H3K9me2: Perbedaan antara revisi

'''H3K9me2''' adalah sebuah modifikasi [[Epigenetika|epigenetik]] kepada protein [[histon H3]] dengan adanya [[Metilasi|dimetilasi]] pada residu [[lisina]] ke-9 di [[protein]] histon H3. H3K9me2 berhubungan kuat dengan aktivitas represi transkripsi,<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|access-date=8 June 2018}}</ref><ref name="Nestler1">{{cite journal|date=October 2011|title=Transcriptional and epigenetic mechanisms of addiction|journal=Nature Reviews. Neuroscience|volume=12|issue=11|pages=623–37|doi=10.1038/nrn3111|pmc=3272277|pmid=21989194|quote=<!--ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figure/F4/ Figure 4: Epigenetic basis of drug regulation of gene expression]</ref><ref name="pmid26472529">{{cite journal|date=August 2015|title=Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms|journal=International Review of Neurobiology|volume=124|pages=151–70|doi=10.1016/bs.irn.2015.07.003|pmc=4690450|pmid=26472529|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.|vauthors=Nestler EJ}}</ref> jumlahnya lebih tinggi pada gen yang diam/inaktif dibandingkan gen aktif, tepatnya di daerah sekitar 10kb dekat situs mulai transkripsi.<ref>{{cite journal|display-authors=6|date=May 2007|title=High-resolution profiling of histone methylations in the human genome|journal=Cell|volume=129|issue=4|pages=823–37|doi=10.1016/j.cell.2007.05.009|pmid=17512414|vauthors=Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K|doi-access=free}}</ref> H3K9me2 menghambat ekspresi gen baik secara pasif (mengambat [[asetilasi]] yang memengaruhi penempelan [[RNA polimerase]] atau faktor regulasinya)<ref>{{cite journal|display-authors=6|date=July 2008|title=Combinatorial patterns of histone acetylations and methylations in the human genome|journal=Nature Genetics|volume=40|issue=7|pages=897–903|doi=10.1038/ng.154|pmc=2769248|pmid=18552846|vauthors=Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K}}</ref> maupun secara aktif (menarik penghambat transkripsi).<ref name="H3K9 methyltransferase G9a and the">{{cite journal|date=April 2011|title=H3K9 methyltransferase G9a and the related molecule GLP|journal=Genes & Development|volume=25|issue=8|pages=781–8|doi=10.1101/gad.2027411|pmc=3078703|pmid=21498567|vauthors=Shinkai Y, Tachibana M}}</ref><ref>{{cite journal|display-authors=6|date=April 2016|title=G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells|journal=Cell Reports|volume=15|issue=1|pages=77–85|doi=10.1016/j.celrep.2016.03.007|pmc=4826439|pmid=27052169|vauthors=Zhang T, Termanis A, Özkan B, Bao XX, Culley J, de Lima Alves F, Rappsilber J, Ramsahoye B, Stancheva I}}</ref> H3K9me2 umumnya terbentang luas di daerah DNA yang miskin gen, disebut juga ''Large Organised Chromatin K9 domains'' (LOCKS). Namun, H3K9me2 juga ditemukan pada daerah kaya gen (''genic'') maupun daerah antargen (''[[Intergenik|intergenic]]'').<ref>{{cite journal|date=January 2010|title=Reassessing the abundance of H3K9me2 chromatin domains in embryonic stem cells|journal=Nature Genetics|volume=42|issue=1|pages=4; author reply 5–6|doi=10.1038/ng0110-4|pmid=20037608|vauthors=Filion GJ, van Steensel B|doi-access=free}}</ref><ref>{{cite journal|date=July 2011|title=Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition|journal=Nature Structural & Molecular Biology|volume=18|issue=8|pages=867–74|doi=10.1038/nsmb.2084|pmc=3150339|pmid=21725293|vauthors=McDonald OG, Wu H, Timp W, Doi A, Feinberg AP}}</ref><ref name="Wen 246–250">{{cite journal|date=February 2009|title=Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells|journal=Nature Genetics|volume=41|issue=2|pages=246–50|doi=10.1038/ng.297|pmc=2632725|pmid=19151716|vauthors=Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP}}</ref><ref>{{cite journal|date=March 2009|title=LOCKing in Cellular Potential|journal=Cell Stem Cell|volume=4|issue=3|pages=192–4|doi=10.1016/j.stem.2009.02.007|pmid=19265653|vauthors=Jørgensen HF, Fisher AG|doi-access=free}}</ref> Proses sintesisnya dikatalisasi oleh [[G9a]], [[EHMT1]], dan [[PRDM2]].