Astrid E. Visser

Step out of the groove: Epigenetic gene control systems and engineered transcription factors

At the linear DNA level, gene activity is believed to be driven by binding of transcription factors, which subsequently recruit the RNA polymerase to the gene promoter region. However, it has become clear that transcriptional activation involves large complexes of many different proteins, which not only directly recruit components of the transcription machinery but also affect the DNA folding. Such proteins, including various chromatin-modifying enzymes, alter among other processes nucleosome positioning and histone modifications and are potentially involved in changing the overall structure of the chromatin and/or the position of chromatin in the nucleus. These epigenetic regulatory features are now known to control and regulate gene expression, although the molecular mechanisms still need to be clarified in more detail. Several diseases are characterized by aberrant gene-expression patterns. Many of these diseases are linked to dysregulation of epigenetic gene-regulatory systems. To interfere with aberrant gene expression, a novel approach is emerging as a disease therapy, involving engineered transcription factors. Engineered transcription factors are based on, for example, zinc-finger proteins (ZFP) that bind DNA in a sequence-specific manner. Engineered transcription factors based on ZFP are fused to effector domains that function to normalize disrupted gene-expression levels. Zinc-finger proteins most likely also influence epigenetic regulatory systems, such as the complex set of chemical histone and DNA modifications, which control chromatin compaction and nuclear organization. In this chapter, we review how epigenetic regulation systems acting at various levels of packaging the genome in the cell nucleus add to gene-expression control at the DNA level. Since an increasing number of diseases are described to have a clear link to epigenetic dysregulation, we here highlight 10 examples of such diseases. In the second part, we describe the different effector domains that have been fused to ZFPs and are capable of activating or silencing endogenous genes, and we illustrate how these effector domains influence epigenetic control mechanisms. Finally, we speculate how accumulating knowledge about epigenetics can be exploited to make such zinc-finger-transcription factors (ZF-TF) even more effective.

Viral protein apoptin as a molecular tool and therapeutic bullet: implications for cancer control

The chicken anemia virus-derived protein apoptin induces apoptosis in human tumor cells via a p53-independent pathway, while leaving normal cells intact. Moreover, apoptin treatment in preclinical animal studies leads to reduced tumor growth or remission without a detectable effect on healthy tissues. Apoptin is activated by a still unknown tumor-specific kinase activity. The mode of action of apoptin is under intense investigation, as certain features make it a promising tool for discovering early events in tumorigenesis, identifying druggable targets for antitumor treatment and possibly serving as an antitumor therapy in itself.

Virtual reality in biological microscopic imaging

Confocal microscopes have recently allowed biologists and biomedical researchers to obtain time dependent 3D data sets of biological. objects, such as cells and tissues. Scientific visualization can provide visual presentations of structural characteristics of these data sets. This paper addresses the role of virtual reality in gaining insight in these presentations. The understanding of structural characteristics of time dependent 3D confocal biological data requires spatial judgments. Perceiving these characteristics is enhanced by using virtual reality technology. The advantage of virtual reality is particularly apparent in the exploration phase of the analysis when the behavior of the underlying biological processes is not a priori known.

Systems biology meets chromatin function. Workshop on Nuclear Organization.

The 4th EMBO Workshop on Nuclear Organization took place between 12 and 15 October 2006 in Gosau, Austria, and was organized by D. Jackson, R. van Driel, H. Lipps and H. Westerhoff. ![][1] It is clear that DNA sequence and transcription factor availability alone are not sufficient for effective gene regulation in eukaryotes. Epigenetic factors at various levels also have an essential role: for example, DNA methylation and histone modifications form the molecular basis of gene regulation by creating chromatin microenvironments that promote or prevent transcription. Gene activation requires complete cascades of chromatin modifiers to prepare the chromatin for transcription. In addition, the topology of the chromatin and the dynamic interactions between nuclear bodies influence genome function. How the appropriate and controlled expression of genes is achieved is clearly a complicated system, both in terms of the number of interacting components and the spatial heterogeneity. In other areas of cell function that are carried out by multi‐enzyme networks, the question of how function arises from the interaction of the relevant components is being addressed by various combined theoretical and experimental approaches termed ‘systems biology’. Such an approach could determine the extent to which known interactions explain chromatin function and identify what remains to be understood. Furthermore, the combination of mathematical and computational modelling with quantitative measurements fulfils an urgent requirement, as it has the rigour to derive robust predictions that can be precisely tested against experimental observations to support or disprove hypotheses. This meeting brought together experts in chromatin function and systems biology to inform each other of the approaches and issues in their respective fields, and to explore whether they are ready to interact to develop the systems biology of chromatin function. Inevitably, few of the participants could claim to span both fields, but the two opening plenary talks by … [1]: /embed/graphic-1.gif