Editing Histone (section)

== Modification{{anchor|Histone_modification}}==
[[File:Histone modifications.png|thumb|center|640px|Schematic representation of histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011]]

A huge catalogue of histone modifications have been described, but a functional understanding of most is still lacking. Collectively, it is thought that histone modifications may underlie a [[histone code]], whereby combinations of histone modifications have specific meanings. However, most functional data concerns individual prominent histone modifications that are biochemically amenable to detailed study.

=== Chemistry ===

==== Lysine methylation ====
<!-- Graphics from here down in this section need captions laymen can understand. -->
[[File:methyl lysine.svg|thumb|300px]]

The addition of one, two, or many methyl groups to lysine has little effect on the chemistry of the histone; methylation leaves the charge of the lysine intact and adds a minimal number of atoms so steric interactions are mostly unaffected. However, proteins containing Tudor, chromo or PHD domains, amongst others, can recognise lysine methylation with exquisite sensitivity and differentiate mono, di and tri-methyl lysine, to the extent that, for some lysines (e.g.: H4K20) mono, di and tri-methylation appear to have different meanings. Because of this, lysine methylation tends to be a very informative mark and dominates the known histone modification functions.
{{Clear}}

==== Glutamine serotonylation ====
Recently it has been shown, that the addition of a [[serotonin]] group to the position 5 glutamine of H3, happens in serotonergic cells such as neurons. This is part of the differentiation of the serotonergic cells. This post-translational modification happens in conjunction with the H3K4me3 modification. The serotonylation potentiates the binding of the general transcription factor [[Transcription factor II D|TFIID]] to the [[TATA box]].<ref>{{cite journal | vauthors = Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, Maze I | title = Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3 | journal = Nature | volume = 567 | issue = 7749 | pages = 535–539 | date = March 2019 | pmid = 30867594 | pmc = 6557285 | doi = 10.1038/s41586-019-1024-7 | bibcode = 2019Natur.567..535F }}</ref>

==== Arginine methylation ====
[[File:methyl arginine.svg|thumb|350px]]

What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e.g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono- or di-methylated, and methylation can be symmetric or asymmetric, potentially with different meanings.

==== Arginine citrullination ====
Enzymes called [[Protein-arginine deiminase|peptidylarginine deiminases]] (PADs) hydrolyze the imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible.<ref>{{cite journal | vauthors = Christophorou MA, Castelo-Branco G, Halley-Stott RP, Oliveira CS, Loos R, Radzisheuskaya A, Mowen KA, Bertone P, Silva JC, Zernicka-Goetz M, Nielsen ML, Gurdon JB, Kouzarides T | title = Citrullination regulates pluripotency and histone H1 binding to chromatin | journal = Nature | volume = 507 | issue = 7490 | pages = 104–8 | date = March 2014 | pmid = 24463520 | pmc = 4843970 | doi = 10.1038/nature12942 | url = https://www.repository.cam.ac.uk/handle/1810/254537 | bibcode = 2014Natur.507..104C }}</ref> PADs can also produce the opposite effect by removing or inhibiting mono-methylation of arginine residues on histones and thus antagonizing the positive effect arginine methylation has on transcriptional activity.<ref>{{cite journal | vauthors = Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T | title = Histone deimination antagonizes arginine methylation | journal = Cell | volume = 118 | issue = 5 | pages = 545–53 | date = September 2004 | pmid = 15339660 | doi = 10.1016/j.cell.2004.08.020 | doi-access = free }}</ref>

==== Lysine acetylation ====
[[File:acetyl lysine.tif|thumb|150px]]

Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects the need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes [[H3K27ac]].
{{Clear}}

==== Serine/threonine/tyrosine phosphorylation ====
[[File:amino acid phosphorylations.tif|thumb|400px]]

Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well-characterised role of [[phosphorylation]] in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as a post-translational modification, and binding domains such as BRCT have been characterised.

=== Effects on transcription ===
Most well-studied histone modifications are involved in control of transcription.