<ref name="Histome H3K9me2" /><ref name="pmid26472529" /><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|access-date=8 June 2018}}</ref> H3K9me2 dapat dihilangkan dengan berbagai enzim demetilase lisina histon (KDM) termasuk KDM1, KDM3, KDM4, dan keluarga KDM7.<ref>{{cite journal|date=May 2008|title=Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease|journal=Genes & Development|volume=22|issue=9|pages=1115–40|doi=10.1101/gad.1652908|pmc=2732404|pmid=18451103|vauthors=Cloos PA, Christensen J, Agger K, Helin K}}</ref><ref name="H3K9 methyltransferase G9a and the" /> Fungsi penting dari H3K9me2 cukup bervariasi, mulai dari komitmen garis keturunan sel,<ref name="Wen 246–250" /><ref>{{cite journal|display-authors=6|date=November 2012|title=G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment|journal=Genes & Development|volume=26|issue=22|pages=2499–511|doi=10.1101/gad.200329.112|pmc=3505820|pmid=23105005|vauthors=Chen X, Skutt-Kakaria K, Davison J, Ou YL, Choi E, Malik P, Loeb K, Wood B, Georges G, Torok-Storb B, Paddison PJ}}</ref> pemrograman ulang sel somatis menjadi [[Sel iPS|sel punca pluripoten terinduksi]],<ref>{{cite journal|display-authors=6|date=2017|title=Reversible dual inhibitor against G9a and DNMT1 improves human iPSC derivation enhancing MET and facilitating transcription factor engagement to the genome|journal=PLOS ONE|volume=12|issue=12|pages=e0190275|bibcode=2017PLoSO..1290275R|doi=10.1371/journal.pone.0190275|pmc=5744984|pmid=29281720|vauthors=Rodriguez-Madoz JR, San Jose-Eneriz E, Rabal O, Zapata-Linares N, Miranda E, Rodriguez S, Porciuncula A, Vilas-Zornoza A, Garate L, Segura V, Guruceaga E, Agirre X, Oyarzabal J, Prosper F|doi-access=free}}</ref> regulasi [[Peradangan|respon peradangan]],<ref name="Harman 2289–23022">{{cite journal|display-authors=6|date=November 2019|title=Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|volume=39|issue=11|pages=2289–2302|doi=10.1161/ATVBAHA.119.312765|pmc=6818986|pmid=31434493|vauthors=Harman JL, Dobnikar L, Chappell J, Stokell BG, Dalby A, Foote K, Finigan A, Freire-Pritchett P, Taylor AL, Worssam MD, Madsen RR, Loche E, Uryga A, Bennett MR, Jørgensen HF}}</ref><ref>{{cite journal|display-authors=6|date=April 2012|title=Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response|journal=The Journal of Experimental Medicine|volume=209|issue=4|pages=661–9|doi=10.1084/jem.20112343|pmc=3328357|pmid=22412156|vauthors=Fang TC, Schaefer U, Mecklenbrauker I, Stienen A, Dewell S, Chen MS, Rioja I, Parravicini V, Prinjha RK, Chandwani R, MacDonald MR, Lee K, Rice CM, Tarakhovsky A}}</ref> dan kecanduan obat.<ref name="Nestler1" /><ref name="Nestler 2014 epigenetics">{{cite journal|date=January 2014|title=Epigenetic mechanisms of drug addiction|journal=Neuropharmacology|volume=76 Pt B|pages=259–68|doi=10.1016/j.neuropharm.2013.04.004|pmc=3766384|pmid=23643695|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.-->|vauthors=Nestler EJ}}</ref><ref name="G9a reverses ΔFosB plasticity">{{cite journal|year=2012|title=Epigenetic regulation in drug addiction|url=http://www.aaem.pl/Epigenetic-regulation-in-drug-addiction,71809,0,2.html|journal=Annals of Agricultural and Environmental Medicine|volume=19|issue=3|pages=491–6|pmid=23020045|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 an 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 his reason, he 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-->|vauthors=Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T}}</ref><ref name="HDACi-induced G9a+H3K9me2 primary source">{{cite journal|display-authors=6|date=April 2013|title=Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation|journal=Nature Neuroscience|volume=16|issue=4|pages=434–40|doi=10.1038/nn.3354|pmc=3609040|pmid=23475113|quote=<!--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 NAc¹⁶.&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).-->|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}}</ref>