H4K20me

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H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the methylation at the 20th lysine residue of the histone H4 protein. This mark can be mono-, di-, or tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

Contents

H4K20me2 is the most common methylation state on histone H4 and was one of the earliest modified histone residues to be identified back in pea and calf extracts in 1969. It is one of only two identified methylated lysine residues on the H4 histone, the other being monomethylated H4K12. [1] [2]

Each degree of methylation at H4K20 has a very different cellular process. The loss of H4K20me3 along with a reduction of H4K16ac is a strong indicator of cancer.

Nomenclature

H4K20me indicates monomethylation of lysine 20 on histone H4 protein subunit: [3]

Abbr.Meaning
H4H4 family of histones
Kstandard abbreviation for lysine
20position of amino acid residue

(counting from N-terminus)

memethyl group
1number of methyl groups added

Lysine methylation

Methylation of lysine.svg

This diagram shows the progressive methylation of a lysine residue. The mono-methylation (second from left) denotes the methylation present in H4K20me. [4]

H4K20me exists in three distinct states as mono-, di- and trimethylation. [4]

H4K20me1

H4K20me1 is associated with transcriptional activation. [5]

H4K20me2

H4K20me2 is similar to H4K20me1 but has a different distribution and this dimethylation controls the cell cycle and DNA damage response. [5] [6]

H4K20me3

H4K20me3 is very different. H4K20me3 represses transcription when present at promoters. H4K20me3 also silences repetitive DNA and transposons. The loss of H4K20me3 defines cancer along with a reduction of H4K16ac. [5] [7]

H4K20me3 is involved in Hutchinson-Gilford Progeria syndrome where patients have premature and very rapid aging caused by de novo mutations that occurs in a gene that encodes lamin A. Lamin A is made but isn't processed properly. This poor processing creates a really abnormal nuclear morphology and disorganized heterochromatin. Patients also don't have appropriate DNA repair, and they also have increased genomic instability. [8]

Cancer marker

The loss of the repressive H4K20me3 mark defines cancer along with a reduction of activating H4K16ac mark. It is not clear how the loss of a repressive and an activating mark is an indicator of cancer. [7] It is not clear exactly how but this reduction happens at repetitive sequences along with general reduced DNA methylation. [9]

Histone modifications

The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as histones. The complexes formed by the looping of the DNA are known as chromatin. The basic structural unit of chromatin is the nucleosome: this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino (N) terminal charged tails are the site of the post-translational modifications, such as the one seen in H3K36me3. [10] [11]

Epigenetic implications

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to complex, combinatorial transcriptional output. It is thought that a Histone code dictates the expression of genes by a complex interaction between the histones in a particular region. [12] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. [13] The purpose of the epigenomic study was to investigate epigenetic changes across the entire genome. This led to chromatin states which define genomic regions by grouping the interactions of different proteins and/or histone modifications together. Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of ChIP-sequencing revealed regions in the genome characterised by different banding. [14] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. [15] A look in to the data obtained led to the definition of chromatin states based on histone modifications. [16]

The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate a genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers. This additional level of annotation allows for a deeper understanding of cell specific gene regulation. [17]

History

H4K20 was one of the earliest modified histone residues to be identified back in pea and calf extracts in 1969. [1]

Genome integrity

H4K20me is important for DNA damage repair, DNA replication and chromatin compaction. [4]

There are a set of H4K20-specific histone methyltransferases (SET8/PR-Set7, SUV4-20H1 and SUV4-20H2). Without these enzymes there is a disruption of genomic instability. [4]

Methods

The histone mark H4K20me can be detected in a variety of ways:

1. Chromatin Immunoprecipitation Sequencing (ChIP-sequencing) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated. It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region. [18]

2. Micrococcal Nuclease sequencing (MNase-seq) is used to investigate regions that are bound by well positioned nucleosomes. Use of the micrococcal nuclease enzyme is employed to identify nucleosome positioning. Well positioned nucleosomes are seen to have enrichment of sequences. [19]

3. Assay for transposase accessible chromatin sequencing (ATAC-seq) is used to look in to regions that are nucleosome free (open chromatin). It uses hyperactive Tn5 transposon to highlight nucleosome localisation. [20] [21] [22]

See also

Related Research Articles

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.

H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria.

H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restoring this modification could reduce age-related decline in memory.

H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implicated in melanoma.