==== Actively transcribed genes ====

Two histone modifications are particularly associated with active transcription:
;''Trimethylation of H3 lysine 4 (H3K4me3)'': This trimethylation occurs at the promoter of active genes<ref>{{cite journal | vauthors = Krogan NJ, Dover J, Wood A, Schneider J, Heidt J, Boateng MA, Dean K, Ryan OW, Golshani A, Johnston M, Greenblatt JF, Shilatifard A | title = The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation | journal = Molecular Cell | volume = 11 | issue = 3 | pages = 721–9 | date = March 2003 | pmid = 12667454 | doi = 10.1016/S1097-2765(03)00091-1 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ng HH, Robert F, Young RA, Struhl K | title = Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity | journal = Molecular Cell | volume = 11 | issue = 3 | pages = 709–19 | date = March 2003 | pmid = 12667453 | doi = 10.1016/S1097-2765(03)00092-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ, Gingeras TR, Schreiber SL, Lander ES | title = Genomic maps and comparative analysis of histone modifications in human and mouse | journal = Cell | volume = 120 | issue = 2 | pages = 169–81 | date = January 2005 | pmid = 15680324 | doi = 10.1016/j.cell.2005.01.001 | doi-access = free }}</ref> and is performed by the [[COMPASS complex]].<ref>{{cite journal | vauthors = Krogan NJ, Dover J, Khorrami S, Greenblatt JF, Schneider J, Johnston M, Shilatifard A | title = COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression | journal = The Journal of Biological Chemistry | volume = 277 | issue = 13 | pages = 10753–5 | date = March 2002 | pmid = 11805083 | doi = 10.1074/jbc.C200023200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R, Stewart AF | title = The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4 | journal = The EMBO Journal | volume = 20 | issue = 24 | pages = 7137–48 | date = December 2001 | pmid = 11742990 | pmc = 125774 | doi = 10.1093/emboj/20.24.7137 }}</ref><ref>{{cite journal | vauthors = Nagy PL, Griesenbeck J, Kornberg RD, Cleary ML | title = A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 1 | pages = 90–4 | date = January 2002 | pmid = 11752412 | pmc = 117519 | doi = 10.1073/pnas.221596698 | bibcode = 2002PNAS...99...90N | doi-access = free }}</ref> Despite the conservation of this complex and histone modification from yeast to mammals, it is not entirely clear what role this modification plays. However, it is an excellent mark of active promoters and the level of this histone modification at a gene's promoter is broadly correlated with transcriptional activity of the gene. The formation of this mark is tied to transcription in a rather convoluted manner: early in [[Transcription (genetics)|transcription]] of a gene, [[RNA polymerase II]] undergoes a switch from [[Transcription (genetics)#Initiation|initiating']] to [[Transcription (genetics)#Elongation|'elongating']], marked by a change in the phosphorylation states of the [[rna polymerase ii#CTD of RNA polymerase|RNA polymerase II C terminal domain (CTD)]]. The same enzyme that [[phosphorylation|phosphorylates]] the CTD also phosphorylates the Rad6 complex,<ref>{{cite journal | vauthors = Wood A, Schneider J, Dover J, Johnston M, Shilatifard A | title = The Bur1/Bur2 complex is required for histone H2B monoubiquitination by Rad6/Bre1 and histone methylation by COMPASS | journal = Molecular Cell | volume = 20 | issue = 4 | pages = 589–99 | date = November 2005 | pmid = 16307922 | doi = 10.1016/j.molcel.2005.09.010 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sarcevic B, Mawson A, Baker RT, Sutherland RL | title = Regulation of the ubiquitin-conjugating enzyme hHR6A by CDK-mediated phosphorylation | journal = The EMBO Journal | volume = 21 | issue = 8 | pages = 2009–18 | date = April 2002 | pmid = 11953320 | pmc = 125963 | doi = 10.1093/emboj/21.8.2009 }}</ref> which in turn adds a ubiquitin mark to H2B K123 (K120 in mammals).