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{{short description|Histone modification – specifically, the dimethylated state of histone H3 at lysine residue 9}}
{{short description|Histone methylation on tail of histone H3 associated with gene bodies}}

'''H3K9me2''' is a covalent [[histone modification]] – specifically, the dimethylated state of [[histone H3]] at [[lysine]] [[Residue (chemistry)#Biochemistry|residue]] 9 – and an [[Epigenetics|epigenetic mark]] that is strongly associated with [[gene repression|transcriptional repression]].<ref name="Histome H3K9me2" /><ref name="Nestler1" /><ref name="pmid26472529" /> H3K9me2 synthesis is catalyzed by [[G9a]], [[G9a-like protein]], and [[PRDM2]].<ref name="Histome H3K9me2">{{cite web |title=H3K9me2 |url=http://www.actrec.gov.in/histome/ptm_sp.php?ptm_sp=H3K9me2 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018}}</ref><ref name="pmid26472529">{{cite journal | vauthors = Nestler EJ | title = Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms | journal = Int. Rev. Neurobiol. | volume = 124 | issue = | pages = 151–170 | date = August 2015 | pmid = 26472529 | pmc = 4690450 | doi = 10.1016/bs.irn.2015.07.003 | quote = Chronic social defeat stress decreases expression of G9a and GLP (G9a-like protein), two histone methyltransferases that catalyze the dimethylation of Lys9 of histone H3 (H3K9me2) (Covington et al., 2011), a mark associated with gene repression.}}</ref><ref name="Histome G9a">{{cite web |title=Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 |url=http://www.actrec.gov.in/histome/enzyme_sp.php?enzyme_sp=Histone-lysine_N-methyltransferase,_H3_lysine-9_specific_3 |publisher=HIstome: The Histone Infobase |accessdate=8 June 2018|quote=}}</ref> The repeat-rich regions of constitutive [[heterochromatin]] are enriched by di[[methylation]] and trimethylation of histone 3 [[lysine]] 9 (H3K9me2 and H3K9me3).<ref>{{cite journal|last1=Nakayama|first1=Jun-ichi|title=Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly.|journal=Science|date=2001|volume= 292|issue= 5514|pages=110–113|pmid=11283354|doi=10.1126/science.1060118|bibcode=2001Sci...292..110N}}</ref>
'''H3K9me2''' is an [[epigenetic]] modification to the DNA packaging protein [[Histone H3]]. It is a mark that indicates the di-[[methylation]] at the 9th [[lysine]] residue of the histone H3 protein and often asociated with [[gene|gene bodies]]


==Nomenclature==
==Nomenclature==

H3K9me2 refers to the di-methylated state of [[lysine]] residue 9 on [[histone H3]]:
H3K9me2indicates [[Methylation|monomethylation]] of [[lysine]] 9 on histone H3 protein subunit:
<ref>{{cite book |isbn=9780127999586 |pages=21–38|title=Epigenetic Gene Expression and Regulation|last1=Huang|first1=Suming|last2=Litt|first2=Michael D.|last3=Ann Blakey|first3=C.|date=2015-11-30}}</ref>
{| class="wikitable" style="text-align:center"
{| class="wikitable" style="text-align:center"
⚫
|Abbr.
⚫
|Meaning
|-
|-
|H3
⚫
| Abbr.
⚫
|H3 family of histones
⚫
| Meaning
|-
|-
⚫
|K
⚫
| [[Histone H3|H3]]
⚫
|standard abbreviation for lysine
⚫
| H3 family of histones
|-
|-
| K
|9
⚫
|position of amino acid residue
⚫
| standard abbreviation for lysine
(counting from N-terminus)
|-
|-
| 9
|me
|methyl group
⚫
| position of [[amino acid residue]]<br/>(counting from N-terminus)
|-
|-
⚫
|2
| me
| [[methyl group]]
|number of methyl groups added
⚫
|-
⚫
| 2
| number of methyl groups added
|}
|}


==Lysine Methylation==
==Clinical significance==

[[File:Methylation-lysine.PNG|Methylation-lysine]]

This diagram shows the progressive methylation of a lysine residue. The di-methylation denotes the methylation present in H3K9me2.

