H4K16 is part what should now be a familiar group of lysines on the N-terminal tail of histone H4. If you’ve been reading about the others, it should come as no surprise that H4K16 also is acetylated and not methylated. But wait; H4K16ac has some unique and interesting properties. Though H4K16ac is associated with transcriptional activation, it can also be linked with repression. The bromodomain of TIP5, part of NoRC, binds to H4K16ac (Zhou and Grummt, 2005). After binding, the NoRC complex serves to silence rDNA by recruiting HATs and DNMTs.
Histone H4K16 Function
An elegant Science paper from 2006 analysed the dynamics of ubiquitously H4K16 acetylated chromatin fibers (Shogren-Knaak et al., 2006). This paper demonstrates that H4K16ac controls both nucleosome-level interactions and higher order chromatin structure. In terms of nucleosome-level dynamics, H4K16ac inhibits the enzyme ACF from creating evenly spaced nucleosomes, which facilitates chromatin compaction and transcriptional repression (Blosser et al., 2009). H4K16ac also inhibits the formation of the 30 nm fiber and inter-fiber interactions (Shogren-Knaak et al., 2006). This suggests that the tail of histone H4 has a very important role in the assembly of higher order chromatin structure. This is also reflected in the fact that H4 has very low sequence variation between species, showing about 10-fold less variation than H2A or H2B (Thatcher and Gorovsky, 1994).
Another major point of interest about H4K16ac is its role in cancer. There is a global reduction in H4K16ac in nearly all human tumours and cancer cells lines (Fraga et al., 2005). This reduction tends to occur at repetitive sequences and co-occurs with a reduction in DNA methylation. Though the mechanism of this reduction in tumour genesis is not yet clear, given the role of H4K16 in chromatin structure its influence is not surprising.
Histone H4K16 Additional Reading
Strohner, R., Nemeth, A., Nightingale, K.P., Grummt, I., Becker, P.B., and Langst, G. (2004). Recruitment of the nucleolar remodeling complex NoRC establishes ribosomal DNA silencing in chromatin. Mol. Cell. Biol. 24, 1791-1798.
This primary paper is a great resource for more information on the NoRC complex and how it is involved in rDNA silencing.
This review looks at the role of histone modifications in cancer. It goes through different proteins which bind histone modfications, and examines how each can act as an oncogene. H4K16 and proteins that bind it are examined closely.
Kalashnikova, A.A., Porter-Goff, M.E., Muthurajan, U.M., Luger, K., and Hansen, J.C. (2013). The role of the nucleosome acidic patch in modulating higher order chromatin structure. J. R. Soc. Interface 10, 20121022.
This paper gives a detailed look at how the tail of histone H4 controls higher order chromatin structure. The paper goes into great detail about the mechanistic basis how this patch recruits other non-histone proteins and forms higher order structures.
- Blosser, T.R., Yang, J.G., Stone, M.D., Narlikar, G.J., and Zhuang, X. (2009). Dynamics of nucleosome remodelling by individual ACF complexes. Nature 462, 1022-1027.
- Fraga, M.F., Ballestar, E., Villar-Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C., Ropero, S., Petrie, K., et al. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37, 391-400.
- Shogren-Knaak, M., Ishii, H., Sun, J.M., Pazin, M.J., Davie, J.R., and Peterson, C.L. (2006). Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844-847.
- Thatcher, T.H., and Gorovsky, M.A. (1994). Phylogenetic analysis of the core histones H2A, H2B, H3, and H4. Nucleic Acids Res. 22, 174-179.
- Zhou, Y., and Grummt, I. (2005). The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr. Biol. 15, 1434-1438.