<ref>{{cite journal |vauthors=Robzyk K, Recht J, Osley MA |date=January 2000 |title=Rad6-dependent ubiquitination of histone H2B in yeast |url=https://www.science.org/doi/10.1126/science.287.5452.501 |journal=Science |volume=287 |issue=5452 |pages=501–4 |bibcode=2000Sci...287..501R |doi=10.1126/science.287.5452.501 |pmid=10642555|url-access=subscription }}</ref> H2BK123Ub occurs throughout transcribed regions, but this mark is required for COMPASS to trimethylate H3K4 at promoters.<ref>{{cite journal |vauthors=Sun ZW, Allis CD |date=July 2002 |title=Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast |url=https://www.nature.com/articles/nature00883 |journal=Nature |volume=418 |issue=6893 |pages=104–8 |bibcode=2002Natur.418..104S |doi=10.1038/nature00883 |pmid=12077605 |s2cid=4338471|url-access=subscription }}</ref><ref>{{cite journal | vauthors = Dover J, Schneider J, Tawiah-Boateng MA, Wood A, Dean K, Johnston M, Shilatifard A | title = Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 32 | pages = 28368–71 | date = August 2002 | pmid = 12070136 | doi = 10.1074/jbc.C200348200 | doi-access = free }}</ref>
;''Trimethylation of H3 lysine 36 ([[H3K36me3]])'': This trimethylation occurs in the body of active genes and is deposited by the methyltransferase Set2.<ref>{{cite journal | vauthors = Strahl BD, Grant PA, Briggs SD, Sun ZW, Bone JR, Caldwell JA, Mollah S, Cook RG, Shabanowitz J, Hunt DF, Allis CD | title = Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression | journal = Molecular and Cellular Biology | volume = 22 | issue = 5 | pages = 1298–306 | date = March 2002 | pmid = 11839797 | pmc = 134702 | doi = 10.1128/MCB.22.5.1298-1306.2002 }}</ref> This protein associates with elongating [[RNA polymerase II]], and H3K36Me3 is indicative of actively transcribed genes.<ref>{{cite journal | vauthors = Li J, Moazed D, Gygi SP | title = Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 51 | pages = 49383–8 | date = December 2002 | pmid = 12381723 | doi = 10.1074/jbc.M209294200 | doi-access = free }}</ref> H3K36Me3 is recognised by the Rpd3 histone deacetylase complex, which removes acetyl modifications from surrounding histones, increasing chromatin compaction and repressing spurious transcription.<ref>{{cite journal | vauthors = Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, Shia WJ, Anderson S, Yates J, Washburn MP, Workman JL | title = Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription | journal = Cell | volume = 123 | issue = 4 | pages = 581–92 | date = November 2005 | pmid = 16286007 | doi = 10.1016/j.cell.2005.10.023 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, Collins SR, Schuldiner M, Chin K, Punna T, Thompson NJ, Boone C, Emili A, Weissman JS, Hughes TR, Strahl BD, Grunstein M, Greenblatt JF, Buratowski S, Krogan NJ | title = Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex | journal = Cell | volume = 123 | issue = 4 | pages = 593–605 | date = November 2005 | pmid = 16286008 | doi = 10.1016/j.cell.2005.10.025 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Joshi AA, Struhl K | title = Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation | journal = Molecular Cell | volume = 20 | issue = 6 | pages = 971–8 | date = December 2005 | pmid = 16364921 | doi = 10.1016/j.molcel.2005.11.021 | doi-access = free }}</ref> Increased chromatin compaction prevents transcription factors from accessing DNA, and reduces the likelihood of new transcription events being initiated within the body of the gene. This process therefore helps ensure that transcription is not interrupted.

