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Relationship: 1802


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Histone deacetylase inhibition leads to Reduced neural crest cell migration

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Histone deacetylase inhibition leads to impeded craniofacial development adjacent Not Specified Not Specified Agnes Aggy (send email) Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

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.