Editing Histone (section)

=== 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}}</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}}</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}}</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}}</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}}</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}}</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>