H4K91ac

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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.

Contents


Nomenclature

H4K91ac indicates acetylation of lysine 91 on histone H4 protein subunit: [1]

Abbr.Meaning
H4 H4 family of histones
Kstandard abbreviation for lysine
91position of amino acid residue
(counting from N-terminus)
ac acetyl group

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. [2] [3]

H4 histone

H4 modifications are not as well known as H3's and H4 have fewer variations which might explain their important function. [4]

H4K91ac

As December 15, 2019, no diseases are attributed to this mark [5] although Pleckstrin homology domain's (PHIP) targetable bromodomain specifically binds H4K91ac which could implicate PHIP in the progression of melanoma. [6] It is found at the transcription start site (TSS) of active and poised genes. [5]

Histone acetyltransferase KAT2A is the specific reader. [5]

Lysine acetylation and deacetylation

Lysine acetylation Lysine acetylation.svg
Lysine acetylation

Proteins are typically acetylated on lysine residues and this reaction relies on acetyl-coenzyme A as the acetyl group donor. In histone acetylation and deacetylation, histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well. [7]

The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation and deacetylation is a significant post-translational regulatory mechanism [8] These regulatory mechanisms are analogous to phosphorylation and dephosphorylation by the action of kinases and phosphatases. Not only can the acetylation state of a protein modify its activity, but this post-translational modification may also crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling. [9] [10] [11]

Epigenetic implications

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodeling 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]

Methods

The histone mark acetylation 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

References

  1. ↑ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. Elsevier Science. pp. 21–38. ISBN   9780127999586.
  2. ↑ Ruthenburg AJ, Li H, Patel DJ, Allis CD (December 2007). "Multivalent engagement of chromatin modifications by linked binding modules". Nature Reviews. Molecular Cell Biology. 8 (12): 983–94. doi:10.1038/nrm2298. PMC   4690530 . PMID   18037899.
  3. ↑ Kouzarides T (February 2007). "Chromatin modifications and their function". Cell. 128 (4): 693–705. doi: 10.1016/j.cell.2007.02.005 . PMID   17320507.
  4. ↑ "Histone Proteins and Modifications". Epigenie. Retrieved 15 December 2019.
  5. 1 2 3 "H4K91ac Post Translational Modification - HIstome". Archived from the original on 19 August 2016. Retrieved 14 December 2019.
  6. ↑ De Semir, David; Bezrookove, Vladimir; Nosrati, Mehdi; Dar, Altaf A.; Wu, Clayton; Shen, Julia; Rieken, Christopher; Venkatasubramanian, Meenakshi; Miller, James R.; Desprez, Pierre-Yves; McAllister, Sean; Soroceanu, Liliana; Debs, Robert J.; Salomonis, Nathan; Schadendorf, Dirk; Cleaver, James E.; Kashani-Sabet, Mohammed (2018). "PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer". Proceedings of the National Academy of Sciences. 115 (25): E5766 –E5775. Bibcode:2018PNAS..115E5766D. doi: 10.1073/pnas.1804779115 . PMC   6016792 . PMID   29866840.
  7. ↑ Sadoul K, Boyault C, Pabion M, Khochbin S (2008). "Regulation of protein turnover by acetyltransferases and deacetylases". Biochimie. 90 (2): 306–12. doi:10.1016/j.biochi.2007.06.009. PMID   17681659.
  8. ↑ Glozak MA, Sengupta N, Zhang X, Seto E (2005). "Acetylation and deacetylation of non-histone proteins". Gene. 363: 15–23. doi:10.1016/j.gene.2005.09.010. PMID   16289629.
  9. ↑ Yang XJ, Seto E (2008). "Lysine acetylation: codified crosstalk with other posttranslational modifications". Mol. Cell. 31 (4): 449–61. doi:10.1016/j.molcel.2008.07.002. PMC   2551738 . PMID   18722172.
  10. ↑ Eddé B, Denoulet P, de Néchaud B, Koulakoff A, Berwald-Netter Y, Gros F (1989). "Posttranslational modifications of tubulin in cultured mouse brain neurons and astroglia". Biol. Cell. 65 (2): 109–117. doi:10.1016/0248-4900(89)90018-x. PMID   2736326.
  11. ↑ Maruta H, Greer K, Rosenbaum JL (1986). "The acetylation of alpha-tubulin and its relationship to the assembly and disassembly of microtubules". J. Cell Biol. 103 (2): 571–579. doi:10.1083/jcb.103.2.571. PMC   2113826 . PMID   3733880.
  12. ↑ Jenuwein T, Allis CD (August 2001). "Translating the histone code". Science. 293 (5532): 1074–80. CiteSeerX   10.1.1.453.900 . doi:10.1126/science.1063127. PMID   11498575. S2CID   1883924.
  13. ↑ 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.
  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. Bibcode:2015GenRe..25.1757S. doi:10.1101/gr.192294.115. ISSN   1088-9051. PMC   4617971 . PMID   26314830.
  22. ↑ 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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