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Histone code
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<h2 id="the-hypothesis">The hypothesis</h2> <p>The hypothesis is that <a href="/facts/Chromatin/ha0TJheJ">chromatin</a>-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as <a href="/facts/Methylation/EvDMWVW5">methylation</a>, <a href="/facts/Acetylation/PNMzRM4r">acetylation</a>, <a href="/facts/ADP-ribosylation/rv6QqIqv">ADP-ribosylation</a>, <a href="/facts/Ubiquitination/hpulmU3m">ubiquitination</a>, <a href="/facts/Citrullination/gsMUqv0n">citrullination</a>, <a href="/facts/SUMO_protein/T5vYKlQd">SUMO</a>-ylation<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> and <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a>) to <a href="/facts/Histone/krb5VJfp">histone</a> tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions remains elusive. However, some specific examples have been worked out in detail. For example, phosphorylation of <a href="/facts/Serine/4duVl30B">serine</a> residues 10 and 28 on <a href="/facts/Histone_H3/MXc7C8v2">histone H3</a> is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of <a href="/facts/Serine/4duVl30B">serine</a> residue 10 and acetylation of a <a href="/facts/Lysine/CEetgA9L">lysine</a> residue 14 on histone H3 is a tell-tale sign of active <a href="/facts/Transcription_(genetics)/bDgp9HDN">transcription</a>. </p> <h3>Modifications</h3> <p>Well characterized modifications to histones include:<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <ul><li><a href="/facts/Methylation/EvDMWVW5">Methylation</a>: Both lysine and arginine residues are known to be methylated. Methylated lysines are the best understood marks of the histone code, as specific methylated lysine match well with gene expression states. Methylation of lysines H3K4 and H3K36 is correlated with transcriptional activation while demethylation of H3K4 is correlated with silencing of the genomic region. Methylation of lysines H3K9 and H3K27 is correlated with transcriptional repression.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> Particularly, <a href="/facts/H3K9me3/uWdDjVsM">H3K9me3</a> is highly correlated with constitutive heterochromatin.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> Methylation of histone lysine also has a role in <a href="/facts/DNA_repair/hsURuYYq">DNA repair</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> For instance, <a href="/facts/H3K36me/Y7MAlAw3">H3K36me</a>3 is required for <a href="/facts/Homologous_recombination/WU0IIVVv">homologous recombinational</a> repair of <a href="/facts/DNA_damage_(naturally_occurring)/CjGTLKGl">DNA double-strand breaks</a>, and H4K20me2 facilitates repair of such breaks by <a href="/facts/Non-homologous_end_joining/xvHqwBPt">non-homologous end joining</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a></li> <li><a href="/facts/Acetylation/PNMzRM4r">Acetylation</a>—by <a href="/facts/Histone_acetyltransferase/gIzJY5fn">HAT</a> (histone acetyl transferase); deacetylation—by <a href="/facts/HDAC/P38q78aV">HDAC</a> (histone deacetylase): Acetylation tends to define the 'openness' of <a href="/facts/Chromatin/ha0TJheJ">chromatin</a> as acetylated histones cannot pack as well together as deacetylated histones.</li> <li><a href="/facts/Phosphorylation/LXUEEeIL">Phosphorylation</a></li> <li><a href="/facts/Ubiquitination/hpulmU3m">Ubiquitination</a></li> <li>SUMOylation<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li></ul> <p>However, there are many more histone modifications, and sensitive <a href="/facts/Mass_spectrometry/RH5WBHJ2">mass spectrometry</a> approaches have recently greatly expanded the catalog.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>A very basic summary of the histone code for gene expression status is given below (histone nomenclature is described <a href="/facts/Histone/krb5VJfp">here</a>): </p> <table><tbody><tr><th rowspan="2">Type ofmodification</th><th colspan="8">Histone</th></tr><tr><th>H3K4</th><th>H3K9</th><th>H3K14</th><th>H3K27</th><th>H3K79</th><th>H3K122</th><th>H4K20</th><th>H2BK5</th></tr><tr><td>mono-<a href="/facts/Methylation/EvDMWVW5">methylation</a></td><th><a href="/facts/Gene_activation/9N4G341I">activation</a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></th><th>activation<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a></th><td></td><th>activation<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a></th><th>activation<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></th><td></td><th>activation<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></th><th>activation<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></th></tr><tr><td>di-methylation</td><th></th><th><a href="/facts/Gene_repression/qGBBQwqS">repression</a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></th><td></td><th>repression<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a></th><th>activation<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></th><td></td><td></td><td></td></tr><tr><td>tri-methylation</td><th>activation<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a></th><th>repression<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></th><td></td><th>repression<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a></th><th>activation,<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a>repression<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></th><td></td><td></td><th>repression<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></th></tr><tr><td><a