Content deleted Content added
m →Modifications: task, replaced: journal=roc → journal=Proc |
|||
| (37 intermediate revisions by 15 users not shown) | |||
Line 1:
{{Short description|Proposed biochemical transcription of genetic information}}
The '''histone code''' is a [[hypothesis]] that the transcription of genetic information encoded in [[DNA]] is in part regulated by chemical modifications (known as ''histone marks'') 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]].
==The hypothesis==
The hypothesis is that [[chromatin]]-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as [[methylation]], [[acetylation]], [[ADP-ribosylation]], [[ubiquitination]], [[citrullination]], [[SUMO protein|SUMO]]-ylation<ref name="Shiio & Eisenman 2003">{{cite journal |last1=Shiio |first1=Yuzuru |last2=Eisenman |first2=Robert N. |title=Histone sumoylation is associated with transcriptional repression |journal=Proceedings of the National Academy of Sciences |date=11 November 2003 |volume=100 |issue=23 |pages=13225–13230 |doi=10.1073/pnas.1735528100 |pmid=14578449 |pmc=263760 |doi-access=free }}</ref> and [[phosphorylation]]) to [[histone]] tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions remains elusive. However, some specific examples have been worked out in detail. For example, phosphorylation of [[serine]] residues 10 and 28 on [[histone H3]] is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of [[serine]] residue 10 and acetylation of a [[lysine]] residue 14 on histone H3 is a tell-tale sign of active [[Transcription (genetics)|transcription]].
[[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 | 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
* [[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.▼
▲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 | 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 |doi=10.7150/jca.23427 |url=}}</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" />
* [[Phosphorylation]]▼
* [[Ubiquitination]]▼
▲Acetylation tends to define the 'openness' of [[chromatin]] as acetylated histones cannot pack as well together as deacetylated histones.
* SUMOylation<ref name="Shiio & Eisenman 2003"/>
▲*[[Phosphorylation]]
▲*[[Ubiquitination]]
However, there are many more histone modifications, and sensitive [[mass spectrometry]] approaches have recently greatly expanded the catalog.<ref name="pmid21925322">{{cite journal |vauthors=Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, etal | title=Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. | journal=Cell | year= 2011 | volume= 146 | issue= 6 | pages= 1016–28 | pmid=21925322 | doi=10.1016/j.cell.2011.08.008 | pmc=3176443 }}</ref>
Line 19 ⟶ 20:
{| class="wikitable" style="text-align:center"
|-
! rowspan="2" | Type of<br />modification
! colspan="8" | Histone
|-
Line 33 ⟶ 34:
| mono-[[methylation]]
!style="background: #dedefa;" | [[gene activation|activation]]<ref name="Benevolenskaya_2007">{{cite journal | author = Benevolenskaya EV | title = Histone H3K4 demethylases are essential in development and differentiation | journal = Biochem. Cell Biol. | volume = 85 | issue = 4 | pages = 435–43 |date=August 2007 | pmid = 17713579 | doi = 10.1139/o07-057 }}</ref>
!style="background: #dedefa;" | activation<ref name="Barski_2007">{{cite journal |vauthors=Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K | title = High-resolution profiling of histone methylations in the human genome | journal = Cell | volume = 129 | issue = 4 | pages = 823–37 |date=May 2007 | pmid = 17512414 | doi = 10.1016/j.cell.2007.05.009 | doi-access = free }}</ref>
|
!style="background: #dedefa;" | activation<ref name="Barski_2007"/>
Line 42 ⟶ 43:
|-
| 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
Line 56 ⟶ 57:
|
!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"/>
|-
Line 65 ⟶ 66:
!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>
|
!style="background: #dedefa;" |activation<ref>{{Cite journal|
|
|
|}
====[[Histone H2B]]====
* [[H2BK5ac]]
* [[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|pages=7357–7362.|doi=10.1073/pnas.0401866101|pmc=409923}}</ref>▼
====[[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
* [[H3K9me2]] -repression
* [[H3K9me3]] is found in constitutively repressed genes.
* [[H3K27me3]] is found in facultatively repressed genes.<ref name="Barski_2007"/>
* [[H3K36me]]
* [[H3K36me2]]
* [[H3K36me3]] is found in actively transcribed gene bodies.
* [[H3K79me2]]
* [[H3K9ac]] is found in actively transcribed promoters.
* [[H3K14ac]] is found in actively transcribed promoters.
* [[H3K23ac]]
* [[H3K27ac]] distinguishes active enhancers from poised enhancers.
* [[H3K36ac]]
* [[H3K56ac]] is a proxy for de novo histone assembly.<ref>{{cite journal |last1=Jeronimo |first1=Célia |last2=Poitras |first2=Christian |last3=Robert |first3=François |title=Histone Recycling by FACT and Spt6 during Transcription Prevents the Scrambling of Histone Modifications |journal=Cell Reports |date=30 July 2019 |volume=28 |issue=5 |pages=1206–1218.e8 |doi=10.1016/j.celrep.2019.06.097 |pmid=31365865 |doi-access=free }}</ref>
* [[H3K122ac]] is enriched in poised promoters and also found in a different type of putative enhancer that lacks H3K27ac.
====[[Histone H4]]====
* [[H4K5ac]]
* [[H4K8ac]]
* [[H4K12ac]]
* [[H4K16ac]]
* [[H4K20me]]
* [[H4K91ac]]
==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 4<sup>19</sup> or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4 Gb / ~150 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>
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==
| |||