Histone code

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Histone code is a term from the scientific field of epigenetics . The histone code hypothesis states that the translation of genetic information encoded in DNA is partly controlled by histone modifications . Histone modifications are chemical modifications to specific proteins - molecules , the histones .

The histone code is part of the epigenetic code . The effect of the histones or histone modification is strongly interwoven with the degree of DNA methylation .

Histones associate with the DNA to form nucleosomes , which in turn bundle into chromatin fibers, which in turn form the more familiar chromosome . Histones are globular proteins with a flexible N-terminus called the tail that protrudes from the nucleosome. Many of the histone tail modifications correlate very well with the chromatin structure. Both the status of the histone modifications and the chromatin structure correlate well with the gene expression levels . Details of gene expression regulation through histone modifications: see table below .

The hypothesis

The core of the histone code hypothesis is that the histone modifications serve to recruit other proteins rather than just stabilizing or destabilizing the histone-DNA interaction. These proteins, which are recruited on the modified histones through specific recognition with the aid of specialized domains , then act actively to actively change the chromatin structure or to promote transcription.

While it is generally accepted that modifications to the histone tails (such as methylation , acetylation , ADP-ribosylation, ubiquitination , citrullination, and phosphorylation ) alter chromatin structure, the exact mechanisms by which these changes to the histone tails alter the DNA histone remain unclear -Influence interactions. Therefore, the idea that combinations of histone modifications guide the interactions with chromatin according to a mapping rule ( code ) remains a hypothesis.

However, some specific examples have been clarified in detail. For example, the 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 characteristic sign of active transcription.

Modifications

Well characterized modifications to histones include:

It is known that both lysine and arginine residues are methylated. Methylated lysines are the best understood markers of the histone code, as specifically methylated lysine correlates well with gene expression states. The methylation of the lysines H3K4 and H3K36 is correlated with the activation of transcription, while the demethylation of H3K4 correlates with the silencing of the genomic region. The methylation of the lysines H3K9 and H3K27 correlates with transcription repression. In particular, H3K9me3 is strongly correlated with constitutive heterochromatin.

  • Acetylation - by HAT (histone acetyltransferase); Deacetylation - by HDAC (histone deacetylase)

Acetylation more or less defines the "openness" of the chromatin, since acetylated histones cannot pack the chromatin as well as deacetylated histones.

However, there are many more histone modifications, and sensitive mass spectrometry approaches have recently expanded the catalog enormously.

A very restrictive summary of a histone code is given in the following table as an example.

The nomenclature of the histone variants (H3K4 etc.) is described under histone modification .

Act. - Gene activation

Repr. - gene repression (see also gene activity )

Type of
modification 		Histone
H3K4 H3K9 H3K14 H3K27 H3K79 H3K122 H4K20 H2BK5
Monomethylation Act. Act. Act. Act. Act. Act.
Dimethylation Act. Repr. Repr. Act.
Trimethylation Act. Repr. Repr. Act.
Repr. 		Repr.
Acetylation Act. Act. Act. Act.
  • H3K4me3 is enriched in transcriptionally active promoters.
  • H3K9me3 is found in constitutively suppressed genes.
  • H3K27me is found in facultative repressive genes.
  • H3K36me3 is found in actively transcribed gene bodies.
  • H3K9ac is found in actively transcribed promoters.
  • H3K14ac is found in actively transcribed promoters.
  • H3K27ac distinguishes active enhancers from blocked enhancers.
  • H3K122ac is enriched in blocked promoters and is also found in another strain of possible enhancer that lacks H3K27ac.

Complexity of the Histone Code

Unlike this simplified model, any real histone code is sometimes very complex. In this way, each of the four standard histones can be modified simultaneously in several different places with several different modifications. To give an idea of ​​this complexity, histone H3 contains nineteen lysines known to be methylated, each of which can be un-, mono-, di-, or tri-methylated. If modifications are independent, this enables 4 to the power of 19 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 when very dense are packed). This does not fully include lysine acetylations (known for H3 at nine residues), arginine methylations (known for H3 at three residues) or threonine / serine / tyrosine phosphorylations (known for H3 at eight residues) mention modifications of other histones. Each nucleosome in a cell can therefore have a different set of modifications, which begs the question of whether there are common patterns of histone modifications.

In a current study of around 40 histone modifications on human gene promoters with over 4000 different combinations, over 3000 combinations were found on just a single promoter. On the other hand, including a set of 17 histone modifications, patterns have been discovered that are collectively present on over 3000 genes. So there are patterns of histone modifications, but they are very complicated. Currently we only have a detailed biochemical understanding of the meaning of a relatively small number of modifications.

Structural determinants of histone recognition by reading, writing and erasing elements (readers, writers, erasers) of the histone code have been demonstrated by a growing number of experimental data.

