API

Relationship: 1802

Title

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Histone deacetylase inhibition leads to Reduced neural crest cell migration

Upstream event

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Histone deacetylase inhibition

Downstream event

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Reduced neural crest cell migration

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 impeded craniofacial development 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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Histone acetylation is regulated by the opposing actions of histone acetylases (HATs) and histone deacetylases (HDACs). Inhibition of HDACs will be lead to hyperacetylation of histones, relaxed chromatin structure and permissive transcription, ultimately resulting in broadly altered gene expression patterns. These alterations in gene expression patterns are likely to be, at least in part, the basis of observable reduction of migration of neural crest cells (NCCs).

Evidence Supporting this KER

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Biological Plausibility

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The formation of neural crest cells (NCCs) takes place after neurulation in the developing embryo. Prior to migration, NCCs undergo epithelial to mesenchymal transition (EMT), characterized by extensively altered cellular morphology by the suppression of E-cadherin transcription (Bhatt et al., 2013). This transcriptional regulation, resulting in released cell adhesion is affected by transcription factors of the Snail family (Cano et al., 2000; Taneyhill et al., 2007; Bolos et al., 2016). The effect of HDAC inhibition on EMT has been studied most extensively in the context of cancer treatment, and numerous studies have been devoted to explore the effectiveness of chemical HDAC inhibitors as potential chemotherapeutics (Drummond et al., 2005). Several studies have found that HDAC inhibition attenuates EMT, though comparatively few focusing on EMT in pre-migratory NCCs. However chromatin immunoprecipitation experiments have demonstrated that a genetic loci of importance to EMT, a target of a Snail family transcription factor, in pre-migratory NCCs exhibits dramatic deacetylation at the time of EMT initiation (Strobl-Mazzulla and Bronner, 2012). This indicates that HDAC inhibition is likely to affect the process of EMT in NCCs as well. Furthermore, in vitro studies have shown attenuation of NCC migration in response to chemical HDAC inhibition (Dreser et al., 2015; Pallocca et al., 2016) and NCC migration has been shown to be affected in vivo by antisense mediated genetic knock down of a specific HDAC encoding gene (DeLaurier et al., 2012).

Empirical Evidence

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In vitro scratch assay data has shown reducing effects of HDAC inhibitors on the migration of NCCs. Different HDAC inhibitors have been shown to exert similar gene regulatory effects on NCCs in vitro (Dreser et al., 2015; Pallocca et al., 2016).
Genetic manipulations have been applied in vivo to show that HDAC4 is important to cranial NCC migration in developing zebrafish (DeLaurier et al., 2012).

Uncertainties and Inconsistencies

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In an in vivo situation, it is uncertain whether observed reduction of NCC migration is caused by the effects of HDAC vs. HAT action on histones, or other proteins that exhibit altered acetylation patterns in response to HDAC inhibition, e.g. tubulin (Hubbert et al., 2002).
Members of the Snail family of proteins have been reported to be dispensable in mammals (Murray and Gridley, 2006), indicating that conclusions regarding the importance of HDAC activity in relation to Snail regulation and EMT must be made with caution.

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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Bhatt, S., Diaz, R., Trainor, P. a, Wu, D.K., Kelley, M.W., Tam, P.L., et al. (2013), Cold Spring Harb Perspect Biol 5: 1–20.

Bolos, V., Peinado, H., Perez-Moreno, M.A., Fraga, M.F., Esteller, M., and Cano, A. (2016), J Cell Sci 129: 1283–1283

Cano, A., Pérez-Moreno, M.A., Rodrigo, I., Locascio, A., Blanco, M.J., Barrio, M.G. del, et al. (2000), Nat Cell Biol 2: 76–83

DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16

Dreser, N., Zimmer, B., Dietz, C., S??gis, E., Pallocca, G., Nyffeler, J., et al. (2015), Neurotoxicology 50: 56–70.

Drummond, D.C., Noble, C.O., Kirpotin, D.B., Guo, Z., Scott, G.K., and Benz, C.C. (2005), Annu Rev Pharmacol Toxicol 45: 495–528.

Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002), Nature 417: 455–458.

Murray, S.A., and Gridley, T. (2006), Proc Natl Acad Sci 103: 10300–10304.

Pallocca, G., Grinberg, M., Henry, M., Frickey, T., Hengstler, J.G., Waldmann, T., et al. (2016), Arch Toxicol 90: 159–180.

Strobl-Mazzulla, P.H., and Bronner, M.E. (2012), J Cell Biol 198: 999–1010.

Taneyhill, L.A., Coles, E.G., and Bronner-Fraser, M. (2007), Development 134: 1481–1490.