href="/facts/Acetylation/PNMzRM4r">acetylation</a></td><td></td><th>activation<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></th><th>activation<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a></th><th>activation<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></th><td></td><th>activation<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></th><td></td><td></td></tr></tbody></table> <h4><a href="/facts/Histone_H2B/h8gyE0fp">Histone H2B</a></h4> <ul><li><a href="/facts/H2BK5ac/BfTRnY33">H2BK5ac</a></li></ul> <h4><a href="/facts/Histone_H3/MXc7C8v2">Histone H3</a></h4> <ul><li><a href="/facts/H3K4me1/D3k2IWBm">H3K4me1</a> - primed enhancers</li> <li><a href="/facts/H3K4me3/FAIpNLLE">H3K4me3</a> is enriched in transcriptionally active promoters.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></li> <li><a href="/facts/H3K9me2/dbWuYLLC">H3K9me2</a> -repression</li> <li><a href="/facts/H3K9me3/uWdDjVsM">H3K9me3</a> is found in constitutively repressed genes.</li> <li><a href="/facts/H3K27me3/KaooAT7Y">H3K27me3</a> is found in facultatively repressed genes.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></li> <li><a href="/facts/H3K36me/Y7MAlAw3">H3K36me</a></li> <li><a href="/facts/H3K36me2/gWC8oXFw">H3K36me2</a></li> <li><a href="/facts/H3K36me3/erUFXDDt">H3K36me3</a> is found in actively transcribed gene bodies.</li> <li><a href="/facts/H3K79me2/GGUongoc">H3K79me2</a></li> <li><a href="/facts/H3K9ac/F9NhFaCs">H3K9ac</a> is found in actively transcribed promoters.</li> <li><a href="/facts/H3K14ac/IKV1aQeB">H3K14ac</a> is found in actively transcribed promoters.</li> <li><a href="/facts/H3K23ac/1bvTyqGq">H3K23ac</a></li> <li><a href="/facts/H3K27ac/6CgY1owS">H3K27ac</a> distinguishes active enhancers from poised enhancers.</li> <li><a href="/facts/H3K36ac/VFhyXBeo">H3K36ac</a></li> <li><a href="/facts/H3K56ac/HD6RQEeg">H3K56ac</a> is a proxy for de novo histone assembly.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></li> <li>H3K122ac is enriched in poised promoters and also found in a different type of putative enhancer that lacks H3K27ac.</li></ul> <h4><a href="/facts/Histone_H4/lcGq1Xpv">Histone H4</a></h4> <ul><li><a href="/facts/H4K5ac/bMQ2JkXt">H4K5ac</a></li> <li><a href="/facts/H4K8ac/3A37QDlR">H4K8ac</a></li> <li><a href="/facts/H4K12ac/bY45snNt">H4K12ac</a></li> <li><a href="/facts/H4K16ac/uqzT2XPJ">H4K16ac</a></li> <li><a href="/facts/H4K20me/mM9qSqfw">H4K20me</a></li> <li><a href="/facts/H4K91ac/td52bmIV">H4K91ac</a></li></ul> <h2 id="complexity">Complexity</h2> <p>Unlike this simplified model, any real histone code has the potential to be massively complex; each of the four standard histones can be simultaneously modified at multiple different sites with multiple different modifications. To give an idea of this complexity, <a href="/facts/Histone_H3/MXc7C8v2">histone H3</a> contains nineteen lysines known to be methylated—each can be un-, mono-, di- or tri-methylated. If modifications are independent, this allows a potential 419 or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4 Gb / ~150 bp = ~44 million histones if they are very tightly packed). And this does not include lysine acetylation (known for H3 at nine residues), arginine methylation (known for H3 at three residues) or threonine/serine/tyrosine phosphorylation (known for H3 at eight residues), not to mention modifications of other histones. </p><p>Every <a href="/facts/Nucleosome/HX5DR9bn">nucleosome</a> in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> <a href="/facts/Mass_spectrometry/RH5WBHJ2">Mass spectrometry</a>-based <a href="/facts/Top-down_proteomics/xQNPy5Ff">top-down proteomics</a> has provided more insight into these patterns by being able to discriminate single molecule co-occurrence from co-localization in the genome or on the same nucleosome.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> A variety of approaches have been used to delve into detailed biochemical mechanisms that demonstrate the importance of interplay between histone modifications. Thus, specific patterns of histone modifications are more common than others. These patterns are functionally important but they are intricate and challenging to study. We currently have the best biochemical understanding of the importance of a relatively small number of discrete modifications and a few combinations. </p><p>Structural determinants of histone recognition by readers, writers, and erasers of the histone code are revealed by a growing body of experimental data.