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Event: 1503

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Histone acetylation, increase

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Histone acetylation, increase
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
organ

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
regulation of protein modification process histone increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Histone deacetylase inhibition leading to testicular atrophy KeyEvent Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed
HDAC inhibition leads to neural tube defects KeyEvent Allie Always (send email) Under Development: Contributions and Comments Welcome
C6R-Derived Protein K7 following Monkeypox infection leads to heart failure KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
mouse Mus musculus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Not Otherwise Specified Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Gene transcription is regulated with the balance between acetylation and deacetylation. A dynamic balance of histone acetylation and histone deacetylation is typically catalyzed by enzymes with histone acetyltransferase (HAT) and HDAC activities. Histone acetylation relaxes chromatin and makes it accessible to transcription factors, whereas deacetylation is associated with gene silencing. The balance can be disturbed also by targeting HAT, not only HDACs. At least theoretically, an activation of HAT might lead to an increase in histone acetylation. The acetylation and deacetylation are modulated on the NH3+ groups of lysine amino acid residues in histones. HDAC inhibition promotes hyperacetylation by inhibiting the deacetylation of histones with classes of H2A, H2B, H3, and H4 in nucleosomes. [Wade et al., 2008]. The inhibition of HDACs results in an accumulation of acetylated proteins such as tubulin or histones.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Histone acetylation is measured by the immunological detection of histone acetylation with anti-acetylated histone antibodies [Richon et al., 2004]. Histone acetylation on chromatin can be measured using the labeling method with sodium [3H]acetate [Gunjan et al., 2001]. The histone acetylation increase is detected as global histone acetylation changes by Western blot or mass spectrometry (MS)-based proteomics methods or as site-specific histone acetylation changes using chromatin immunoprecipitation (ChIP) or ChIP-on-Chip.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The histone acetylation increase by HDIs is well conserved between species from lower organisms to mammals.

・MAA, an HDAC inhibitor, induces acetylation of histones H3 and H4 in Sprague-Dawley rats (Rattus norvegicus) [Wade et al., 2008].

・It is also reported that MAA promotes acetylation of H4 in HeLa cells (Homo sapiens) and spleens from C57BL/6 mice (Mus musculus) treated with MAA [Jansen et al., 2014].

・VPA, an HDAC inhibitor, induces hyperacetylation of histone H4 in protein extract of mouse embryos (Mus musculus) exposed in utero for 1 hr to VPA [Di Renzo et al., 2007a].

・Apicidin, MS-275 and sodium butyrate, HDAC inhibitors, induce hyperacetylation of histone H4 in homogenates from mouse embryos (Mus musculus) after the treatments [Di Renzo et al., 2007b].

・MAA acetylates histones H3K9 and H4K12 in limbs of CD1 mice (Mus musculus) [Dayan and Hales, 2014].

References

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

Dayan, C. and Hales, B.F. (2014), "Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro", Birth Defects Res (Part B) 101:254-261

Di Renzo, F. et al. (2007a), "Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity", Toxicol and Appl Pharmacol 220:178-185

Di Renzo, F. et al. (2007b), "Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate", Toxicol Sci 98:582-588

Gunjan, A. et al. (2001), "Core histone acetylation is regulated by linker histone stoichiometry in vivo", J Biol Chem 276:3635-3640

Jansen, M.S. et al. (2014), "Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition", Proc Natl Acad Sci USA 101:7199-7204

Richon, V.M. et al. (2004), "Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo", Methods Enzymol 376:199-205

Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831