H2A may lack many the fancy tail modifications that have make H3 and H4 so popular in epigenetics. H2A may not accessorize like H3, but it sure knows how master an outfit change: H2A has the most variants which give a dizzying array of diversity to nucleosome composition. H2A variants differ from each other mostly at their C-terminus which is responsible for intra-nucleosome binding and DNA binding. The acidic patch is also altered between variants, which is involved in higher order chromatin organization.
Histone H2A Variants
The universal H2A variants H2A.X and H2A.Z are found in almost all organisms (Talbert and Henikoff, 2010). Phosphorylation of H2A.X at serine 139 (termed γ-H2A.X) is an early response to double strand breaks, leading to structural changes and eventually repair (Rogakou et al., 1999). H2A.Z has many roles, including transcriptional activation and repression and heterochromatin formation (Rogakou et al., 1999; Zlatanova and Thakar, 2008). H2A.Bbd (Barr body deficient) is mammal specific, and is the fastest evolving histone gene (Eirin-Lopez et al., 2008). It is believed be involved in opening chromatin structure, similar to acetylation (Tolstorukov et al., 2012). Macro H2A is unique in that it contains a non-histone macro-domain, and is involved in regulation of transcription, chromatin structure, and DNA repair (Han et al., 2011). See additional reading for a review on all the H2A variants.
Histone H2A Modifications
But wait, there’s more! H2A does indeed have modifications of its own. One modification of note is H2A monoubiquitination (H2Aub1). This modification is performed by the Polycomb Repressor Complex 1 (PRC1) which is responsible for epigenetic silencing, particularly at Hox genes during development (Osley, 2006). Unsurprisingly, H2Aub1 is associated with repression of gene expression at Hox loci. H2A can also be acetylated at K5 and K9 (Beck et al., 2006), phosphorylated at S1 (Zhang et al., 2004) and methylated at R3 (Ancelin et al., 2006). Many of these modifications are involved in the early DNA damage response (Ikura et al., 2007).
Histone H2A Additional Reading:
The review gives great detail on H2A variants and the role of each from the regulation of gene expression perspective.
This review covers recent findings on the ubiquitylation of H2A and its role. The authors focus on transcription, but also discuss other relevant cellular processes.
- Ancelin, K., Lange, U.C., Hajkova, P., Schneider, R., Bannister, A.J., Kouzarides, T., and Surani, M.A. (2006). Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat. Cell Biol. 8, 623-630.
- Beck, H.C., Nielsen, E.C., Matthiesen, R., Jensen, L.H., Sehested, M., Finn, P., Grauslund, M., Hansen, A.M., and Jensen, O.N. (2006). Quantitative proteomic analysis of post-translational modifications of human histones. Mol. Cell. Proteomics 5, 1314-1325.
- Eirin-Lopez, J.M., Ishibashi, T., and Ausio, J. (2008). H2A.Bbd: a quickly evolving hypervariable mammalian histone that destabilizes nucleosomes in an acetylation-independent way. FASEB J. 22, 316-326.
- Han, W., Li, X., and Fu, X. (2011). The macro domain protein family: structure, functions, and their potential therapeutic implications. Mutat. Res. 727, 86-103.
- Ikura, T., Tashiro, S., Kakino, A., Shima, H., Jacob, N., Amunugama, R., Yoder, K., Izumi, S., Kuraoka, I., Tanaka, K., et al. (2007). DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol. Cell. Biol. 27, 7028-7040.
- Osley, M.A. (2006). Regulation of histone H2A and H2B ubiquitylation. Brief Funct. Genomic Proteomic 5, 179-189.
- Rogakou, E.P., Boon, C., Redon, C., and Bonner, W.M. (1999). Megabase chromatin domains involved in DNA double-strand breaks in vivo. J. Cell Biol. 146, 905-916.
- Talbert, P.B., and Henikoff, S. (2010). Histone variants–ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol. 11, 264-275.
- Tolstorukov, M.Y., Goldman, J.A., Gilbert, C., Ogryzko, V., Kingston, R.E., and Park, P.J. (2012). Histone variant H2A.Bbd is associated with active transcription and mRNA processing in human cells. Mol. Cell 47, 596-607.
- Zhang, Y., Griffin, K., Mondal, N., and Parvin, J.D. (2004). Phosphorylation of histone H2A inhibits transcription on chromatin templates. J. Biol. Chem. 279, 21866-21872.
- Zlatanova, J., and Thakar, A. (2008). H2A.Z: view from the top. Structure 16, 166-179.