Histone code
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code.[1] The main role of histones is in associating with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus (taken to be the tail) that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.
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[edit] The Hypothesis
The hypothesis is that chromatin-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as methylation, acetylation, ADP-ribosylation, ubiquitination and phosphorylation) to histone tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions remains elusive. However, some specific examples have been worked out in detail. For example, phosphorylation of serine residues 10 and 28 on histone H3 is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of serine residue 10 and acetylation of a lysine residue 14 on histone H3 is a tell-tale sign of active transcription.
[edit] Modifications
Possible modifications to the tails are[2]:
- Acetylation - by HAT (histone acetyl transferase); deacetylation - by HDAC (histone deacetylase)
Deacetylation allows tight arrangement of chromatin, preventing gene expression, while acetylation may occur to open up the chromatin.
Methylation of lysines H3K4 and H3K36 is correlated with transcriptional activation while demethylation of H3K4 is correlated with silencing of the genomic region. Methylation of lysines H3K9 and H3K27 is correlated with transcriptional repression.[3] Particularly, H3K9me3 is highly correlated with constitutive heterochromatin.[4]
The histone code can be summarized in the following table:
| Type of modification |
Histone | ||||||
|---|---|---|---|---|---|---|---|
| H3K4 | H3K9 | H3K14 | H3K27 | H3K79 | H4K20 | H2BK5 | |
| mono-methylation | activation[5] | activation[6] | activation[6] | activation[6][7] | activation[6] | activation[6] | |
| di-methylation | repression[3] | repression[3] | activation[7] | ||||
| tri-methylation | activation[8] | repression[6] | repression[6] | activation,[7] repression[6] |
repression[3] | ||
| acetylation | activation[8] | activation[8] | |||||
Notes:
- H3K4me3 is found in actively transcribed promoters, particularly just after the transcription start site.
- H3K9me3 is found in constitutively repressed genes.
- H3K27me is found in facultatively repressed genes.[6]
- H3K36me3 is found in actively transcribed gene bodies.
- H3K9ac is found in actively transcribed promoters.
- H3K14ac is found in actively transcribed promoters.
Structural determinants of histone recognition by readers, writers and erasers of the histone code are revealed by a growing body of experimental data.[9]
[edit] See also
[edit] References
- ^ Jenuwein T, Allis C (2001). "Translating the histone code". Science 293 (5532): 1074–80. doi:10.1126/science.1063127. PMID 11498575.
- ^ Strahl B, Allis C (2000). "The language of covalent histone modifications". Nature 403 (6765): 41–5. doi:10.1038/47412. PMID 10638745.
- ^ a b c d Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome.". BMC Genomics 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2667539.
- ^ Hublitz, Philip; Albert, Mareike; Peters, Antoine (28 April 2009). "Mechanisms of Transcriptional Repression by Histone Lysine Methylation". The International Journal of Developmental Biology (Basel) 10 (1387): 335–354. ISSN 1696-3547.
- ^ Benevolenskaya EV (August 2007). "Histone H3K4 demethylases are essential in development and differentiation". Biochem. Cell Biol. 85 (4): 435–43. doi:10.1139/o07-057. PMID 17713579.
- ^ a b c d e f g h i Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414.
- ^ a b c Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, Blobel GA, Vakoc CR (April 2008). "DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells". Mol. Cell. Biol. 28 (8): 2825–39. doi:10.1128/MCB.02076-07. PMC 2293113. PMID 18285465. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2293113.
- ^ a b c Koch CM, Andrews RM, Flicek P, Dillon SC, Karaöz U, Clelland GK, Wilcox S, Beare DM, Fowler JC, Couttet P, James KD, Lefebvre GC, Bruce AW, Dovey OM, Ellis PD, Dhami P, Langford CF, Weng Z, Birney E, Carter NP, Vetrie D, Dunham I (June 2007). "The landscape of histone modifications across 1% of the human genome in five human cell lines". Genome Res. 17 (6): 691–707. doi:10.1101/gr.5704207. PMC 1891331. PMID 17567990. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1891331.
- ^ Wang M, Mok MW, Harper H, Lee WH, Min J, Knapp S, Oppermann U, Marsden B, Schapira M (24 Aug 2010). "Structural Genomics of Histone Tail Recognition". Bioinformatics Epub (20): 2629–2630. doi:10.1093/bioinformatics/btq491. PMC 2951094. PMID 20739309. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2951094.
