H4K12 is yet another lysine on the N-terminal tail of histone H4 that yet again is acetylated and not methylated. Starting to sound familiar? Like H4K8ac, H4K12ac is part of a “backbone” of histone modifications that are associated with active promoters (Wang et al., 2008). H4K12ac is localized to the promoter, like other H4 acetylations; however, H4 localizes more to gene bodies than the other acetylations. (Wang et al., 2008). This suggests that H4K8ac serves to facilitate transcriptional elongation (Cho et al., 1998).
H4K12ac appears to be vital for learning and memory. One of the most interesting papers on H4K12ac showed its importance in controlling gene expression in the hippocampus associated with memory consolidation (Peleg et al., 2010). Most importantly, the authors showed that normal age-related decline in memory could be ameliorated by restoration of H4K12ac.
Histone H4K12 Function
Recently it has been shown that H4K12ac is important in paternal influence on early gene expression in the zygote. Sperm chromatin is packaged with protamines instead of histones for the majority (85%) of the genome, serving to inactivate transcription. The rest of the genome is occupied by the traditional histone octamers. Data have shown some of this remaining portion of the chromatin bear H4 lysine acetylations that are passed into the zygote and may be involved in early embryo development (van der Heijden et al., 2006). Further studies found that H4K12ac was enriched surrounding transcriptional start sites, and that the genes it occupied had a significant bias toward developmental functions (Paradowska et al., 2012). Several of these genes were also shown to actually be expressed at high levels in the early zygote (Paradowska et al., 2012). Whether other histone acetylations are equally as important for embryo development remains to be seen.
Histone H4K12 Additional Reading
This review looks at the roles of various histone acetylations in memory. It pays particular attention to H4K12ac, and give a comprehensive look at how this and other acetylations are intricately involved in learning and memory.
Ito, T., Umehara, T., Sasaki, K., Nakamura, Y., Nishino, N., Terada, T., Shirouzu, M., Padmanabhan, B., Yokoyama, S., Ito, A., and Yoshida, M. (2011). Real-Time Imaging of Histone H4K12–Specific Acetylation Determines the Modes of Action of Histone Deacetylase and Bromodomain Inhibitors. Chem. Biol. 18, 495-507.
For those interested in more detail on the mechanistic details of the catalysis of H4K12ac and the mode of action of inhibitors, this is a very detailed, well designed experiment to read through. The paper also gives some limited background on H4K12ac and its biological relevance.
- Cho, H., Orphanides, G., Sun, X., Yang, X.J., Ogryzko, V., Lees, E., Nakatani, Y., and Reinberg, D. (1998). A human RNA polymerase II complex containing factors that modify chromatin structure. Mol. Cell. Biol. 18, 5355-5363.
- Paradowska, A.S., Miller, D., Spiess, A.N., Vieweg, M., Cerna, M., Dvorakova-Hortova, K., Bartkuhn, M., Schuppe, H.C., Weidner, W., and Steger, K. (2012). Genome wide identification of promoter binding sites for H4K12ac in human sperm and its relevance for early embryonic development. Epigenetics 7, 1057-1070.
- Peleg, S., Sananbenesi, F., Zovoilis, A., Burkhardt, S., Bahari-Javan, S., Agis-Balboa, R.C., Cota, P., Wittnam, J.L., Gogol-Doering, A., Opitz, L., et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328, 753-756.
- van der Heijden, G.W., Derijck, A.A., Ramos, L., Giele, M., van der Vlag, J., and de Boer, P. (2006). Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin. Dev. Biol. 298, 458-469.
- Wang, Z., Zang, C., Rosenfeld, J.A., Schones, D.E., Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Peng, W., Zhang, M.Q., and Zhao, K. (2008). Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40, 897-903.