H3K23ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 23rd lysine residue of the histone H3 protein.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R17me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 17th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R8me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 8th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R2me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 2nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H4R3me2 is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the di-methylation at the 3rd arginine residue of the histone H4 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

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  2. ↑ Metzger, Eric; Wang, Sheng; Urban, Sylvia; Willmann, Dominica; Schmidt, Andreas; Offermann, Anne; Allen, Anita; Sum, Manuela; Obier, Nadine; Cottard, Félicie; Ulferts, Svenja; Preca, Bogdan-Tiberius; Hermann, Bianca; Maurer, Jochen; Greschik, Holger (2019-05-06). "KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells". Nature Structural & Molecular Biology. 26 (5): 361–371. doi:10.1038/s41594-019-0219-9. ISSN   1545-9985.
  3. ↑ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. Elsevier Science. pp. 21–35. ISBN   9780127999586.
  4. 1 2 3 4 Jorgensen, S.; Schotta, G.; Sorensen, C. S. (2013). "Histone H4 Lysine 20 methylation: Key player in epigenetic regulation of genomic integrity". Nucleic Acids Research. 41 (5): 2797–2806. doi:10.1093/nar/gkt012. PMC   3597678 . PMID   23345616.
  5. 1 2 3 "Histone H4K20 Review" . Retrieved 21 November 2019.
  6. ↑ Paquin, Karissa L.; Howlett, Niall G. (2018). "Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark". Molecular Cancer Research. 16 (9): 1335–1345. doi: 10.1158/1541-7786.MCR-17-0688 . PMC   7083049 . PMID   29858375.
  7. 1 2 Wang, Y.; Jia, S. (2009). "Degrees make all the difference: The multifunctionality of histone H4 lysine 20 methylation". Epigenetics. 4 (5): 273–6. doi:10.4161/epi.4.5.9212. PMC   5116398 . PMID   19571682.
  8. ↑ Arancio, Walter; Pizzolanti, Giuseppe; Genovese, Swonild I.; Pitrone, Maria; Giordano, Carla (2014). "Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review". Gerontology. 60 (3): 197–203. doi:10.1159/000357206. hdl: 10447/93705 . PMID   24603298. S2CID   2459118.
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  14. ↑ Filion GJ, van Bemmel JG, Braunschweig U, Talhout W, Kind J, Ward LD, Brugman W, de Castro IJ, Kerkhoven RM, Bussemaker HJ, van Steensel B (October 2010). "Systematic protein location mapping reveals five principal chromatin types in Drosophila cells". Cell. 143 (2): 212–24. doi:10.1016/j.cell.2010.09.009. PMC   3119929 . PMID   20888037.
  15. ↑ Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, et al. (modENCODE Consortium) (December 2010). "Identification of functional elements and regulatory circuits by Drosophila modENCODE". Science. 330 (6012): 1787–97. Bibcode:2010Sci...330.1787R. doi:10.1126/science.1198374. PMC   3192495 . PMID   21177974.
  16. ↑ Kharchenko PV, Alekseyenko AA, Schwartz YB, Minoda A, Riddle NC, Ernst J, et al. (March 2011). "Comprehensive analysis of the chromatin landscape in Drosophila melanogaster". Nature. 471 (7339): 480–5. Bibcode:2011Natur.471..480K. doi:10.1038/nature09725. PMC   3109908 . PMID   21179089.
  17. ↑ Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, et al. (Roadmap Epigenomics Consortium) (February 2015). "Integrative analysis of 111 reference human epigenomes". Nature. 518 (7539): 317–30. Bibcode:2015Natur.518..317.. doi:10.1038/nature14248. PMC   4530010 . PMID   25693563.
  18. ↑ "Whole-Genome Chromatin IP Sequencing (ChIP-Seq)" (PDF). Illumina. Retrieved 23 October 2019.
  19. ↑ "MAINE-Seq/Mnase-Seq". illumina. Retrieved 23 October 2019.
  20. ↑ Buenrostro, Jason D.; Wu, Beijing; Chang, Howard Y.; Greenleaf, William J. (2015). "ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide". Current Protocols in Molecular Biology. 109: 21.29.1–21.29.9. doi:10.1002/0471142727.mb2129s109. ISBN   9780471142720. PMC   4374986 . PMID   25559105.
  21. ↑ Schep, Alicia N.; Buenrostro, Jason D.; Denny, Sarah K.; Schwartz, Katja; Sherlock, Gavin; Greenleaf, William J. (2015). "Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions". Genome Research. 25 (11): 1757–1770. doi:10.1101/gr.192294.115. ISSN   1088-9051. PMC   4617971 . PMID   26314830.
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