Editing Heterochromatin

{{short description|Compact and highly condensed form of chromatin}}
'''Heterochromatin''' is a tightly packed form of [[DNA]] or ''[[DNA_condensation|condensed DNA]]'', which comes in multiple varieties. These varieties lie on a continuum between the two extremes of '''[[constitutive heterochromatin]]''' and '''[[facultative heterochromatin]]'''. Both play a role in the [[gene expression|expression of genes]]. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002),<ref>{{cite journal | vauthors = Volpe TA, Kidner C, Hall IM, Teng G, Grewal SI, Martienssen RA | s2cid = 2613813 | title = Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi | journal = Science | volume = 297 | issue = 5588 | pages = 1833–7 | date = September 2002 | pmid = 12193640 | doi = 10.1126/science.1074973 | bibcode = 2002Sci...297.1833V | doi-access = free }}</ref> and many other papers since,<ref>{{Cite web|url=https://www.researchgate.net/post/What_is_the_current_evidence_showing_active_transcription_withinin_heterochromatin|title=What is the current evidence showing active transcription withinin...|website=www.researchgate.net|access-date=2016-04-30}}</ref> much of this DNA is in fact transcribed, but it is continuously [[Messenger RNA#Eukaryotic mRNA turnover|turned over]] via [[RNA-induced transcriptional silencing]] (RITS). Recent studies with [[Electron microscope|electron microscopy]] and [[osmium tetroxide|OsO<sub>4</sub>]] staining reveal that the dense packing is not due to the chromatin.<ref>{{cite journal | vauthors = Ou HD, Phan S, Deerinck TJ, Thor A, Ellisman MH, O'Shea CC | title = ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells | journal = Science | volume = 357 | issue = 6349 | pages = eaag0025 | date = July 2017 | pmid = 28751582 | pmc = 5646685 | doi = 10.1126/science.aag0025 }}</ref>

Constitutive heterochromatin can affect the genes near itself (e.g. [[position-effect variegation]]). It is usually [[Repeated sequence (DNA)|repetitive]] and forms structural functions such as [[centromeres]] or [[telomeres]], in addition to acting as an attractor for other gene-expression or repression signals.

Facultative heterochromatin is the result of genes that are [[Gene silencing|silenced]] through a mechanism such as [[Histone acetylation and deacetylation|histone deacetylation]] or [[Piwi-interacting RNA]] (piRNA) through [[RNA interference#Transcriptional silencing|RNAi]]. It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active.<ref>{{cite journal | vauthors = Oberdoerffer P, Sinclair DA | title = The role of nuclear architecture in genomic instability and ageing | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 9 | pages = 692–702 | date = September 2007 | pmid = 17700626 | doi = 10.1038/nrm2238 | s2cid = 15674132 | url = http://www.nature.com/nrm/journal/v8/n9/box/nrm2238_BX2.html }}</ref>

Heterochromatin has been associated with the [[H3K9me2|di-]] and [[H3K9me3|tri]] -methylation of [[Histone code#Histone_H3|H3K9]] in certain portions of the human genome.<ref name="Rosenfeld_2009">{{cite journal | vauthors = Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ | title = Determination of enriched histone modifications in non-genic portions of the human genome | journal = BMC Genomics | volume = 10 | issue = 1 | pages = 143 | date = March 2009 | pmid = 19335899 | pmc = 2667539 | doi = 10.1186/1471-2164-10-143 | doi-access = free }}</ref>  [[H3K9me3]]-related [[methyltransferase]]s appear to have a pivotal role in modifying heterochromatin during lineage commitment at the onset of [[organogenesis]] and in maintaining lineage fidelity.<ref name="pmid30606806">{{cite journal | vauthors = Nicetto D, Donahue G, Jain T, Peng T, Sidoli S, Sheng L, Montavon T, Becker JS, Grindheim JM, Blahnik K, Garcia BA, Tan K, Bonasio R, Jenuwein T, Zaret KS | display-authors = 6 | title = H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification | journal = Science | volume = 363 | issue = 6424 | pages = 294–297 | date = January 2019 | pmid = 30606806 | doi = 10.1126/science.aau0583 | pmc = 6664818 | bibcode = 2019Sci...363..294N }}</ref>

== Structure ==
[[File:Heterochromatin vs. euchromatin.svg|thumb|Heterochromatin vs. euchromatin]]

