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Relationship: 1997

Title

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 acetylation, increase leads to Cell cycle, disrupted

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Histone acetylation, increase

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Cell cycle, disrupted

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 leading to testicular atrophy	adjacent	Moderate	Moderate	Brendan Ferreri-Hanberry (send email)	Open for citation & comment	WPHA/WNT Endorsed

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

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

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

Upon histone acetylation increase, cell cycle regulation is disrupted, where acetylation in the promoter region of the coding genes has a close correlation [Gurvich et al., 2004]. Transient histone hyperacetylation was sufficient for the activation of molecules involving cell cycle regulation such as inducing p21 gene expression [Wu et al., 2001]. Histone hyperacetylating agents butyrate and TSA induced mRNA expression of cell cycle regulator gene [Archer et al., 1998]. SAHA induced the accumulation of acetylated histones in the chromatin of the gene regulating cell cycle [Richon et al., 2000].

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

The histone acetylation causes cell cycle disruption in several pathways, in which the specific molecule involvement remains uncertain.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Histone acetylation occurs in a dose-dependent manner with the treatment of chidamide for 48 hrs [Yuan et al., 2019]. The expression of proteins related to G₀/G₁ cell cycle arrest, p21, and phosphorylated p53 is increased in a dose-dependent manner [Yuan et al., 2019].

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Dose-response of histone acetylation and expression of p21 and phosphorylated p53 showed that treatment with 0.5, 1, or 2 microM of chidamide for 48hrs induced histone acetylation in RPMI8226 myeloma cells, while 2, 4, or 8 microM of chidamide for 48 hrs induced histone acetylation in U266 myeloma cells [Yuan et al., 2019]. Chidamide treatment in 0.5, 1, or 2 microM in RPMI8226 or 2, 4, or 8 microM in U266 induced G₀/G₁ arrest in the myeloma cells [Yuan et al., 2019]. Dose-response of valproic acid (VPA) showed that 5, 10, and 20 mM of VPA inhibited HDAC6 and HDAC7 activity in 293T cells, and 0.1-2 mM of VPA induced acetylation of lysine in H3 in U937 cells [Gurvich et al., 2004]. The p21 protein level was induced with the treatment of 0.25-2 mM of VPA in U937 cells [Gurvich et al., 2004].

Time-scale

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

Time course for histone H4 hyperacetylation in response to repeated doses of TSA every 8 hrs showed that histone hyperacetylation was peaked in 12 hrs in an 8-fold increase and showed a 5-fold increase in 24 hrs compared to control [Wu et al., 2001]. TSA (0.3 microM) induced cell cycle regulator p21 mRNA expression in 1 hr after stimulation and the induction is returned to the basal level in 24 hrs [Wu et al., 2001]. Sodium butyrate (5 mM) and repetitive doses of TSA (0.3 microM, every 8 hrs) induced the p21 mRNA level in 24 hrs in HT-29 cells [Wu et al., 2001]. Acetylation of p21 promoter and p21 mRNA induction were correlated in the treatment of valproic acid and analogs [Gurvich et al., 2004]. MAA-induced acetylation increases in histones H3 and H4 was occurred in 4, 8, 12 hrs and returned to basal level in 24 hrs after the treatment in rat testis [Wade et al., 2008].

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

The relationship between increased histone acetylation and cell cycle disruption is likely well conserved between species. The present KER focuses on the pathway of p21, a cell-cycle regulator, leading to apoptosis. The examples are only given for mammals:

Chidamide induced histone acetylation and cell cycle arrest in RPMI8226 and U266 human myeloma cells (Homo sapiens) [Yuan et al., 2019].
TSA and sodium butyrate induced cell cycle regulator p21 mRNA expression in HT-29 human colon carcinoma cells (Homo sapiens) [Wu et al., 2001].
VPA increased acetylation of histone H3 from 3 hrs to 72 hrs after the treatment and increased p21 expression in 24 hrs after the treatment in K562 cells (Homo sapiens) [Gurvich et al., 2004].
Scriptaid, an HDI, up-regulated p21 mRNA expression in mouse embryonic kidney cells (Mus musculus) [Chen et al., 2011].