==== Repressed genes ====

Three histone modifications are particularly associated with repressed genes:
;''Trimethylation of H3 lysine 27 (H3K27me3)'': This histone modification is deposited by the [[polycomb]] complex PRC2.<ref>{{cite journal | vauthors = Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D | title = Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein | journal = Genes & Development | volume = 16 | issue = 22 | pages = 2893–905 | date = November 2002 | pmid = 12435631 | pmc = 187479 | doi = 10.1101/gad.1035902 }}</ref> It is a clear marker of gene repression,<ref name="pmid12351676">{{cite journal |vauthors=Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y |date=November 2002 |title=Role of histone H3 lysine 27 methylation in Polycomb-group silencing |url=https://www.science.org/doi/10.1126/science.1076997 |journal=Science |volume=298 |issue=5595 |pages=1039–43 |bibcode=2002Sci...298.1039C |doi=10.1126/science.1076997 |pmid=12351676 |s2cid=6265267|url-access=subscription }}</ref> and is likely bound by other proteins to exert a repressive function. Another [[polycomb]] complex, PRC1, can bind [[H3K27me3]]<ref name="pmid12351676"/> and adds the histone modification H2AK119Ub which aids chromatin compaction.<ref>{{cite journal | vauthors = de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M, Koseki H, Brockdorff N | title = Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation | journal = Developmental Cell | volume = 7 | issue = 5 | pages = 663–76 | date = November 2004 | pmid = 15525528 | doi = 10.1016/j.devcel.2004.10.005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y | title = Role of histone H2A ubiquitination in Polycomb silencing | journal = Nature | volume = 431 | issue = 7010 | pages = 873–8 | date = October 2004 | pmid = 15386022 | doi = 10.1038/nature02985 | s2cid = 4344378 | bibcode = 2004Natur.431..873W | hdl = 10261/73732 }}</ref> Based on this data it appears that PRC1 is recruited through the action of PRC2, however, recent studies show that PRC1 is recruited to the same sites in the absence of PRC2.<ref>{{cite journal | vauthors = Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, Wutz A, Vidal M, Elderkin S, Brockdorff N | title = RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3 | journal = Cell | volume = 148 | issue = 4 | pages = 664–78 | date = February 2012 | pmid = 22325148 | pmc = 3281992 | doi = 10.1016/j.cell.2011.12.029 }}</ref><ref>{{cite journal | vauthors = Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D | title = PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes | journal = Molecular Cell | volume = 45 | issue = 3 | pages = 344–56 | date = February 2012 | pmid = 22325352 | pmc = 3293217 | doi = 10.1016/j.molcel.2012.01.002 }}</ref>
;''Di and tri-methylation of H3 lysine 9 (H3K9me2/3)'': H3K9me2/3 is a well-characterised marker for [[heterochromatin]], and is therefore strongly associated with gene repression. The formation of heterochromatin has been best studied in the yeast ''[[Schizosaccharomyces pombe]]'', where it is initiated by recruitment of the [[RNA-induced transcriptional silencing]] (RITS) complex to double stranded RNAs produced from [[centromeric]] repeats.<ref>{{cite journal | vauthors = Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal SI, Moazed D | title = RNAi-mediated targeting of heterochromatin by the RITS complex | journal = Science | volume = 303 | issue = 5658 | pages = 672–6 | date = January 2004 | pmid = 14704433 | pmc = 3244756 | doi = 10.1126/science.1093686 | bibcode = 2004Sci...303..672V }}</ref> RITS recruits the Clr4 [[histone methyltransferase]] which deposits H3K9me2/3.<ref>{{cite journal |vauthors=Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T |date=August 2000 |title=Regulation of chromatin structure by site-specific histone H3 methyltransferases |url=https://www.nature.com/articles/35020506 |journal=Nature |volume=406 |issue=6796 |pages=593–9 |bibcode=2000Natur.406..593R |doi=10.1038/35020506 |pmid=10949293 |s2cid=205008015|url-access=subscription }}</ref> This process is called [[histone methylation]]. H3K9Me2/3 serves as a binding site for the recruitment of Swi6 ([[heterochromatin protein 1]] or HP1, another classic heterochromatin marker)<ref>{{cite journal |vauthors=Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T |date=March 2001 |title=Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain |url=https://www.nature.com/articles/35065138 |journal=Nature |volume=410 |issue=6824 |pages=120–4 |bibcode=2001Natur.410..120B |doi=10.1038/35065138 |pmid=11242054 |s2cid=4334447|url-access=subscription }}</ref><ref>{{cite journal |vauthors=Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T |date=March 2001 |title=Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins |url=https://www.nature.com/articles/35065132 |journal=Nature |volume=410 |issue=6824 |pages=116–20 |bibcode=2001Natur.410..116L |doi=10.1038/35065132 |pmid=11242053 |s2cid=4331863|url-access=subscription }}</ref> which in turn recruits further repressive activities including histone modifiers such as [[histone deacetylase]]s and [[histone methyltransferase]]s.<ref>{{cite journal | vauthors = Bajpai G, Jain I, Inamdar MM, Das D, Padinhateeri R | title = Binding of DNA-bending non-histone proteins destabilizes regular 30-nm chromatin structure | journal = PLOS Computational Biology | volume = 13 | issue = 1 | pages = e1005365 | date = January 2017 | pmid = 28135276 | pmc = 5305278 | doi = 10.1371/journal.pcbi.1005365 | bibcode = 2017PLSCB..13E5365B | doi-access = free }}</ref>
;''Trimethylation of H4 lysine 20 ([[H4K20me]]3)'': This modification is tightly associated with heterochromatin,<ref name="pmid15145825">{{cite journal | vauthors = Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T | title = A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin | journal = Genes & Development | volume = 18 | issue = 11 | pages = 1251–62 | date = June 2004 | pmid = 15145825 | pmc = 420351 | doi = 10.1101/gad.300704 }}</ref><ref>{{cite journal | vauthors = Kourmouli N, Jeppesen P, Mahadevhaiah S, Burgoyne P, Wu R, Gilbert DM, Bongiorni S, Prantera G, Fanti L, Pimpinelli S, Shi W, Fundele R, Singh PB | title = Heterochromatin and tri-methylated lysine 20 of histone H4 in animals | journal = Journal of Cell Science | volume = 117 | issue = Pt 12 | pages = 2491–501 | date = May 2004 | pmid = 15128874 | doi = 10.1242/jcs.01238 | doi-access = free }}</ref> although its functional importance remains unclear. This mark is placed by the Suv4-20h methyltransferase, which is at least in part recruited by [[heterochromatin protein 1]].<ref name="pmid15145825"/>

