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Histone code

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The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications (known as histone marks) to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code.[1] Histones associate 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.

The hypothesis[edit]

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, citrullination, SUMO-ylation[2] 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.

Schematic representation of histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011


Well characterized modifications to histones include:[3]

  • Methylation: Both lysine and arginine residues are known to be methylated. Methylated lysines are the best understood marks of the histone code, as specific methylated lysine match well with gene expression states. 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.[4] Particularly, H3K9me3 is highly correlated with constitutive heterochromatin.[5] Methylation of histone lysine also has a role in DNA repair.[6] For instance, H3K36me3 is required for homologous recombinational repair of DNA double-strand breaks, and H4K20me2 facilitates repair of such breaks by non-homologous end joining.[6]
  • Acetylation—by HAT (histone acetyl transferase); deacetylation—by HDAC (histone deacetylase): Acetylation tends to define the 'openness' of chromatin as acetylated histones cannot pack as well together as deacetylated histones.
  • Phosphorylation
  • Ubiquitination
  • SUMOylation[2]

However, there are many more histone modifications, and sensitive mass spectrometry approaches have recently greatly expanded the catalog.[7]

A very basic summary of the histone code for gene expression status is given below (histone nomenclature is described here):

Type of
H3K4 H3K9 H3K14 H3K27 H3K79 H3K122 H4K20 H2BK5
mono-methylation activation[8] activation[9] activation[9] activation[9][10] activation[9] activation[9]
di-methylation repression[4] repression[4] activation[10]
tri-methylation activation[11] repression[9] repression[9] activation,[10]
acetylation activation[11] activation[11] activation[12] activation[13]

Histone H2B[edit]

Histone H3[edit]

  • H3K4me1 - primed enhancers
  • H3K4me3 is enriched in transcriptionally active promoters.[14]
  • H3K9me2 -repression
  • H3K9me3 is found in constitutively repressed genes.
  • H3K27me3 is found in facultatively repressed genes.[9]
  • H3K36me
  • H3K36me2
  • H3K36me3 is found in actively transcribed gene bodies.
  • H3K79me2
  • H3K9ac is found in actively transcribed promoters.
  • H3K14ac is found in actively transcribed promoters.
  • H3K23ac
  • H3K27ac distinguishes active enhancers from poised enhancers.
  • H3K36ac
  • H3K56ac is a proxy for de novo histone assembly.[15]
  • H3K122ac is enriched in poised promoters and also found in a different type of putative enhancer that lacks H3K27ac.

Histone H4[edit]


Unlike this simplified model, any real histone code has the potential to be massively complex; each of the four standard histones can be simultaneously modified at multiple different sites with multiple different modifications. To give an idea of this complexity, histone H3 contains nineteen lysines known to be methylated—each can be un-, mono-, di- or tri-methylated. If modifications are independent, this allows a potential 419 or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4 Gb / ~150 bp = ~44 million histones if they are very tightly packed). And this does not include lysine acetylation (known for H3 at nine residues), arginine methylation (known for H3 at three residues) or threonine/serine/tyrosine phosphorylation (known for H3 at eight residues), not to mention modifications of other histones.[citation needed]

Every nucleosome in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes.[16] Mass spectrometry-based top-down proteomics has provided more insight into these patterns by being able to discriminate single molecule co-occurrence from co-localization in the genome or on the same nucleosome.[17] A variety of approaches have been used to delve into detailed biochemical mechanisms that demonstrate the importance of interplay between histone modifications. Thus, specific patterns of histone modifications are more common than others. These patterns are functionally important but they are intricate and challenging to study. We currently have the best biochemical understanding of the importance of a relatively small number of discrete modifications and a few combinations.

Structural determinants of histone recognition by readers, writers, and erasers of the histone code are revealed by a growing body of experimental data.[18]

See also[edit]


  1. ^ Jenuwein T, Allis C (2001). "Translating the histone code". Science. 293 (5532): 1074–80. CiteSeerX doi:10.1126/science.1063127. PMID 11498575. S2CID 1883924.
  2. ^ a b Shiio, Yuzuru; Eisenman, Robert N. (11 November 2003). "Histone sumoylation is associated with transcriptional repression". Proceedings of the National Academy of Sciences. 100 (23): 13225–13230. doi:10.1073/pnas.1735528100. PMC 263760. PMID 14578449.
  3. ^ Strahl B, Allis C (2000). "The language of covalent histone modifications". Nature. 403 (6765): 41–5. Bibcode:2000Natur.403...41S. doi:10.1038/47412. PMID 10638745. S2CID 4418993.
  4. ^ 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.
  5. ^ Hublitz, Philip; Albert, Mareike; Peters, Antoine (28 April 2009). "Mechanisms of Transcriptional Repression by Histone Lysine Methylation". The International Journal of Developmental Biology. 10 (1387). Basel: 335–354. doi:10.1387/ijdb.082717ph. ISSN 1696-3547. PMID 19412890.
  6. ^ a b Wei S, Li C, Yin Z, Wen J, Meng H, Xue L, Wang J (2018). "Histone methylation in DNA repair and clinical practice: new findings during the past 5-years". J Cancer. 9 (12): 2072–2081. doi:10.7150/jca.23427. PMC 6010677. PMID 29937925.
  7. ^ Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, et al. (2011). "Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification". Cell. 146 (6): 1016–28. doi:10.1016/j.cell.2011.08.008. PMC 3176443. PMID 21925322.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ Creyghton, MP (Dec 2010). "Histone H3K27ac separates active from poised enhancers and predicts developmental state". Proc Natl Acad Sci USA. 107 (50): 21931–6. doi:10.1073/pnas.1016071107. PMC 3003124. PMID 21106759.
  13. ^ Pradeepa, Madapura M.; Grimes, Graeme R.; Kumar, Yatendra; Olley, Gabrielle; Taylor, Gillian C. A.; Schneider, Robert; Bickmore, Wendy A. (2016-04-18). "Histone H3 globular domain acetylation identifies a new class of enhancers". Nature Genetics. 48 (6): 681–686. doi:10.1038/ng.3550. ISSN 1546-1718. PMC 4886833. PMID 27089178.
  14. ^ Liang, G (2004). "Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome". Proc. Natl. Acad. Sci. USA. 101 (19): 7357–7362. Bibcode:2004PNAS..101.7357L. doi:10.1073/pnas.0401866101. PMC 409923. PMID 15123803.
  15. ^ Jeronimo, Célia; Poitras, Christian; Robert, François (30 July 2019). "Histone Recycling by FACT and Spt6 during Transcription Prevents the Scrambling of Histone Modifications". Cell Reports. 28 (5): 1206–1218.e8. doi:10.1016/j.celrep.2019.06.097. PMID 31365865.
  16. ^ Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, et al. (2008). "Combinatorial patterns of histone acetylations and methylations in the human genome". Nat Genet. 40 (7): 897–903. doi:10.1038/ng.154. PMC 2769248. PMID 18552846.
  17. ^ Taylor BC, Young NL (10 Feb 2021). "Combinations of histone post-translational modifications". Biochemical Journal. 487 (3): 511–532. doi:10.1042/BCJ20200170. PMID 33567070.
  18. ^ 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. 26 (20): 2629–2630. doi:10.1093/bioinformatics/btq491. PMC 2951094. PMID 20739309.

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