Histone code: Difference between revisions

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The '''histone code''' is a [[hypothesis]] that the transcription of genetic information encoded in [[DNA]] is in part regulated by chemical modifications to [[histone]] proteins, primarily on their unstructured ends. Together with similar modifications such as [[DNA methylation]] it is part of the [[epigenetic code]].<ref name="Jenuwein">{{cite journal |vauthors=Jenuwein T, Allis C |title=Translating the histone code |journal=Science |volume=293 |issue=5532 |pages=1074–80 |year=2001 |pmid=11498575 |doi=10.1126/science.1063127|citeseerx=10.1.1.453.900 |s2cid=1883924 }}</ref> Histones associate with [[DNA]] to form [[nucleosome]]s, which themselves bundle to form [[chromatin]] fibers, which in turn make up the more familiar [[chromosome]]. Histones are globular proteins with a flexible [[N-terminus]] (taken to be the tail) that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the '''histone code hypothesis''' is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via [[protein ___domain]]s specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription.

For details of gene expression regulation by histone modifications see [[Histone code#Modifications|table below]].

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

===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}}</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}}</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]] 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]]

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| di-methylation

!style="background: #dedefa;" | repression<ref>{{Cite journal|lastlast1=Liu|firstfirst1=Yuhao|last2=Liu|first2=Kunpeng|last3=Yin|first3=Liufan|last4=Yu|first4=Yu|last5=Qi|first5=Ji|last6=Shen|first6=Wen-Hui|last7=Zhu|first7=Jun|last8=Zhang|first8=Yijing|last9=Dong|first9=Aiwu|date=2019-07-02|title=H3K4me2 functions as a repressive epigenetic mark in plants|journal=Epigenetics & Chromatin|volume=12|issue=1|pages=40|doi=10.1186/s13072-019-0285-6|issn=1756-8935|pmc=6604379|pmid=31266517}}</ref>

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

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

!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>

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!style="background: #dedefa;" |activation<ref>{{Cite journal|lastlast1=Pradeepa|firstfirst1=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>

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

* [[H3K4me1]] - primed enhancers

* [[H3K4me3]] is enriched in transcriptionally active promoters.<ref>{{cite journal|last1=Liang|first1=G|title=Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome|journal=Proc. Natl. Acad. Sci. USA|date=2004|volume=101|issue=19|pages=7357–7362|doi=10.1073/pnas.0401866101|pmid=15123803|pmc=409923|bibcode=2004PNAS..101.7357L|doi-access=free}}</ref>

* [[H3K9me2]] -repression

* [[H3K9me3]] is found in constitutively repressed genes.