==Understanding 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.<ref>{{cite journal | vauthors = Ruthenburg AJ, Li H, Patel DJ, Allis CD | title = Multivalent engagement of chromatin modifications by linked binding modules | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 12 | pages = 983–94 | date = December 2007 | pmid = 18037899 | doi = 10.1038/nrm2298 | pmc = 4690530 }}</ref><ref>{{cite journal | vauthors = Kouzarides T | title = Chromatin modifications and their function | journal = Cell | volume = 128 | issue = 4 | pages = 693–705 | date = February 2007 | pmid = 17320507 | doi = 10.1016/j.cell.2007.02.005 }}</ref>

==Epigenetic implications==

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling 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.<ref>{{cite journal | vauthors = Jenuwein T, Allis CD | title = Translating the histone code | journal = Science | volume = 293 | issue = 5532 | pages = 1074–80 | date = August 2001 | pmid = 11498575 | doi = 10.1126/science.1063127 }}</ref> The current understanding and interpretation of histones comes from two large scale projects: [[ENCODE]] and the Epigenomic roadmap.<ref>{{cite journal | vauthors = Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermüller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaöz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Löytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrímsdóttir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ | display-authors = 6 | title = Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project | journal = Nature | volume = 447 | issue = 7146 | pages = 799–816 | date = June 2007 | pmid = 17571346 | pmc = 2212820 | doi = 10.1038/nature05874 | collaboration = The ENCODE Project Consortium | bibcode = 2007Natur.447..799B }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Systematic protein location mapping reveals five principal chromatin types in Drosophila cells | journal = Cell | volume = 143 | issue = 2 | pages = 212–24 | date = October 2010 | pmid = 20888037 | pmc = 3119929 | doi = 10.1016/j.cell.2010.09.009 }}</ref> Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance.<ref>{{cite journal | vauthors = Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, Washietl S, Arshinoff BI, Ay F, Meyer PE, Robine N, Washington NL, Di Stefano L, Berezikov E, Brown CD, Candeias R, Carlson JW, Carr A, Jungreis I, Marbach D, Sealfon R, Tolstorukov MY, Will S, Alekseyenko AA, Artieri C, Booth BW, Brooks AN, Dai Q, Davis CA, Duff MO, Feng X, Gorchakov AA, Gu T, Henikoff JG, Kapranov P, Li R, MacAlpine HK, Malone J, Minoda A, Nordman J, Okamura K, Perry M, Powell SK, Riddle NC, Sakai A, Samsonova A, Sandler JE, Schwartz YB, Sher N, Spokony R, Sturgill D, van Baren M, Wan KH, Yang L, Yu C, Feingold E, Good P, Guyer M, Lowdon R, Ahmad K, Andrews J, Berger B, Brenner SE, Brent MR, Cherbas L, Elgin SC, Gingeras TR, Grossman R, Hoskins RA, Kaufman TC, Kent W, Kuroda MI, Orr-Weaver T, Perrimon N, Pirrotta V, Posakony JW, Ren B, Russell S, Cherbas P, Graveley BR, Lewis S, Micklem G, Oliver B, Park PJ, Celniker SE, Henikoff S, Karpen GH, Lai EC, MacAlpine DM, Stein LD, White KP, Kellis M | display-authors = 6 | title = Identification of functional elements and regulatory circuits by Drosophila modENCODE | journal = Science | volume = 330 | issue = 6012 | pages = 1787–97 | date = December 2010 | pmid = 21177974 | pmc = 3192495 | doi = 10.1126/science.1198374 | collaboration = modENCODE Consortium | bibcode = 2010Sci...330.1787R }}</ref> A look in to the data obtained led to the definition of chromatin states based on histone modifications.<ref>{{cite journal | vauthors = Kharchenko PV, Alekseyenko AA, Schwartz YB, Minoda A, Riddle NC, Ernst J, Sabo PJ, Larschan E, Gorchakov AA, Gu T, Linder-Basso D, Plachetka A, Shanower G, Tolstorukov MY, Luquette LJ, Xi R, Jung YL, Park RW, Bishop EP, Canfield TK, Sandstrom R, Thurman RE, MacAlpine DM, Stamatoyannopoulos JA, Kellis M, Elgin SC, Kuroda MI, Pirrotta V, Karpen GH, Park PJ | display-authors = 6 | title = Comprehensive analysis of the chromatin landscape in Drosophila melanogaster | journal = Nature | volume = 471 | issue = 7339 | pages = 480–5 | date = March 2011 | pmid = 21179089 | doi = 10.1038/nature09725 | pmc = 3109908 | bibcode = 2011Natur.471..480K }}</ref> Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions.
* [[H3K4me3]]-promoters
* [[H3K4me1]]- primed enhancers
* [[H3K36me3]]-gene bodies
* [[H3K27me3]]-polycomb repression
* H3K9me3-heterochromatin

