H4R3me2

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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. [1]

Contents

Nomenclature

The name of this modification indicates dimethylation of arginine 3 on histone H4 protein subunit: [2]

Abbr.Meaning
H4H4 family of histones
Rstandard abbreviation for arginine
3position of amino acid residue

(counting from N-terminus)

memethyl group
2number of methyl groups added

Arginine

Arginine methylation by type I and II PRMTs. Arginine methylation.svg
Arginine methylation by type I and II PRMTs.

Arginine can be methylated once (monomethylated arginine) or twice (dimethylated arginine). Methylation of arginine residues is catalyzed by three different classes of protein arginine methyltransferases. [1]

Arginine methylation affects the interactions between proteins and has been implicated in a variety of cellular processes, including protein trafficking, signal transduction, and transcriptional regulation. [3]

Arginine methylation plays a major role in gene regulation because of the ability of the PRMTs to deposit key activating (histone H4R3me2, H3R2me2, H3R17me2, H3R26me2) or repressive (H3R2me2, H3R8me2, H4R3me2) histone marks.

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.

Mechanism and function of modification

JMJD6, a Jumonji domain-containing protein, was reported to demethylate H4R3me2. [4] H4R3me2 is a major mark deposited by Prmt5. [4] H4R8me2s is linked to transcriptional repression and is tightly linked with H4R3me2s methylation. [4]

Epigenetic implications

The post-translational modification of histone tails by either histone-modifying complexes or chromatin remodeling complexes is interpreted by the cell and leads 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. [5] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. [6] 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 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 characterized by different banding. [7] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. [8] A look in to the data obtained led to the definition of chromatin states based on histone modifications. [9] Certain modifications were mapped and enrichment was seen to localize in certain genomic regions.

The human genome is 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. [10] [11]

Clinical significance

There is evidence of crosstalk between H4R3me2 and H3K9ac and H3K14ac in cell differentiation and the response to cocaine. [1]

Methods

The histone mark 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. [12]

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. [13]

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. [14] [15] [16]

See also

Related Research Articles

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 4th lysine residue of the histone H3 protein and 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.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

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.

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

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.

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.

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.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th 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.

References

  1. 1 2 3 Blanc, Roméo S.; Richard, Stéphane (2017). "Arginine Methylation: The Coming of Age". Molecular Cell. 65 (1): 8–24. doi: 10.1016/j.molcel.2016.11.003 . PMID   28061334.
  2. ↑ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (30 November 2015). Epigenetic Gene Expression and Regulation. pp. 21–38. ISBN   9780127999586.
  3. ↑ McBride, A.; Silver, P. (2001). "State of the Arg: Protein Methylation at Arginine Comes of Age". Cell. 106 (1): 5–8. doi: 10.1016/S0092-8674(01)00423-8 . PMID   11461695. S2CID   17755108.
  4. 1 2 3 Di Lorenzo, Alessandra; Bedford, Mark T. (2011). "Histone arginine methylation". FEBS Letters. 585 (13): 2024–2031. doi:10.1016/j.febslet.2010.11.010. PMC   3409563 . PMID   21074527.
  5. ↑ Jenuwein T, Allis CD (August 2001). "Translating the histone code". Science. 293 (5532): 1074–80. doi:10.1126/science.1063127. PMID   11498575. S2CID   1883924.
  6. ↑ Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, et al. (The ENCODE Project Consortium) (June 2007). "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project". Nature. 447 (7146): 799–816. Bibcode:2007Natur.447..799B. doi:10.1038/nature05874. PMC   2212820 . PMID   17571346.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Lee, Yun Hwa; Ma, Hui; Tan, Tuan Zea; Ng, Swee Siang; Soong, Richie; Mori, Seiichi; Fu, Xin-Yuan; Zernicka-Goetz, Magdalena; Wu, Qiang (2012). "Protein Arginine Methyltransferase 6 Regulates Embryonic Stem Cell Identity". Stem Cells and Development. 21 (14): 2613–2622. doi:10.1089/scd.2011.0330. PMC   5729635 . PMID   22455726.
  12. ↑ "Whole-Genome Chromatin IP Sequencing (ChIP-Seq)" (PDF). Illumina. Retrieved 23 October 2019.
  13. ↑ "MAINE-Seq/Mnase-Seq". illumina. Retrieved 23 October 2019.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Song, L.; Crawford, G. E. (2010). "DNase-seq: A High-Resolution Technique for Mapping Active Gene Regulatory Elements across the Genome from Mammalian Cells". Cold Spring Harbor Protocols. 2010 (2): pdb.prot5384. doi:10.1101/pdb.prot5384. ISSN   1559-6095. PMC   3627383 . PMID   20150147.
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