Histone code: Difference between revisions

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===Modifications===

Well characterized modifications to histones include:<ref name="Strahl">{{cite journal |vauthors=Strahl B, Allis C |title=The language of covalent histone modifications |journal=Nature |volume=403 |issue=6765 |pages=41–5 |year=2000 |pmid=10638745 |doi=10.1038/47412|bibcode=2000Natur.403...41S |s2cid=4418993 }}</ref>

* [[Methylation]]: Both lysine and arginine residues are known to be methylated. Methylated lysines are the best understood marks of the histone code, as specific methylated lysine match well with gene expression states. Methylation of lysines H3K4 and H3K36 is correlated with transcriptional activation while demethylation of H3K4 is correlated with silencing of the genomic region. Methylation of lysines H3K9 and H3K27 is correlated with transcriptional repression.<ref name="Rosenfeld_2009">{{cite journal | last1 = Rosenfeld | first1 = Jeffrey A | last2 = Wang | first2 = Zhibin | last3 = Schones | first3 = Dustin | last4 = Zhao | first4=Keji | last5 = DeSalle | first5 = Rob | last6= Zhang | first6 = Michael Q | title = Determination of enriched histone modifications in non-genic portions of the human genome. | journal = BMC Genomics | volume = 10 | date = 31 March 2009 | pmid= 19335899 | doi = 10.1186/1471-2164-10-143 | pages = 143 | pmc = 2667539 | doi-access = free }}</ref> Particularly, [[H3K9me3]] is highly correlated with constitutive heterochromatin.<ref name="Hublitz">{{cite journal | last1 = Hublitz | first1 = Philip | last2 = Albert | first2 = Mareike | last3 = Peters | first3 = Antoine | title = Mechanisms of Transcriptional Repression by Histone Lysine Methylation | journal = The International Journal of Developmental Biology | volume = 10 | issue = 1387 | pages = 335–354 | ___location = Basel | date = 28 April 2009 | doi = 10.1387/ijdb.082717ph | pmid = 19412890 | issn =1696-3547| doi-access = free }}</ref> Methylation of histone lysine also has a role in [[DNA repair]].<ref name="pmid29937925">{{cite journal |vauthors=Wei S, Li C, Yin Z, Wen J, Meng H, Xue L, Wang J |title=Histone methylation in DNA repair and clinical practice: new findings during the past 5-years |journal=J Cancer |volume=9 |issue=12 |pages=2072–2081 |date=2018 |pmid=29937925 |pmc=6010677 |doi=10.7150/jca.23427 }}</ref> For instance, [[H3K36me|H3K36me3]]3 is required for [[homologous recombination]]al repair of [[DNA damage (naturally occurring)|DNA double-strand breaks]], and H4K20me2 facilitates repair of such breaks by [[non-homologous end joining]].<ref name="pmid29937925" />

* [[Acetylation]]—by [[Histone acetyltransferase|HAT]] (histone acetyl transferase); deacetylation—by [[HDAC]] (histone deacetylase): Acetylation tends to define the 'openness' of [[chromatin]] as acetylated histones cannot pack as well together as deacetylated histones.

* [[Phosphorylation]]

* [[Ubiquitination]]

* SUMOylation<ref name="Shiio & Eisenman 2003"/>

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{| class="wikitable" style="text-align:center"

|-

! rowspan="2" | Type of<br />modification

! colspan="8" | Histone

|-

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| di-methylation

!style="background: #dedefa;" |

!style="background: #ffdead;" |[[gene repression|repression]]<ref name="Rosenfeld_2009"/>

|

!style="background: #ffdead;" | repression<ref name = "Rosenfeld_2009"/>

!style="background: #dedefa;" | activation<ref name="Steger_2008"/>

|

|

|

|-

| tri-methylation

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|

!style="background: #ffdead;" | repression<ref name="Barski_2007"/>

!style="background: #ffffa2;" | activation,<ref name="Steger_2008"/><br />repression<ref name="Barski_2007"/>

|

|

|

!style="background: #ffdead;" | repression<ref name="Rosenfeld_2009"/>

|-

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!style="background: #dedefa;" | activation<ref name="Koch_2007"/>