Individual evidence

  1. ↑ T. Jenuwein, C. Allis: Translating the histone code. In: Science. 293 (5532), 2001, pp. 1074-1080. doi: 10.1126 / science.1063127 . PMID 11498575 .
  2. ↑ Bilian Jin, Yajun Li, Keith D. Robertson: DNA Methylation - Superior or Subordinate in the Epigenetic Hierarchy? In: Genes Cancer. 2 (6), Jun 2011, pp. 607-617. doi: 10.1177 / 1947601910393957 . PMC 3174260 (free full text). PMID 21941617
  3. ^ B. Strahl, C. Allis: The language of covalent histone modifications. In: Nature. 403 (6765), 2000, pp. 41-45. doi: 10.1038 / 47412 . PMID 10638745 .
  4. ↑ a b c d Jeffrey A Rosenfeld, Zhibin Wang, Dustin Schones, Keji Zhao, Rob DeSalle, Michael Q Zhang: Determination of enriched histone modifications in non-genic portions of the human genome. In: BMC Genomics. 10, March 31, 2009, p. 143. doi: 10.1186 / 1471-2164-10-143 . PMC 2667539 (free full text). PMID 19335899 .
  5. ↑ Philip Hublitz, Mareike Albert, Antoine Peters: Mechanisms of Transcriptional Repression by histone lysine methylation. In: The International Journal of Developmental Biology. Basel 10 (1387), April 28, 2009, pp. 335-354. ISSN  1696-3547 .
  6. ^ M. Tan, H. Luo, S. Lee, F. Jin, JS Yang, E. Montellier et al .: Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. In: Cell. 146 (6), 2011, pp. 1016-1028. doi: 10.1016 / j.cell.2011.08.008 . PMC 3176443 (free full text). PMID 21925322 .
  7. ↑ EV Benevolenskaya: histone H3K4 demethylases are essential in development and differentiation. In: Biochem. Cell Biol. 85 (4), Aug 2007, pp. 435-443. doi: 10.1139 / o07-057 . PMID 17713579 .
  8. ↑ a b c d e f g h i A. Barski, S. Cuddapah, K. Cui, TY Roh, DE Schones, Z. Wang, G. Wei, I. Chepelev, K. Zhao: High-resolution profiling of histone methylations in the human genome. In: Cell. 129 (4), May 2007, pp. 823-837. doi: 10.1016 / j.cell.2007.05.009 . PMID 17512414 .
  9. ↑ a b c D. J. Steger, MI Lefterova, L. Ying, AJ Stonestrom, M. Schupp, D. Zhuo, AL Vakoc, JE Kim, J. Chen, MA Lazar, GA Blobel, CR Vakoc: DOT1L / KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. In: Mol. Cell. Biol. 28 (8), April 2008, pp. 2825-2839. doi: 10.1128 / MCB.02076-07 . PMID 18285465 . PMC 2293113 (free full text).
  10. ↑ a b c CM Koch, RM Andrews, P. Flicek, SC Dillon, U. Karaöz, GK Clelland, S. Wilcox, DM Beare, JC Fowler, P. Couttet, KD James, GC Lefebvre, AW Bruce, OM Dovey, PD Ellis, P. Dhami, CF Langford, Z. Weng, E. Birney, NP Carter, D. Vetrie, I. Dunham: The landscape of histone modifications across 1% of the human genome in five human cell lines. In: Genome Res. 17 (6), June 2007, pp. 691-707. doi: 10.1101 / gr.5704207 . PMID 17567990 . PMC 1891331 (free full text).
  11. ↑ MP Creyghton: Histone H3K27ac separate active from poised enhancers and predicts developmental state. In: Proc Natl Acad Sci USA. 107 (50), Dec 2010, pp. 21931-21936. doi: 10.1073 / pnas.1016071107 .
  12. ↑ Madapura M. Pradeepa, Graeme R. Grimes, Yatendra Kumar, Gabrielle Olley, Gillian CA Taylor, Robert Schneider, Wendy A. Bickmore: Histone H3 globular domain acetylation identifies a new class of enhancers. In: Nature Genetics. April 18, 2016. advance online publication. doi: 10.1038 / ng.3550 .
  13. ↑ G. Liang: Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. In: Proc. Natl. Acad. Sci. UNITED STATES. 101, 2004, pp. 7357-7362. doi: 10.1073 / pnas.0401866101 .
  14. ↑ Z. Wang, C. Zang, JA Rosenfeld, DE Schones, A. Barski, S. Cuddapah et al: Combinatorial patterns of histone acetylations and methylations in the human genome. In: Nat Genet. 40 (7), 2008, pp. 897-903. doi: 10.1038 / ng.154 . PMC 2769248 (free full text). PMID 18552846 .
  15. ↑ M. Wang, MW Mok, H. Harper, WH Lee, J. Min, S. Knapp, U. Oppermann, B. Marsden, M. Schapira: Structural Genomics of Histone Tail Recognition. In: Bioinformatics. 26 (20), Aug 24, 2010, pp. 2629-2630. doi: 10.1093 / bioinformatics / btq491 . PMC 2951094 (free full text). PMID 20739309 .

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