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.<ref>{{cite journal | vauthors = Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M | display-authors = 8 | title = Integrative analysis of 111 reference human epigenomes | journal = Nature | volume = 518 | issue = 7539 | pages = 317–30 | date = February 2015 | pmid = 25693563 | doi = 10.1038/nature14248 | collaboration = Roadmap Epigenomics Consortium | pmc = 4530010 | bibcode = 2015Natur.518..317. }}</ref>

===Friedreich's ataxia===
===Friedreich's ataxia===


[[R-loop]]'s are found with H3K9me2 mark at [[FXN]] in [[Friedreich's ataxia]] cells.<ref>{{cite journal |title=R Loops and Links to Human Disease |journal=Journal of Molecular Biology |volume=429 |issue=21 |pages=3168–3180 |doi=10.1016/j.jmb.2016.08.031 |pmid=27600412 |pmc=5478472 |year=2017 |last1=Richard |first1=Patricia |last2=Manley |first2=James L. }}</ref>
[[R-loop]]'s are found with H3K9me2 mark at [[FXN]] in [[Friedreich's ataxia]] cells.<ref>{{cite journal |title=R Loops and Links to Human Disease |journal=Journal of Molecular Biology |volume=429 |issue=21 |pages=3168–3180 |doi=10.1016/j.jmb.2016.08.031 |pmid=27600412 |pmc=5478472 |year=2017 |last1=Richard |first1=Patricia |last2=Manley |first2=James L. }}</ref>


