Biology:H4K5ac

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Short description: Histone acetylation on tail of histone H4

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.[1] It is enriched at the transcription start site (TSS) and along gene bodies.[2] Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.[3]


Nomenclature

H4K5ac indicates acetylation of lysine 5 on histone H4 protein subunit: [4]

Abbr. Meaning
H4 H4 family of histones
K standard abbreviation for lysine
5 position 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.[5][6]

H4 histone

H4 modifications are not as well known as H3's and H4 has fewer variations which might explain their important function. [1]

H4K5ac

H4K5 is acetylated by TIP60 and CBP/p300 proteins.[1] CAP/p300 open transcriptional start site chromatin by acetylating histones.[1] H4K5ac has also been implicated in epigenetic bookmarking which allows gene expression patterns to be faithfully passed to daughter cells through mitosis.[1] Important cell-type specific genes are marked in some way that prevents them from being compacted during mitosis and ensures their rapid transcription.[1] H4K5ac appears to prime activity-dependent genes expressed during learning.[1]

Lysine acetylation and deacetylation

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]

Clinical significance

H4K5ac is implicated in inflammatory bowel disease and Crohn's disease.[2]

See also

  • Histone acetylation

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Histone H4K5 Review". https://epigenie.com/key-epigenetic-players/histone-proteins-and-modifications/histone-h4k5/. Retrieved 2 December 2019. 
  2. ↑ 2.0 2.1 "H4K5ac Post Translational Modification - HIstome". http://www.actrec.gov.in/histome/ptm_sp.php?ptm_sp=H4K5ac. Retrieved 2 December 2019. 
  3. ↑ Shang, Wei-Hao; Hori, Tetsuya; Westhorpe, Frederick G.; Godek, Kristina M.; Toyoda, Atsushi; Misu, Sadahiko; Monma, Norikazu; Ikeo, Kazuho et al. (2016). "Acetylation of histone H4 lysine 5 and 12 is required for CENP-A deposition into centromeres". Nature Communications 7: 13465. doi:10.1038/ncomms13465. PMID 27811920. Bibcode: 2016NatCo...713465S. 
  4. ↑ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. Elsevier Science. pp. 21–38. ISBN 9780127999586. 
  5. ↑ "Multivalent engagement of chromatin modifications by linked binding modules". Nature Reviews. Molecular Cell Biology 8 (12): 983–94. December 2007. doi:10.1038/nrm2298. PMID 18037899. 
  6. ↑ "Chromatin modifications and their function". Cell 128 (4): 693–705. February 2007. doi:10.1016/j.cell.2007.02.005. PMID 17320507. 
  7. ↑ "Regulation of protein turnover by acetyltransferases and deacetylases". Biochimie 90 (2): 306–12. 2008. doi:10.1016/j.biochi.2007.06.009. PMID 17681659. 
  8. ↑ "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23. 2005. doi:10.1016/j.gene.2005.09.010. PMID 16289629. 
  9. ↑ "Lysine acetylation: codified crosstalk with other posttranslational modifications". Mol. Cell 31 (4): 449–61. 2008. doi:10.1016/j.molcel.2008.07.002. PMID 18722172. 
  10. ↑ "Posttranslational modifications of tubulin in cultured mouse brain neurons and astroglia". Biol. Cell 65 (2): 109–117. 1989. doi:10.1016/0248-4900(89)90018-x. PMID 2736326. 
  11. ↑ "The acetylation of alpha-tubulin and its relationship to the assembly and disassembly of microtubules". J. Cell Biol. 103 (2): 571–579. 1986. doi:10.1083/jcb.103.2.571. PMID 3733880. 
  12. ↑ "Translating the histone code". Science 293 (5532): 1074–80. August 2001. doi:10.1126/science.1063127. PMID 11498575. 
  13. ↑ "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project". Nature 447 (7146): 799–816. June 2007. doi:10.1038/nature05874. PMID 17571346. Bibcode: 2007Natur.447..799B. 
  14. ↑ "Systematic protein location mapping reveals five principal chromatin types in Drosophila cells". Cell 143 (2): 212–24. October 2010. doi:10.1016/j.cell.2010.09.009. PMID 20888037. 
  15. ↑ "Identification of functional elements and regulatory circuits by Drosophila modENCODE". Science 330 (6012): 1787–97. December 2010. doi:10.1126/science.1198374. PMID 21177974. Bibcode: 2010Sci...330.1787R. 
  16. ↑ "Comprehensive analysis of the chromatin landscape in Drosophila melanogaster". Nature 471 (7339): 480–5. March 2011. doi:10.1038/nature09725. PMID 21179089. Bibcode: 2011Natur.471..480K. 
  17. ↑ "Integrative analysis of 111 reference human epigenomes". Nature 518 (7539): 317–30. February 2015. doi:10.1038/nature14248. PMID 25693563. Bibcode: 2015Natur.518..317.. 
  18. ↑ "Whole-Genome Chromatin IP Sequencing (ChIP-Seq)". https://www.illumina.com/Documents/products/datasheets/datasheet_chip_sequence.pdf. Retrieved 23 October 2019. 
  19. ↑ "MAINE-Seq/Mnase-Seq". https://www.illumina.com/science/sequencing-method-explorer/kits-and-arrays/maine-seq-mnase-seq-nucleo-seq.html?langsel=/us/. 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. 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. 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. PMID 20150147. 



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