==== Bivalent promoters ====

Analysis of histone modifications in embryonic stem cells (and other stem cells) revealed many gene promoters carrying both [[#Actively transcribed genes|H3K4Me3]] and [[#Repressed genes|H3K27Me3]], in other words these promoters display both activating and repressing marks simultaneously. This peculiar combination of modifications marks genes that are poised for transcription; they are not required in stem cells, but are rapidly required after differentiation into some lineages. Once the cell starts to differentiate, these bivalent promoters are resolved to either active or repressive states depending on the chosen lineage.<ref>{{cite journal | vauthors = Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES | title = A bivalent chromatin structure marks key developmental genes in embryonic stem cells | journal = Cell | volume = 125 | issue = 2 | pages = 315–26 | date = April 2006 | pmid = 16630819 | doi = 10.1016/j.cell.2006.02.041 | doi-access = free }}</ref>

=== Other functions ===

==== DNA damage repair ====

Marking sites of DNA damage is an important function for histone modifications. Without a repair marker, DNA would get destroyed by damage accumulated from sources such as the [[ultraviolet radiation]] of the sun.
; ''Phosphorylation of H2AX at serine 139 (γH2AX)'': Phosphorylated [[H2AX]] (also known as gamma H2AX) is a marker for [[DNA double strand breaks]],<ref name="pmid9488723">{{cite journal | vauthors = Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM | title = DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 10 | pages = 5858–68 | date = March 1998 | pmid = 9488723 | doi = 10.1074/jbc.273.10.5858 | doi-access = free }}</ref> and forms part of the [[DNA repair#Global response to DNA damage|response to DNA damage]].<ref name="pmid10959836"/><ref>{{cite journal | vauthors = Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A | title = Genomic instability in mice lacking histone H2AX | journal = Science | volume = 296 | issue = 5569 | pages = 922–7 | date = May 2002 | pmid = 11934988 | pmc = 4721576 | doi = 10.1126/science.1069398 | bibcode = 2002Sci...296..922C }}</ref> H2AX is phosphorylated early after detection of DNA double strand break, and forms a domain extending many kilobases either side of the damage.<ref name="pmid9488723"/><ref>{{cite journal | vauthors = Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M | title = Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break | journal = Current Biology | volume = 14 | issue = 19 | pages = 1703–11 | date = October 2004 | pmid = 15458641 | pmc = 4493763 | doi = 10.1016/j.cub.2004.09.047 | bibcode = 2004CBio...14.1703S }}</ref><ref>{{cite journal | vauthors = Rogakou EP, Boon C, Redon C, Bonner WM | title = Megabase chromatin domains involved in DNA double-strand breaks in vivo | journal = The Journal of Cell Biology | volume = 146 | issue = 5 | pages = 905–16 | date = September 1999 | pmid = 10477747 | pmc = 2169482 | doi = 10.1083/jcb.146.5.905 }}</ref> Gamma H2AX acts as a binding site for the protein MDC1, which in turn recruits key DNA repair proteins<ref>{{cite journal |vauthors=Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ |date=February 2003 |title=MDC1 is a mediator of the mammalian DNA damage checkpoint |url=https://www.nature.com/articles/nature01446 |journal=Nature |volume=421 |issue=6926 |pages=961–6 |bibcode=2003Natur.421..961S |doi=10.1038/nature01446 |pmid=12607005 |s2cid=4410773|url-access=subscription }}</ref> (this complex topic is well reviewed in<ref>{{cite journal |vauthors=Bekker-Jensen S, Mailand N |date=December 2010 |title=Assembly and function of DNA double-strand break repair foci in mammalian cells |url=https://www.sciencedirect.com/science/article/abs/pii/S1568786410003150 |journal=DNA Repair |volume=9 |issue=12 |pages=1219–28 |doi=10.1016/j.dnarep.2010.09.010 |pmid=21035408|url-access=subscription }}</ref>) and as such, gamma H2AX forms a vital part of the machinery that ensures genome stability.
