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H3K27ac

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

H3K27ac is associated with the higher activation of transcription and therefore defined as an active enhancer mark. H3K27ac is found at both proximal and distal regions of transcription start site (TSS).

Lysine acetylation and deacetylation

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Lysine acetylation

Proteins are typically acetylated on lysine residues, and the acetylation 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.[1]

The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation and deacetylation is a significant post-translational regulatory mechanism[2] 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 there has been a recent suggestion that this post-translational modification may also crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling.[3][4][5]

In the field of epigenetics, histone acetylation (and deacetylation) have been shown to be important mechanisms in the regulation of gene transcription. Histones, however, are not the only proteins regulated by post-translational acetylation.

Nomenclature

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H3K27ac indicates acetylation of lysine 27 on histone H3 protein subunit: [6]

Abbr. Meaning
H3 H3 family of histones
K standard abbreviation for lysine
27 position of amino acid residue
(counting from N-terminus)
ac acetyl group

Histone modifications

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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.[7][8]

Epigenetic implications

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The posttranslational modification of histone tails by either histone-modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to the 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.[9] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap.[10] 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 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.[11] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance.[12] A look in to the data obtained led to the definition of chromatin states based on histone modifications.[13]

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.[14]

Poising with H3K4me1

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Since the H3K27ac and H3K27me3 modification is at the same location on the histone tail, they antagonize each other.[15] H3K27ac is often used to find active enhancers and poised enhancers subtracting from another enhancer mark H3K4me1 that contains all enhancers.[16]


Upregulation of genes

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Acetylation is usually linked to the upregulation of genes. This is the case in H3K27ac which is an active enhancer mark. It is found in distal and proximal regions of genes. It is enriched in Transcriptional start sites (TSS). H3K27ac shares a location with H3K27me3 and they interact in an antagonistic manner.

Alzheimer's

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H3K27ac is enriched in the regulatory regions of genes implicated in Alzheimer's disease, including those in tau and amyloid neuropathology. [17]

Methods

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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

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References

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  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. Elsevier Science. pp. 21–38. ISBN 9780127999586.
  7. ^ 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.
  8. ^ Kouzarides T (February 2007). "Chromatin modifications and their function". Cell. 128 (4): 693–705. doi:10.1016/j.cell.2007.02.005. PMID 17320507. S2CID 11691263.
  9. ^ Jenuwein T, Allis CD (August 2001). "Translating the histone code". Science. 293 (5532): 1074–80. doi:10.1126/science.1063127. PMID 11498575. S2CID 1883924.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ F, Tie (2009). "CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing". Development. 136 (18): 3131–3141. doi:10.1242/dev.037127. PMC 2730368. PMID 19700617.
  16. ^ Creyghton, Menno P. (December 14, 2010). "Histone H3K27ac separates active from poised enhancers and predicts developmental state". PNAS. 107 (50): 21931–21936. doi:10.1073/pnas.1016071107. PMC 3003124. PMID 21106759.
  17. ^ Marzi, S. J.; Leung, S. K.; Ribarska, T.; Hannon, E.; Smith, A. R.; Pishva, E.; Poschmann, J.; Moore, K.; Troakes, C.; Al-Sarraj, S.; Beck, S.; Newman, S.; Lunnon, K.; Schalkwyk, L. C.; Mill, J. (2018). "A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex". Nature Neuroscience. 21 (11): 1618–1627. doi:10.1038/s41593-018-0253-7. hdl:10871/35331. PMID 30349106. S2CID 53024153.
  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.
  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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