When you think H3K4, think activation. Whether it’s methylated or acetylated, this site will turn on genes faster than you can say PRDM9. Acetylation of all histone residues are activating, and H3K4 is no exception. The real interest in H3K4 lies in its methylation. Methylation of this fourth amino acid residue from the N-terminus of histone H3 is one of the most studied histone modifications, and with good reason: it’s tightly associated with the promoters of active genes. Like all lysine residues, H3K4 can be mono, di, or tri methylated, and each have slightly different distributions. H3K4me3 is favored by researchers looking to get the most bang for their buck, since it is the methylation state associated with transcriptional start sites of actively transcribed genes (Barski et al., 2007).
Histone H3K4 and Transcription
So how can a tiny methyl group be so important for transcription? Methylation doesn’t open up the chromatin by changing its charge like acetylation does. While this is still an active area of research, it is clear that specific histone methylation states regulate transcription by promoting the binding of positive transcription factors and blocking negative ones. For example, H3K4me3 recruits the chromatin remodeling factors CHD1 (Flanagan et al., 2005) and BPTF (Li et al., 2006) which open chromatin, while preventing the binding of the repressive NuRD (Nishioka et al., 2002) and INHAT complexes (Schneider et al., 2004).
The link between H3K4 and transcription is about is clear-cut as relationships get in the epigenetic world, but of course it isn’t 100%, that would just be too easy. The most notable exception is the existence of “bivalent domains” where H3K4me3 occupies the same promoter as repressive marks, such as H3K27me3 often at important developmental genes (Bernstein et al., 2006). While there role is still largely unknown, it is believed that these domains have a role in keeping promoters developmental genes inactive, yet “poised” to be transcribed (Voigt et al., 2013). This makes a lot of sense, since H3K4me appears to be very important in development. H3K4 methylation enzymes were initially identified as regulators of Hox genes.
A relatively recent paper has further elucidated the mechanism by which H3K4me3 promotes rapid gene activation (Lauberth et al., 2013). The paper demonstrates how some specific protein interactions with H3K4me3 direct the formation of the preinitiation complex at p53 regulated promoters.
Histone H3K4 Additional Reading
This is a detailed review of H3K4 methylation. Specifics about the deposition and reading of H3K4 are presented, as well as how this mark affects chromatin structure on a broad scale.
This is a key paper defining the localization of all common histone methylations in the human genome. Definitely worth a read, this is a great resource.
Histone H3K4 References
- Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Schones, D.E., Wang, Z., Wei, G., Chepelev, I., and Zhao, K. (2007). High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837.
- Bernstein, B.E., Mikkelsen, T.S., Xie, X., Kamal, M., Huebert, D.J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326.
- Flanagan, J.F., Mi, L.Z., Chruszcz, M., Cymborowski, M., Clines, K.L., Kim, Y., Minor, W., Rastinejad, F., and Khorasanizadeh, S. (2005). Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1181-1185.
- Lauberth, S.M., Nakayama, T., Wu, X., Ferris, A.L., Tang, Z., Hughes, S.H., and Roeder, R.G. (2013). H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell 152, 1021-1036.
- Li, H., Ilin, S., Wang, W., Duncan, E.M., Wysocka, J., Allis, C.D., and Patel, D.J. (2006). Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91-95.
- Nishioka, K., Chuikov, S., Sarma, K., Erdjument-Bromage, H., Allis, C.D., Tempst, P., and Reinberg, D. (2002). Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev. 16, 479-489.
- Ruthenburg, A.J., Allis, C.D., and Wysocka, J. (2007). Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol. Cell 25, 15-30.
- Schneider, R., Bannister, A.J., Weise, C., and Kouzarides, T. (2004). Direct binding of INHAT to H3 tails disrupted by modifications. J. Biol. Chem. 279, 23859-23862.
- Voigt, P., Tee, W.W., and Reinberg, D. (2013). A double take on bivalent promoters. Genes Dev. 27, 1318-1338.