;''Acetylation of H3 lysine 56 (H3K56Ac)'': H3K56Acx is required for genome stability.<ref>{{cite journal | vauthors = Ozdemir A, Spicuglia S, Lasonder E, Vermeulen M, Campsteijn C, Stunnenberg HG, Logie C | title = Characterization of lysine 56 of histone H3 as an acetylation site in Saccharomyces cerevisiae | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 25949–52 | date = July 2005 | pmid = 15888442 | doi = 10.1074/jbc.C500181200 | doi-access = free | hdl = 2066/32314 | hdl-access = free }}</ref><ref>{{cite journal |vauthors=Masumoto H, Hawke D, Kobayashi R, Verreault A |date=July 2005 |title=A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response |url=https://www.nature.com/articles/nature03714 |journal=Nature |volume=436 |issue=7048 |pages=294–8 |bibcode=2005Natur.436..294M |doi=10.1038/nature03714 |pmid=16015338 |s2cid=4414433|url-access=subscription }}</ref> H3K56 is acetylated by the p300/Rtt109 complex,<ref>{{cite journal | vauthors = Driscoll R, Hudson A, Jackson SP | title = Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56 | journal = Science | volume = 315 | issue = 5812 | pages = 649–52 | date = February 2007 | pmid = 17272722 | pmc = 3334813 | doi = 10.1126/science.1135862 | bibcode = 2007Sci...315..649D }}</ref><ref>{{cite journal |vauthors=Han J, Zhou H, Horazdovsky B, Zhang K, Xu RM, Zhang Z |date=February 2007 |title=Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication |url=https://www.science.org/doi/10.1126/science.1133234 |journal=Science |volume=315 |issue=5812 |pages=653–5 |bibcode=2007Sci...315..653H |doi=10.1126/science.1133234 |pmid=17272723 |s2cid=19056605|url-access=subscription }}</ref><ref>{{cite journal | vauthors = Das C, Lucia MS, Hansen KC, Tyler JK | title = CBP/p300-mediated acetylation of histone H3 on lysine 56 | journal = Nature | volume = 459 | issue = 7243 | pages = 113–7 | date = May 2009 | pmid = 19270680 | pmc = 2756583 | doi = 10.1038/nature07861 | bibcode = 2009Natur.459..113D }}</ref> but is rapidly deacetylated around sites of DNA damage. H3K56 acetylation is also required to stabilise stalled replication forks, preventing dangerous replication fork collapses.<ref>{{cite journal | vauthors = Han J, Zhou H, Li Z, Xu RM, Zhang Z | title = Acetylation of lysine 56 of histone H3 catalyzed by RTT109 and regulated by ASF1 is required for replisome integrity | journal = The Journal of Biological Chemistry | volume = 282 | issue = 39 | pages = 28587–96 | date = September 2007 | pmid = 17690098 | doi = 10.1074/jbc.M702496200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wurtele H, Kaiser GS, Bacal J, St-Hilaire E, Lee EH, Tsao S, Dorn J, Maddox P, Lisby M, Pasero P, Verreault A | title = Histone H3 lysine 56 acetylation and the response to DNA replication fork damage | journal = Molecular and Cellular Biology | volume = 32 | issue = 1 | pages = 154–72 | date = January 2012 | pmid = 22025679 | pmc = 3255698 | doi = 10.1128/MCB.05415-11 }}</ref> Although in general mammals make far greater use of histone modifications than microorganisms, a major role of H3K56Ac in DNA replication exists only in fungi, and this has become a target for antibiotic development.<ref>{{cite journal | vauthors = Wurtele H, Tsao S, Lépine G, Mullick A, Tremblay J, Drogaris P, Lee EH, Thibault P, Verreault A, Raymond M | title = Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy | journal = Nature Medicine | volume = 16 | issue = 7 | pages = 774–80 | date = July 2010 | pmid = 20601951 | pmc = 4108442 | doi = 10.1038/nm.2175 }}</ref>
; ''Trimethylation of H3 lysine 36 (H3K36me3)''
:H3K36me3 has the ability to recruit the MSH2-MSH6 (hMutSα) complex of the [[DNA mismatch repair]] pathway.<ref>{{cite journal | vauthors = Li F, Mao G, Tong D, Huang J, Gu L, Yang W, Li GM | title = The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα | journal = Cell | volume = 153 | issue = 3 | pages = 590–600 | date = April 2013 | pmid = 23622243 | pmc = 3641580 | doi = 10.1016/j.cell.2013.03.025 }}</ref> Consistently, regions of the human genome with high levels of H3K36me3 accumulate less somatic mutations due to [[DNA mismatch repair|mismatch repair]] activity.<ref>{{cite journal | vauthors = Supek F, Lehner B | title = Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes | journal = Cell | volume = 170 | issue = 3 | pages = 534–547.e23 | date = July 2017 | pmid = 28753428 | doi = 10.1016/j.cell.2017.07.003 | doi-access = free | hdl = 10230/35343 | hdl-access = free }}</ref>

