API

Relationship: 1807

Title

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Altered, Gene Expression leads to Altered differentiation

Upstream event

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Altered, Gene Expression

Downstream event

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Altered differentiation

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leads to neural tube defects adjacent Not Specified Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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During early embryonic development of the nervous system-specific developmental genes need to be activated in a highly regulated and concerted manner. Genes need to be expressed (or silenced) at the right time and space. If this concerted regulation is disturbed this may lead to severe malformations in the later fetus. The type of malformation depends strongly on the timing of disturbance, i.e. during which developmental stage the disturbance happened. For the development of neural tube defects, especially neural tube closure, the disturbance must happen before neurulation at the stage when neuroepithelial cells arise. Therefore, for this AOP the imbalance of gene expression must occur before neural tube closure. However, compare AOP23 the inhibition of neural crest migration by HDAC inhibition happens later in embryonic development.

Evidence Supporting this KER

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Biological Plausibility

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Gene expression during embryonic development is a highly regulated process. The genes need to be expressed and silenced at the right time and place. Therefore, if cells that are determined to differentiate into e.g. NEP wrongly express neural crest marker genes this may lead to a failure of neural tube closure. One reason for this effect is that these cells lose their epithelial character and undergo an epithelial mesenchymal transition as neural crest cells do (Park and Gumbiner, 2010). In summary, imbalanced gene expression may lead to the differentiation of the wrong cell type at the wrong time and space.

Empirical Evidence

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It was shown that HDAC inhibition changes the gene expression pattern during the differentiation of hESC towards NEP cells. Furthermore, the changed differentiation track points to a wrong differentiation towards neural crest cells (Balmer et al., 2014).

The differentiation track of hESC towards NEP is strongly disturbed in vitro by 6 different (structurally not related) HDAC inhibitors in a comparable manner (Rempel et al., 2015).

TSA treated chicken embryos showed a disturbed gene expression pattern of the posterior neural tube, that points to a wrong differentiation track towards neural crest cells (Murko et al., 2013).

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Balmer, N. V., Klima, S., Rempel, E. et al. (2014). From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88, 1451-1468. doi:10.1007/s00204-014-1279-6

Murko, C., Lagger, S., Steiner, M. et al. (2013). Histone deacetylase inhibitor trichostatin a induces neural tube defects and promotes neural crest specification in the chicken neural tube. Differentiation 85, 55-66. doi:10.1016/j.diff.2012.12.001

Park, K. S. and Gumbiner, B. M. (2010). Cadherin 6b induces bmp signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest. Development 137, 2691-2701. doi:10.1242/dev.050096

Rempel, E., Hoelting, L., Waldmann, T. et al. (2015). A transcriptome-based classifier to identify developmental toxicants by stem cell testing: Design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol 89, 1599-1618. doi:10.1007/s00204-015-1573-y