Upstream eventHistone acetylation, increase
Altered, Gene Expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leads to neural tube defects||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
The structure of chromatin is a major component of gene regulation in eukaryotes by providing or preventing accessibility for the transcriptional machinery to the relevant regulatory DNA sequences. Histone acetylation is one of the major posttranslational modifications that are involved in the regulation of gene expression. Generally spoken, acetylation is correlated with actively transcribed genes, whereas hypoacetylation is involved in gene silencing.
Evidence Supporting this KER
In all eukaryotes, the DNA containing the genetic information of an organism is organized in chromatin. The basic unit of chromatin is the nucleosome around which the naked DNA is wrapped. A nucleosome consists of two copies of each of the core histones H2A, H2B, H3 and H4 (Luger et al., 1997). In general, chromatin is a permissive structure for all DNA-dependent processes such as DNA replication, recombination, repair, and transcription and therefore also for gene expression. However, chromatin structure is very dynamically regulated and can be made accessible for the transcriptional machinery and is, therefore, an important mechanism of gene regulation. One mechanism of chromatin structural regulation is the post-translational modifications of the histone proteins including the acetylation of lysine residues (reviewed in (Bannister and Kouzarides, 2011; Bannister et al., 2002; Kouzarides, 2007; Tessarz and Kouzarides, 2014)). These modifications serve as a docking station for further proteins and protein complexes that finally open or close the chromatin structure and allow or inhibit access of the transcriptional machinery (Musselman et al., 2012) or directly influence DNA histone interaction (reviewed in (Tessarz and Kouzarides, 2014). Histones get acetylated by histone acetyltransferases (HAT) and deacetylated by histone deacetylases (HDAC) (reviewed in (Gallinari et al., 2007; Bannister and Kouzarides, 2011; Kouzarides, 2007)). In general, it can be assumed, hyperacetylated histones are associated with actively transcribed genes, whereas hypoacetylation of histones is involved in gene silencing.
The first direct evidence that histone acetylation has an impact on gene expression came from mutation studies in yeast. Using ChIP on chip analysis showed that mutation or deletions of HDAC enzymes lead to changed gene expression levels on a subset of genes (Xu et al., 2005; Bernstein et al., 2000; Robyr et al., 2002).
In the Drosophila cell line S2, it was shown that deregulation of transcription occurs only by know-down (RNAi) HDAC enzymes, that at least class 1 and 3 HDAC enzymes have an influence on gene expression (measured via gene chips). However, this study did not show a direct link between histone acetylation and gene expression (Foglietti et al., 2006).
In mice knockout of HDACs are mostly embryonically lethal. However, the use of embryonic stem cells and the expression and acetylation profiles shows that also in mice an imbalance of histone acetylation may lead to changes in gene expression (Zupkovitz et al., 2006).
Major gene expression changes were observed during the differentiation of hESC towards neuroectodermal progenitor cells. In these studies also the acetylation status of the deregulated genes was investigated by chromatin immunoprecipitation (Balmer et al., 2014; Balmer et al., 2012)
Uncertainties and Inconsistencies
All above-mentioned analysis are indirect or in purified systems.
Therefore a direct cause-consequence relation is difficult to obtain.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Balmer, N. V., Weng, M. K., Zimmer, B. et al. (2012). Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet 21, 4104-4114. doi:10.1093/hmg/dds239
Balmer, N. V., Klima, S., Rempel, E. et al. (2014). From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88, 1451-1468. doi:10.1007/s00204-014-1279-6
Bannister, A. J., Schneider, R. and Kouzarides, T. (2002). Histone methylation: Dynamic or static? Cell 109, 801-806. doi:S0092867402007985 [pii]
Bannister, A. J. and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Res 21, 381-395. doi:10.1038/cr.2011.22
Bernstein, B. E., Tong, J. K. and Schreiber, S. L. (2000). Genomewide studies of histone deacetylase function in yeast. Proc Natl Acad Sci U S A 97, 13708-13713. doi:10.1073/pnas.250477697
Foglietti, C., Filocamo, G., Cundari, E. et al. (2006). Dissecting the biological functions of drosophila histone deacetylases by rna interference and transcriptional profiling. J Biol Chem 281, 17968-17976. doi:10.1074/jbc.M511945200
Gallinari, P., Di Marco, S., Jones, P. et al. (2007). Hdacs, histone deacetylation and gene transcription: From molecular biology to cancer therapeutics. Cell Res 17, 195-211. doi:7310149 [pii]
Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705.
Musselman, C. A., Lalonde, M. E., Cote, J. et al. (2012). Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol 19, 1218-1227. doi:10.1038/nsmb.2436
Robyr, D., Suka, Y., Xenarios, I. et al. (2002). Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109, 437-446.
Tessarz, P. and Kouzarides, T. (2014). Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol 15, 703-708. doi:10.1038/nrm3890
Xu, F., Zhang, K. and Grunstein, M. (2005). Acetylation in histone h3 globular domain regulates gene expression in yeast. Cell 121, 375-385. doi:10.1016/j.cell.2005.03.011
Zupkovitz, G., Tischler, J., Posch, M. et al. (2006). Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol 26, 7913-7928. doi:10.1128/MCB.01220-06