==== Chromosome condensation ====

; ''Phosphorylation of H3 at serine 10 (phospho-H3S10)'': The mitotic kinase [[aurora B]] phosphorylates histone H3 at serine 10, triggering a cascade of changes that mediate mitotic chromosome condensation.<ref>{{cite journal |vauthors=Wilkins BJ, Rall NA, Ostwal Y, Kruitwagen T, Hiragami-Hamada K, Winkler M, Barral Y, Fischle W, Neumann H |date=January 2014 |title=A cascade of histone modifications induces chromatin condensation in mitosis |url=https://www.science.org/doi/10.1126/science.1244508 |journal=Science |volume=343 |issue=6166 |pages=77–80 |bibcode=2014Sci...343...77W |doi=10.1126/science.1244508 |pmid=24385627 |hdl-access=free |s2cid=7698266 |hdl=11858/00-001M-0000-0015-11C0-5}}</ref><ref>{{cite journal |vauthors=Johansen KM, Johansen J |date=2006 |title=Regulation of chromatin structure by histone H3S10 phosphorylation |url=https://link.springer.com/article/10.1007/s10577-006-1063-4 |journal=Chromosome Research |volume=14 |issue=4 |pages=393–404 |doi=10.1007/s10577-006-1063-4 |pmid=16821135 |s2cid=8556959|url-access=subscription }}</ref> Condensed chromosomes therefore stain very strongly for this mark, but H3S10 phosphorylation is also present at certain chromosome sites outside mitosis, for example in pericentric heterochromatin of cells during G2. H3S10 phosphorylation has also been linked to DNA damage caused by [[R-loop]] formation at highly transcribed sites.<ref>{{cite journal | vauthors = Castellano-Pozo M, Santos-Pereira JM, Rondón AG, Barroso S, Andújar E, Pérez-Alegre M, García-Muse T, Aguilera A | title = R loops are linked to histone H3 S10 phosphorylation and chromatin condensation | journal = Molecular Cell | volume = 52 | issue = 4 | pages = 583–90 | date = November 2013 | pmid = 24211264 | doi = 10.1016/j.molcel.2013.10.006 | doi-access = free }}</ref>

;''Phosphorylation H2B at serine 10/14 (phospho-H2BS10/14)'': Phosphorylation of H2B at serine 10 (yeast) or serine 14 (mammals)  is also linked to chromatin condensation, but for the very different purpose of mediating chromosome condensation during apoptosis.<ref>{{cite journal | vauthors = Cheung WL, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen CA, Beeser A, Etkin LD, Chernoff J, Earnshaw WC, Allis CD | title = Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase | journal = Cell | volume = 113 | issue = 4 | pages = 507–17 | date = May 2003 | pmid = 12757711 | doi = 10.1016/s0092-8674(03)00355-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ahn SH, Cheung WL, Hsu JY, Diaz RL, Smith MM, Allis CD | title = Sterile 20 kinase phosphorylates histone H2B at serine 10 during hydrogen peroxide-induced apoptosis in S. cerevisiae | journal = Cell | volume = 120 | issue = 1 | pages = 25–36 | date = January 2005 | pmid = 15652479 | doi = 10.1016/j.cell.2004.11.016 | doi-access = free }}</ref> This mark is not simply a late acting bystander in apoptosis as yeast carrying mutations of this residue are resistant to hydrogen peroxide-induced apoptotic cell death.