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Histone/krb5VJfp">Histone</a></li> <li><a href="/facts/Histone-modifying_enzymes/JC9zSUvu">Histone-modifying enzymes</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="http://www.cellsignal.com/reference/pathway/histone_modification.html">Cellsignal.com Histone Modifications with function and attached references</a></li> <li><a href="http://www.epigentek.com/docs/histonetable.pdf">Histone Code Overview sheet</a></li> <li><a href="http://www.activemotif.com/documents/1815.pdf">Histone Modification Guide</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Jenuwein T, Allis C (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. <a href="/wiki/CiteSeerX_(identifier)" target="_blank">/wiki/CiteSeerX_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Shiio, Yuzuru; Eisenman, Robert N. (11 November 2003). "Histone sumoylation is associated with transcriptional repression". Proceedings of the National Academy of Sciences. 100 (23): 13225–13230. doi:10.1073/pnas.1735528100. PMC 263760. PMID 14578449. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC263760" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC263760</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Strahl B, Allis C (2000). "The language of covalent histone modifications". Nature. 403 (6765): 41–5. Bibcode:2000Natur.403...41S. doi:10.1038/47412. PMID 10638745. S2CID 4418993. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome". BMC Genomics. 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Hublitz, Philip; Albert, Mareike; Peters, Antoine (28 April 2009). "Mechanisms of Transcriptional Repression by Histone Lysine Methylation". The International Journal of Developmental Biology. 10 (1387). Basel: 335–354. doi:10.1387/ijdb.082717ph. ISSN 1696-3547. PMID 19412890. <a href="https://doi.org/10.1387%2Fijdb.082717ph" target="_blank">https://doi.org/10.1387%2Fijdb.082717ph</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Wei S, Li C, Yin Z, Wen J, Meng H, Xue L, Wang J (2018). "Histone methylation in DNA repair and clinical practice: new findings during the past 5-years". J Cancer. 9 (12): 2072–2081. doi:10.7150/jca.23427. PMC 6010677. PMID 29937925. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010677" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010677</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Wei S, Li C, Yin Z, Wen J, Meng H, Xue L, Wang J (2018). "Histone methylation in DNA repair and clinical practice: new findings during the past 5-years". J Cancer. 9 (12): 2072–2081. doi:10.7150/jca.23427. PMC 6010677. PMID 29937925. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010677" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010677</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Shiio, Yuzuru; Eisenman, Robert N. (11 November 2003). "Histone sumoylation is associated with transcriptional repression". Proceedings of the National Academy of Sciences. 100 (23): 13225–13230. doi:10.1073/pnas.1735528100. PMC 263760. PMID 14578449. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC263760" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC263760</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, et al. (2011). "Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification". Cell. 146 (6): 1016–28. doi:10.1016/j.cell.2011.08.008. PMC 3176443. PMID 21925322. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176443" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176443</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Benevolenskaya EV (August 2007). "Histone H3K4 demethylases are essential in development and differentiation". Biochem. Cell Biol. 85 (4): 435–43. doi:10.1139/o07-057. PMID 17713579. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. <a href="https://doi.org/10.1016%2Fj.cell.2007.05.009" target="_blank">https://doi.org/10.1016%2Fj.cell.2007.05.009</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. <a href="https://doi.org/10.1016%2Fj.cell.2007.05.009" target="_blank">https://doi.org/10.1016%2Fj.cell.2007.05.009</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. <a href="https://doi.org/10.1016%2Fj.cell.2007.05.009" target="_blank">https://doi.org/10.1016%2Fj.cell.2007.05.009</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, Blobel GA, Vakoc CR (April 2008). "DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells". Mol. Cell. Biol. 28 (8): 2825–39. doi:10.1128/MCB.02076-07. PMC 2293113. PMID 18285465. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293113" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293113</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. <a href="https://doi.org/10.1016%2Fj.cell.2007.05.009" target="_blank">https://doi.org/10.1016%2Fj.cell.2007.05.009</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (May 2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. <a href="https://doi.org/10.1016%2Fj.cell.2007.05.009" target="_blank">https://doi.org/10.1016%2Fj.cell.2007.05.009</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome". BMC Genomics. 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome". BMC Genomics. 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, Blobel GA, Vakoc CR (April 2008). "DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells". Mol. Cell. 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