It doesn’t take a PhD in Biochemistry to guess what heterochromatin protein 1 (HP1) does. HP1 is a family of three proteins that are vital for the formation of transcriptionally inactive heterochromatin. There are three HP1 protein family members in humans, each encoded by their own gene: HP1α, encoded by CBX5; HP1β, encoded by CBX1; and HP1γ, encoded by CBX3. The structure and function of these genes is highly homologous from Drosophila to humans suggesting a very important, evolutionarily conserved function (Norwood et al., 2004).
HP1 proteins are part of chromodomain superfamily, meaning they contain the methyl lysine binding chromodomain. The chromodomain of HP1 proteins binds to methylated H3K9 and is required for its transcriptional repressive activity (Jacobs et al., 2001). HP1 proteins also contain a similar domain unique to this family called the chromoshadow domain. The chromoshadow domain is responsible for binding other HP1 proteins as well as other interactors such as SUV39H1 (Cowieson et al., 2000).
Epigenetic Role of HP1 Proteins
The classical mechanism of HP1 mediated heterochromatin formation is as follows: H3K9me2/3 recruits HP1α/β which then recruits the H3K9 methyltransferase SUV39H1. SUV39H1 then methylates more H3K9me2/3, creating a positive feedback loop spreading down the chromosome (Lachner et al., 2001). The propagation of the H3K9me2/3 mark and HP1 itself then serve to bind additional proteins leading to heterochromatin formation and gene silencing. DNA methyltransferases, for example, are recruited by HP1 (Tamaru and Selker, 2001).
All three HP1 proteins are found in heterochromatic regions, but HP1γ is also found in euchromatin (Minc et al., 2000). HP1γ that is phosphorylated at Ser83 is exclusively located at euchromatin (Lomberk et al., 2006). Ser83P-HP1γ has impaired silencing activity and marks areas of transcriptional elongation (Lomberk et al., 2006). This discovery lead to the idea that HP1 operates with a similar code to the histone code, which is currently an area of active research.
HP1 Additional Reading
This review focuses on the history, domain structure, and evolutionary conservation of the HP1 family. It’s a great starting point and has a lot of good info, but other resources are better for those seeking a mechanistic understanding of HP1.
This is an older review, but the topics it covers have changed little. This is a great resource to gain a deeper understanding of the mechanistic basis for HP1-mediate heterochromatin formation.
Kwon, S.H., and Workman, J.L. (2011). The changing faces of HP1: From heterochromatin formation and gene silencing to euchromatic gene expression: HP1 acts as a positive regulator of transcription. Bioessays 33, 280-289.
This review examines the little known positive roles of HP1 on transcription. The paper also does a good job of touching on most of the known roles of HP1 proteins, but the section towards the end on HP1 on a positive transcriptional regulator is really worth a read.
- Cowieson, N.P., Partridge, J.F., Allshire, R.C., and McLaughlin, P.J. (2000). Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis. Curr. Biol. 10, 517-525.
- Jacobs, S.A., Taverna, S.D., Zhang, Y., Briggs, S.D., Li, J., Eissenberg, J.C., Allis, C.D., and Khorasanizadeh, S. (2001). Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3. EMBO J. 20, 5232-5241.
- Lachner, M., O’Carroll, D., Rea, S., Mechtler, K., and Jenuwein, T. (2001). Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116-120.
- Lomberk, G., Bensi, D., Fernandez-Zapico, M.E., and Urrutia, R. (2006). Evidence for the existence of an HP1-mediated subcode within the histone code. Nat. Cell Biol. 8, 407-415.
- Minc, E., Courvalin, J.C., and Buendia, B. (2000). HP1gamma associates with euchromatin and heterochromatin in mammalian nuclei and chromosomes. Cytogenet. Cell Genet. 90, 279-284.
- Norwood, L.E., Grade, S.K., Cryderman, D.E., Hines, K.A., Furiasse, N., Toro, R., Li, Y., Dhasarathy, A., Kladde, M.P., Hendrix, M.J., Kirschmann, D.A., and Wallrath, L.L. (2004). Conserved properties of HP1(Hsalpha). Gene 336, 37-46.
- Tamaru, H., and Selker, E.U. (2001). A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277-283.