltet werden kann. In transgenen Fab7 Linien gezeigt, dass das Fab7 Element im Zuge seiner Aktivierung transkri-biert wird. Um die Zellgedächtnis-vermittelnden Abschnitte des Fab7 Elements zu bestimmen, wurden Fliegen mit gekürzten Fab7 Konstrukten hergestellt. Diese waren zwar in der Lage den repri-mierten Zustand zu bewahren, konnten jedoch nicht in den aktivierten umgeschaltet werden. Diese Beobachtung ließ vermuten, dass der proximale Abschnitt von Fab7 einen Promotor besitzt, da diese Linien keine Transkription durch die gekürzten Elemente zeigten. Im Wt wurde Transkription des endogenen Fab7 Elements gefunden. Das Fab7 Element wird dabeibidirektional und seg-mentspezifisch transkribiert. Weitere regulatorische Sequenzen des BX-C zeigten ebenfalls segmentspezifische. Die Regulation der homöotischen Gene des BX-C scheint somit durch die Transkription cis-regulatorischer Abschnitte maßgeblich mitbestimmt zu werden

Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis

SummaryDespite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC

Entwicklung und Akzeptanz multimedialer Zeitschriften

Entwicklung und Akzeptanz multimedialer Zeitschriften. - München : Fischer, 1999. - 276 S. - (Reihe Medien-Skripten ; 33). - Zugl.: Augsburg, Univ., Diss., 1999 u.d.T.: Multimediale Zeitschriften im Spannungsfeld entwicklungsspezifischer Möglichkeiten und der Nutzerakzeptan

Transcription through Intergenic Chromosomal Memory Elements of the Drosophila Bithorax Complex Correlates with an Epigenetic Switch

The proteins of the trithorax and Polycomb groups maintain the differential expression pattern of homeotic genes established by the early embryonic patterning system during development. These proteins generate stable and heritable chromatin structures by acting via particular chromosomal memory elements. We established a transgenic assay system showing that the Polycomb group response elements bxd and Mcp confer epigenetic inheritance throughout development. With previously published data for the Fab7 cellular memory module, we confirmed the cellular memory function of Polycomb group response elements. In Drosophila melanogaster, several of these memory elements are located in the large intergenic regulatory regions of the homeotic bithorax complex. Using a transgene assay, we showed that transcription through a memory element correlated with the relief of silencing imposed by the Polycomb group proteins and established an epigenetically heritable active chromatin mode. A memory element remodeled by the process of transcription was able to maintain active expression of a reporter gene throughout development. Thus, transcription appears to reset and change epigenetic marks at chromosomal memory elements regulated by the Polycomb and trithorax proteins. Interestingly, in the bithorax complex of D. melanogaster, the segment-specific expression of noncoding intergenic transcripts during embryogenesis seems to fulfill this switching role for memory elements regulating the homeotic genes

Modelling the excitation force of a standard tapping machine on lightweight floor structures

International audienceUp to now the research and development in the field of building acoustics is based mainly on measurements. In consequence the development and optimization of a new building component is a very tedious and expensive task. A considerable reduction of these costs could be achieved, if the optimization relying on measurements would be replaced-at least to some extent-by a computational prediction model. For these models it is necessary to represent not only the component and the adjacent rooms but also the excitation in a suitable way. This paper gives an overview of models for the excitation generated by a standard tapping machine taking into account the interaction between the impacting steel cylinders of the tapping machine and the vibrating surface of the floor

Repression of human γ-globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter

Binding of the stage selector protein (SSP) to the stage selector element (SSE) in the human γ-globin promoter contributes to the preferential expression of the γ-gene in fetal erythroid cells. The SSP contains the transcription factor CP2 and an erythroid-specific partner, NF-E4. The NF-E4 gene encodes a 22-kDa polypeptide employing a non-AUG initiation codon. Antisera specific to NF-E4 detects this species and an additional 14 kDa protein, which initiates from an internal methionine. Enforced expression of p14 NF-E4 in the K562 fetal/erythroid cell line, and in primary erythroid cord blood progenitors, results in repression of γ-gene expression. Biochemical studies reveal that p14 NF-E4 interacts with CP2, resulting in diminished association of CP2 with the SSE in chromatin immunoprecipitation assays. p45 NF-E2 recruitment to the γ-promoter is also lost, resulting in a reduction in RNA polymerase II and TBP binding and a fall in promoter transcriptional activity. This effect is specific, as enforced expression of a mutant form of p14 NF-E4, which fails to interact with CP2, also fails to repress γ-gene expression in K562 cells. These findings provide one potential mechanism that could contribute to the autonomous silencing of the human γ-genes in adult erythroid cells