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H3K27ac

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H3K27acis anepigeneticmodification to the DNA packaging proteinhistone H3.It is a mark that indicatesacetylationof thelysineresidue atN-terminalposition 27 of the histone H3 protein.

H3K27ac is associated with the higher activation oftranscriptionand therefore defined as anactiveenhancermark. H3K27ac is found at both proximal and distal regions oftranscription start site(TSS).

Lysine acetylation and deacetylation

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Lysine acetylation

Proteins are typically acetylated onlysineresidues, and the acetylation reaction relies onacetyl-coenzyme Aas the acetyl group donor. Inhistone acetylation and deacetylation,histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part ofgene regulation.Typically, these reactions are catalyzed byenzymeswithhistone acetyltransferase(HAT) orhistone deacetylase(HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.[1]

The regulation oftranscription 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 ofkinasesandphosphatases.Not only can the acetylation state of a protein modify its activity, but there has been a recent suggestion that thispost-translational modificationmay also crosstalk withphosphorylation,methylation,ubiquitination,sumoylation, and others for dynamic control of cellular signaling.[3][4][5]

In the field ofepigenetics,histone acetylation(anddeacetylation) have been shown to be important mechanisms in the regulation of gene transcription. Histones, however, are not the only proteins regulated bypost-translationalacetylation.

Nomenclature

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H3K27ac indicates acetylation oflysine27 on histone H3 protein subunit: [6]

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

Histone modifications

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The genomic DNA of eukaryotic cells is wrapped around special protein molecules known ashistones.The complexes formed by the looping of the DNA are known aschromatin.The basic structural unit of chromatin is thenucleosome: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. Thecarboxyl (C) terminalend 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 inH3K36me3.[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 aHistone codedictates 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:ENCODEand 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 ofChIP-sequencingrevealed 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 asenhancers.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 andH3K27me3modification 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 markH3K4me1that 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 inTranscriptional start sites(TSS). H3K27ac shares a location withH3K27me3and they interact in an antagonistic manner.

Alzheimer's

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H3K27ac is enriched in the regulatory regions of genes implicated inAlzheimer'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 andimmunoprecipitated.It results in good optimization and is usedin vivoto 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 hyperactiveTn5 transposonto 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.PMID17681659.
  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.PMID16289629.
  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.PMC2551738.PMID18722172.
  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.PMID2736326.
  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.PMC2113826.PMID3733880.
  6. ^Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30).Epigenetic Gene Expression and Regulation.Elsevier Science. pp. 21–38.ISBN9780127999586.
  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.PMC4690530.PMID18037899.
  8. ^Kouzarides T (February 2007)."Chromatin modifications and their function".Cell.128(4): 693–705.doi:10.1016/j.cell.2007.02.005.PMID17320507.S2CID11691263.
  9. ^Jenuwein T, Allis CD (August 2001). "Translating the histone code".Science.293(5532): 1074–80.doi:10.1126/science.1063127.PMID11498575.S2CID1883924.
  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.PMC2212820.PMID17571346.
  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.PMC3119929.PMID20888037.
  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.PMC3192495.PMID21177974.
  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.PMC3109908.PMID21179089.
  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.PMC4530010.PMID25693563.
  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.PMC2730368.PMID19700617.
  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.PMC3003124.PMID21106759.
  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.PMID30349106.S2CID53024153.
  18. ^"Whole-Genome Chromatin IP Sequencing (ChIP-Seq)"(PDF).Illumina.Retrieved23 October2019.
  19. ^"MAINE-Seq/Mnase-Seq".illumina.Retrieved23 October2019.
  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.ISBN9780471142720.PMC4374986.PMID25559105.
  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.ISSN1088-9051.PMC4617971.PMID26314830.
  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.ISSN1559-6095.PMC3627383.PMID20150147.
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