==Methods==


The histone mark can be detected in a variety of ways:
===Addiction===
{{See also|Addiction#Neuroepigenetic mechanisms}}
{{Expand section|coverage of content from these sources.<ref name="Nestler1">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 | date = November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB serves as one of the master control proteins governing this structural plasticity.&nbsp;... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression.&nbsp;... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1).&nbsp;... The net result is c-fos gene repression.&nbsp;... G9a and ΔFosB share many of the same target genes.&nbsp;... Histone methylation is directly regulated by drugs of abuse as well: global levels of histone 3 lysine 9 dimethylation (H3K9me2) are reduced in the NAc after chronic cocaine37 and a genome-wide screen revealed alterations in H3K9me2 binding on the promoters of numerous genes in this brain region32; both increases and decreases were observed, indicating again that epigenetic modifications at individual genes often defy global changes. The global decrease in H3K9me2 in the NAc is likely mediated by cocaine-induced downregulation of two HMTs, G9a and G9a-like protein (GLP), which catalyze H3K9me2<sup>37</sup>. These adaptations mediate enhanced responsiveness to cocaine, as selective knockout or pharmacological inhibition of G9a in the NAc promotes cocaine-induced behaviors, whereas G9a overexpression has the opposite effect. G9a likewise mediates the ability of cocaine to increase the spine density of NAc MSNs<sup>37</sup> (Box 2). Interestingly, there is a functional feedback loop between G9a and ΔFosB: ΔFosB seems to be responsible for cocaine-induced suppression of G9a, and G9a binds to and represses the fosb promoter, such that G9a downregulation may promote the accumulation of ΔFosB observed after chronic cocaine<sup>37</sup>. In addition, G9a and ΔFosB share many of the same target genes.&nbsp;... The mechanisms underlying such gene desensitization and priming remain incompletely understood; our hypothesis is that epigenetic mechanisms are crucial (Figure 3B). A subset of primed genes show reduced binding of G9a and H3K9me2 at their promoters in the NAc, suggesting the involvement of this epigenetic mark<sup>37</sup>. Desensitization of the c-fos gene in the NAc, discussed above and depicted in Figure 4, involves stable increases in the binding of ΔFosB, G9a, and related co-repressors, which—although not affecting steady-state levels of c-Fos mRNA—dramatically repress its inducibility to subsequent drug exposure<sup>91</sup>.}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figure/F4/ Figure 4: Epigenetic basis of drug regulation of gene expression]</ref><ref name="Nestler 2014 epigenetics">{{cite journal | vauthors = Nestler EJ | title = Epigenetic mechanisms of drug addiction | journal = Neuropharmacology | volume = 76 Pt B | issue = | pages = 259–268 | date = January 2014 | pmid = 23643695 | pmc = 3766384 | doi = 10.1016/j.neuropharm.2013.04.004 | quote = Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine’s effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors.&nbsp;... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).<br />G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a).&nbsp;... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine’s behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation. }}</ref><ref name="A feat of epigenetic engineering">{{cite journal | vauthors = Whalley K | title = Psychiatric disorders: a feat of epigenetic engineering | journal = Nature Reviews. Neuroscience | volume = 15 | issue = 12 | pages = 768–9 | date = December 2014 | pmid = 25409693 | doi = 10.1038/nrn3869 | quote = The authors showed that expression of constructs that promote transcriptional activation (Fosb-ZFP‑p65 and Fosb-TALE‑VP64) in the mouse NAc increased levels of Fosb as well as the level of H3K9 acetylation (an activating histone modification) at the Fosb promoter. Conversely, expression of a construct containing a transcriptionally repressive domain (Fosb-ZFP‑G9a) decreased Fosb expression and increased the level of the repressive histone modification H3K9me2. Thus, the engineered transcription factors induced specific histone modifications and regulated Fosb expression in vivo.<br />Cocaine exposure induces Fosb expression in the NAc, and the authors showed that expression of Fosb-ZFP‑G9a blocked this induction. Furthermore, Fosb-ZFP‑G9a expression blocked the cocaine-induced enrichment of phosphorylated CREB at the Fosb promoter. H3K9me2 therefore regulates cocaine-induced Fosb expression by inhibiting transcription factor binding.&nbsp;... Susceptibility to depression has been linked to reduced FOSB levels in humans and animal models. The authors showed here that expression of Fosb-ZFP‑G9a increased depression-like behaviour in a chronic social defeat stress model, indicating that the H3K9me2 modification mediates this effect.<br />This study shows that single epigenetic modifications can modulate both Fosb expression and its behavioural effects.}}</ref><ref name="G9a reverses ΔFosB plasticity">{{cite journal | vauthors = Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T | title = Epigenetic regulation in drug addiction | journal = Ann. Agric. Environ. Med. | volume = 19 | issue = 3 | pages = 491–496 | year = 2012 | pmid = 23020045 | doi = | url = http://www.aaem.pl/Epigenetic-regulation-in-drug-addiction,71809,0,2.html | quote = For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken&nbsp;... Methylation of histones is a vital consideration in the cocaine-induced remodelling of chromatin. Chronic cocaine treatment reduces the dimethylation of lysine 9 on histone H3, (H3K9me2) in the Accumbens nucleus (through suppressing the G9a gene coding for histone-dimethyltransferase), which modifies the expression of many other genes. Cocaine also induces high ΔFosB levels which inhibits the histone-dimethyltransferase, thus, in addition reducing the H3 dimethylation.&nbsp;... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription}}</ref><ref name="HDACi-induced G9a+H3K9me2 primary source">{{cite journal | vauthors = Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ | title = Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation | journal = Nat. Neurosci. | volume = 16 | issue = 4 | pages = 434–440 | date = April 2013 | pmid = 23475113 | pmc = 3609040 | doi = 10.1038/nn.3354 | quote = <!-- While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine<sup>1,3,4,13,14</sup>, studies suggest that more chronic regimens block psychostimulant-induced plasticity<sup>3,5,11,12</sup>.&nbsp;... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug<sup>1,3,4,13,14</sup>. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression<sup>3</sup> or decreased acquisition of behavioral adaptations to drug<sup>5,11,12</sup>. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes.--> In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression. The same complexity has been reported previously with local knockdown of HDAC5 in the NAc<sup>16</sup>.&nbsp;... The interaction between cocaine and MS-275 reported here is noteworthy. Either cocaine or MS-275 treatment alone caused global increases in H3 acetylation and increases in GABAA subunit gene expression, but when combined, these treatments caused increases in global repressive H3K9me2, most likely driven by a loss of HDAC1 and a subsequent gain in H3ac at H3K9 KMT promoters, that prevented cocaine-induced increases in GABAA subunit gene expression and inhibitory tone in NAc (Supplementary Fig. 5). <!--The results highlight a unique mode of biological regulation that provides further insight into mechanisms of chromatin regulation in the adult brain. Results of the present study also specifically inform the mechanisms underlying the prolonged actions of HDAC inhibitors in NAc and broaden current knowledge of molecular and chromatin endpoints for novel addiction treatments.-->}}</ref>|date=June 2018|small=no|period=no}}


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.<ref>{{cite web |title=Whole-Genome Chromatin IP Sequencing (ChIP-Seq) |url=https://www.illumina.com/Documents/products/datasheets/datasheet_chip_sequence.pdf |website=Illumina |accessdate=23 October 2019}}</ref>
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==References==