===Addiction===

Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions.<ref name=RobisonNestler>{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–637 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref><ref>{{cite journal | vauthors = Hitchcock LN, Lattal KM | title = Histone-mediated epigenetics in addiction | journal = Progress in Molecular Biology and Translational Science | volume = 128 | pages = 51–87 | date = 2014 | pmid = 25410541 | pmc = 5914502 | doi = 10.1016/B978-0-12-800977-2.00003-6 | publisher = Academic Press | isbn = 9780128009772 }}</ref><ref>{{cite journal | vauthors = McQuown SC, Wood MA | title = Epigenetic regulation in substance use disorders | journal = Current Psychiatry Reports | volume = 12 | issue = 2 | pages = 145–153 | date = April 2010 | pmid = 20425300 | pmc = 2847696 | doi = 10.1007/s11920-010-0099-5 }}</ref>  Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.<ref name=RobisonNestler />

[[Cigarette#consumtpion|Cigarette]] smokers (about 15% of the US population) are usually addicted to [[nicotine]].<ref>{{Cite web | url=https://www.drugabuse.gov/publications/tobacco-nicotine-e-cigarettes/nicotine-addictive | title=Is nicotine addictive?}}</ref>  After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the [[nucleus accumbens]] of the brain, causing 61% increase in FosB expression.<ref>{{cite journal | vauthors = Levine A, Huang Y, Drisaldi B, Griffin EA, Pollak DD, Xu S, Yin D, Schaffran C, Kandel DB, Kandel ER | title = Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ra109 | date = November 2011 | pmid = 22049069 | pmc = 4042673 | doi = 10.1126/scitranslmed.3003062 }}</ref>  This would also increase expression of the [[Alternative splicing|splice variant]] [[FosB#Delta FosB|Delta FosB]].  In the [[nucleus accumbens]] of the brain, [[FosB#Delta FosB|Delta FosB]] functions as a "sustained molecular switch" and "master control protein" in the development of an [[addiction]].<ref>{{cite journal |vauthors=Ruffle JK |date=November 2014 |title=Molecular neurobiology of addiction: what's all the (Δ)FosB about? |url=https://www.tandfonline.com/doi/abs/10.3109/00952990.2014.933840?journalCode=iada20 |journal=The American Journal of Drug and Alcohol Abuse |volume=40 |issue=6 |pages=428–37 |doi=10.3109/00952990.2014.933840 |pmid=25083822 |s2cid=19157711|url-access=subscription }}</ref><ref>{{cite journal | vauthors = Nestler EJ, Barrot M, Self DW | title = DeltaFosB: a sustained molecular switch for addiction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11042–6 | date = September 2001 | pmid = 11572966 | pmc = 58680 | doi = 10.1073/pnas.191352698 | bibcode = 2001PNAS...9811042N | doi-access = free }}</ref>

About 7% of the US population is addicted to [[Alcoholism|alcohol]].  In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain [[amygdala]] complex.  This acetylation is an activating mark for pronociceptin.  The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.<ref>{{cite journal |vauthors=D'Addario C, Caputi FF, Ekström TJ, Di Benedetto M, Maccarrone M, Romualdi P, Candeletti S |date=February 2013 |title=Ethanol induces epigenetic modulation of prodynorphin and pronociceptin gene expression in the rat amygdala complex |url=https://link.springer.com/article/10.1007/s12031-012-9829-y |journal=Journal of Molecular Neuroscience |volume=49 |issue=2 |pages=312–9 |doi=10.1007/s12031-012-9829-y |pmid=22684622 |s2cid=14013417|url-access=subscription }}</ref>

[[Methamphetamine]] addiction occurs in about 0.2% of the US population.<ref>{{Cite web | url=https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-scope-methamphetamine-abuse-in-united-states |title = What is the scope of methamphetamine abuse in the United States?}}</ref>  Chronic methamphetamine use causes [[Histone methylation#Function|methylation of the lysine]] in position 4 of histone 3 located at the [[Promoter (genetics)|promoters]] of the ''[[c-fos]]'' and the ''[[CCR2|C-C chemokine receptor 2]] (ccr2)'' genes, activating those genes in the nucleus accumbens (NAc).<ref name=Godino>{{cite journal | vauthors = Godino A, Jayanthi S, Cadet JL | title = Epigenetic landscape of amphetamine and methamphetamine addiction in rodents | journal = Epigenetics | volume = 10 | issue = 7 | pages = 574–80 | date = 2015 | pmid = 26023847 | pmc = 4622560 | doi = 10.1080/15592294.2015.1055441 }}</ref>  c-fos is well known to be important in [[addiction]].<ref>{{cite journal | vauthors = Cruz FC, Javier Rubio F, Hope BT | title = Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction | journal = Brain Research | volume = 1628 | issue = Pt A | pages = 157–73 | date = December 2015 | pmid = 25446457 | pmc = 4427550 | doi = 10.1016/j.brainres.2014.11.005 }}</ref>  The ''ccr2'' gene is also important in addiction, since mutational inactivation of this gene impairs addiction.<ref name=Godino />