Key Event Title
|Level of Biological Organization|
Key Event Components
|regulation of protein modification process||histone||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Histone deacetylase inhibition leading to testicular atrophy||KeyEvent|
|HDAC inhibition leads to neural tube defects||KeyEvent|
|Not Otherwise Specified||Moderate|
Key Event Description
Gene transcription is regulated with the balance between acetylation and deacetylation. A dynamic balance of histone acetylation and histone deacetylation are 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 lease theoretically, an activation of HAT might lead to increase in histone acetylation. The acetylation and deacetylation are modulated on the NH3+ groups of lysine amino acid residues in histones. DNA in acetylated histones is more accessible for transcription factors, leading to increase in gene expression. HDAC inhibition promotes the hyperacetylation by inhibiting deacetylation of histones with classes of H2A, H2B, H3 and H4 in nucleosomes. [Wade et al., 2008]. The inhibition of HDACs result in an accumulation of acetylated proteins such as tubulin or histones.
How It Is Measured or Detected
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 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 proteomic methods or as site specific histone acetylation changes using chromatin immunoprecipitation (ChIP) or ChIP-on-Chip.
Domain of Applicability
The histone acetylation increase by HDIs is well conserved between species from lower organism to mammals.
・MAA, a HDAC inhibitor, induces acetylation of histones H3 and H4 in Sprague-Dawley (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, a HDAC inhibitor, induces hyperacetylation of histone H4 in protein extract of mouse embryos (Mus musculus) exposed in utero for 1h 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].
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