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.<ref>{{cite web |title=MAINE-Seq/Mnase-Seq |url=https://www.illumina.com/science/sequencing-method-explorer/kits-and-arrays/maine-seq-mnase-seq-nucleo-seq.html?langsel=/us/ |website=illumina |accessdate=23 October 2019}}</ref>

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.<ref name="BuenrostroWu2015">{{cite journal|last1=Buenrostro|first1=Jason D.|last2=Wu|first2=Beijing|last3=Chang|first3=Howard Y.|last4=Greenleaf|first4=William J.|title=ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide|year=2015|pages=21.29.1–21.29.9|doi=10.1002/0471142727.mb2129s109|pmid=25559105|journal=Current Protocols in Molecular Biology|volume=109|pmc=4374986|isbn=9780471142720}}</ref><ref name="SchepBuenrostro2015">{{cite journal|last1=Schep|first1=Alicia N.|last2=Buenrostro|first2=Jason D.|last3=Denny|first3=Sarah K. |last4=Schwartz |first4=Katja |last5=Sherlock |first5=Gavin |last6=Greenleaf |first6=William J. |title=Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions|journal=Genome Research|volume=25|issue=11|year=2015|pages=1757–1770|issn=1088-9051|doi=10.1101/gr.192294.115|pmid=26314830|pmc=4617971}}</ref><ref name="SongCrawford2010">{{cite journal|last1=Song|first1=L.|last2=Crawford|first2=G. E.|title=DNase-seq: A High-Resolution Technique for Mapping Active Gene Regulatory Elements across the Genome from Mammalian Cells|journal=Cold Spring Harbor Protocols|volume=2010|issue=2|year=2010|pages=pdb.prot5384|issn=1559-6095|doi=10.1101/pdb.prot5384|pmid=20150147|pmc=3627383}}</ref>

== See also ==
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* [[Histone methylation]]
* [[Histone methyltransferase]]
* [[Methyllysine]]

== References ==
{{reflist}}
{{reflist}}


[[Category:Epigenetics]]
[[Category:Epigenetics]]
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[[Category:Addiction|Δ]]
[[Category:Posttranslational modification]]
[[Category:Posttranslational modification]]

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==References==
{{Reflist}}

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[[Category:Epigenetics]]

Revision as of 04:08, 18 December 2019

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein and often asociated with gene bodies

Nomenclature

H3K9me2indicates monomethylation of lysine 9 on histone H3 protein subunit: [1]

Abbr. Meaning
H3 H3 family of histones
K standard abbreviation for lysine
9 position of amino acid residue

(counting from N-terminus)

me methyl group
2 number of methyl groups added

Lysine Methylation

Methylation-lysine

This diagram shows the progressive methylation of a lysine residue. The di-methylation denotes the methylation present in H3K9me2.

Understanding 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.[2][3]

Epigenetic implications

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling 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.[4] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap.[5] 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.[6] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance.[7] A look in to the data obtained led to the definition of chromatin states based on histone modifications.[8] Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions.

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.[9]

Friedreich's ataxia

R-loop's are found with H3K9me2 mark at FXN in Friedreich's ataxia cells.[10]

Methods

The histone mark 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.[11]

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.[12]

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.[13][14][15]

See also

References

  1. ^ Huang, Suming; Litt, Michael D.; Ann Blakey, C. (2015-11-30). Epigenetic Gene Expression and Regulation. pp. 21–38. ISBN 9780127999586.
  2. ^ 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.
  3. ^ Kouzarides T (February 2007). "Chromatin modifications and their function". Cell. 128 (4): 693–705. doi:10.1016/j.cell.2007.02.005. PMID 17320507.
  4. ^ Jenuwein T, Allis CD (August 2001). "Translating the histone code". Science. 293 (5532): 1074–80. doi:10.1126/science.1063127. PMID 11498575.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ Richard, Patricia; Manley, James L. (2017). "R Loops and Links to Human Disease". Journal of Molecular Biology. 429 (21): 3168–3180. doi:10.1016/j.jmb.2016.08.031. PMC 5478472. PMID 27600412.
  11. ^ "Whole-Genome Chromatin IP Sequencing (ChIP-Seq)" (PDF). Illumina. Retrieved 23 October 2019.
  12. ^ "MAINE-Seq/Mnase-Seq". illumina. Retrieved 23 October 2019.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.

References

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