!style="background: #dedefa;" | activation<ref>{{cite journal|last1=Creyghton|first1=MP|title=Histone H3K27ac separates active from poised enhancers and predicts developmental state|journal=Proc Natl Acad Sci USA|date=Dec 2010|volume=107|issue=50|pages=21931–6|doi=10.1073/pnas.1016071107|pmid=21106759|pmc=3003124|doi-access=free}}</ref>

|

!style="background: #dedefa;" |activation<ref>{{Cite journal|last1=Pradeepa|first1=Madapura M.|last2=Grimes|first2=Graeme R.|last3=Kumar|first3=Yatendra|last4=Olley|first4=Gabrielle|last5=Taylor|first5=Gillian C. A.|last6=Schneider|first6=Robert|last7=Bickmore|first7=Wendy A.|date=2016-04-18|title=Histone H3 globular ___domain acetylation identifies a new class of enhancers|journal=Nature Genetics|language=en|volume=48|issue=6|doi=10.1038/ng.3550|issn=1546-1718|pages=681–686|pmid=27089178|pmc=4886833}}</ref>

|

|

|}

====[[Histone H2B]]====

* [[H2BK5ac]]

====[[Histone H3]]====

* [[H3K4me1]] - primed enhancers

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* [[H3K36me3]] is found in actively transcribed gene bodies.

* [[H3K79me2]]

* [[H3K9ac]] is found in actively transcribed promoters.

* [[H3K14ac]] is found in actively transcribed promoters.

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==Complexity==

Unlike this simplified model, any real histone code has the potential to be massively complex; each of the four standard histones can be simultaneously modified at multiple different sites with multiple different modifications. To give an idea of this complexity, [[histone H3]] contains nineteen lysines known to be methylated—each can be un-, mono-, di- or tri-methylated. If modifications are independent, this allows a potential 4¹⁹ or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4&nbsp;Gb / ~150&nbsp;bp = ~44 million histones if they are very tightly packed). And this does not include lysine acetylation (known for H3 at nine residues), arginine methylation (known for H3 at three residues) or threonine/serine/tyrosine phosphorylation (known for H3 at eight residues), not to mention modifications of other histones.{{cn|date=March 2023}}

Every [[nucleosome]] in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes.<ref name="pmid18552846">{{cite journal |vauthors=Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, etal | title=Combinatorial patterns of histone acetylations and methylations in the human genome. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 7 | pages= 897–903 | pmid=18552846 | doi=10.1038/ng.154 | pmc=2769248 }}</ref> Therefore[[Mass spectrometry]]-based [[top-down proteomics]] has provided more insight into these patterns by being able to discriminate single molecule co-occurrence from co-localization in the genome or on the same nucleosome.<ref name="Taylor">{{cite journal |vauthors=Taylor BC, Young NL |title=Combinations of histone post-translational modifications |journal=Biochemical Journal |volume=487 |issue=3 |pages=511–532 |date=10 Feb 2021 |pmid=33567070 |doi=10.1042/BCJ20200170}}</ref> A variety of approaches have been used to delve into detailed biochemical mechanisms that demonstrate the importance of interplay between histone modifications. Thus, specific patterns of histone modifications doare more common than others. These patterns are functionally occurimportant but they are very intricate, and wechallenging to study. We currently have detailedthe best biochemical understanding of the importance of a relatively small number of discrete modifications and a few combinations.

Structural determinants of histone recognition by readers, writers, and erasers of the histone code are revealed by a growing body of experimental data.<ref name="Wang">{{cite journal |vauthors=Wang M, Mok MW, Harper H, Lee WH, Min J, Knapp S, Oppermann U, Marsden B, Schapira M |title=Structural Genomics of Histone Tail Recognition |journal=Bioinformatics |volume=26|issue=20 |pages=2629–2630 |date=24 Aug 2010 |pmid=20739309 |pmc=2951094 |doi=10.1093/bioinformatics/btq491}}</ref>

==See also==

* [[Histone]]

* [[Histone-modifying enzymes]]

==References==