[[Chromatin]] is found in two varieties: [[euchromatin]] and heterochromatin.<ref>
{{cite journal
| author = Elgin, S.C.
| title = Heterochromatin and gene regulation in ''Drosophila''
| year = 1996
| journal = [[Current Opinion in Genetics & Development]]
| issn = 0959-437X
| volume = 6
| pages = 193–202
| doi = 10.1016/S0959-437X(96)80050-5
| pmid = 8722176
| issue = 2| url = https://openscholarship.wustl.edu/cgi/viewcontent.cgi?article=1213&context=bio_facpubs
}}
</ref> Originally, the two forms were distinguished cytologically by how intensely they get stained – the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin was given its name for this reason by botanist Emil Heitz who discovered that heterochromatin remained darkly stained throughout the entire cell cycle, unlike euchromatin whose stain disappeared during interphase.<ref>{{Cite journal |last1=Penagos-Puig |first1=Andrés |last2=Furlan-Magaril |first2=Mayra |date=2020-09-18 |title=Heterochromatin as an Important Driver of Genome Organization |journal=Frontiers in Cell and Developmental Biology |volume=8 |doi=10.3389/fcell.2020.579137 |doi-access=free |issn=2296-634X |pmc=7530337 |pmid=33072761}}</ref> Heterochromatin is usually localized to the periphery of the [[Cell nucleus|nucleus]].
Despite this early dichotomy, recent evidence in both animals<ref>
{{cite journal | vauthors = van Steensel B | title = Chromatin: constructing the big picture | journal = The EMBO Journal | volume = 30 | issue = 10 | pages = 1885–95 | date = May 2011 | pmid = 21527910 | pmc = 3098493 | doi = 10.1038/emboj.2011.135 }}
</ref> and plants<ref>
{{cite journal | vauthors = Roudier F, Ahmed I, Bérard C, Sarazin A, Mary-Huard T, Cortijo S, Bouyer D, Caillieux E, Duvernois-Berthet E, Al-Shikhley L, Giraut L, Després B, Drevensek S, Barneche F, Dèrozier S, Brunaud V, Aubourg S, Schnittger A, Bowler C, Martin-Magniette ML, Robin S, Caboche M, Colot V | display-authors = 6 | title = Integrative epigenomic mapping defines four main chromatin states in Arabidopsis | journal = The EMBO Journal | volume = 30 | issue = 10 | pages = 1928–38 | date = May 2011 | pmid = 21487388 | pmc = 3098477 | doi = 10.1038/emboj.2011.103 }}
</ref> has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations of [[epigenetic]] marks.

Heterochromatin mainly consists of genetically inactive [[satellite DNA|satellite sequences]],<ref>
{{cite journal | vauthors = Lohe AR, Hilliker AJ, Roberts PA | title = Mapping simple repeated DNA sequences in heterochromatin of Drosophila melanogaster | journal = Genetics | volume = 134 | issue = 4 | pages = 1149–74 | date = August 1993 | doi = 10.1093/genetics/134.4.1149 | pmid = 8375654 | pmc = 1205583 | url = http://www.genetics.org/cgi/content/full/134/4/1149 }}
</ref> and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all.<ref>
{{cite journal | vauthors = Lu BY, Emtage PC, Duyf BJ, Hilliker AJ, Eissenberg JC | title = Heterochromatin protein 1 is required for the normal expression of two heterochromatin genes in Drosophila | journal = Genetics | volume = 155 | issue = 2 | pages = 699–708 | date = June 2000 | doi = 10.1093/genetics/155.2.699 | pmid = 10835392 | pmc = 1461102 | url = http://www.genetics.org/cgi/content/full/155/2/699 }}
</ref> Both [[centromere]]s and [[telomere]]s are heterochromatic, as is the [[Barr body]] of the second, inactivated [[X chromosome|X-chromosome]] in a female.

== Function ==
[[File:General model for duplication of heterochromatin during cell division.svg|thumb|General model for duplication of heterochromatin during cell division]]
[[File:Heterochromatic versus euchromatic nuclei.jpg|thumb|Microscopy of heterochromatic versus euchromatic nuclei ([[H&E stain]]).]]
Heterochromatin has been associated with several functions, from gene regulation to the protection of chromosome integrity;<ref>
{{cite journal | vauthors = Grewal SI, Jia S | title = Heterochromatin revisited | journal = Nature Reviews. Genetics | volume = 8 | issue = 1 | pages = 35–46 | date = January 2007 | pmid = 17173056 | doi = 10.1038/nrg2008 | s2cid = 31811880 | url = https://zenodo.org/record/1233527 | quote = An up-to-date account of the current understanding of repetitive DNA, which usually doesn't contain genetic information. If evolution makes sense only in the context of the regulatory control of genes, we propose that heterochromatin, which is the main form of chromatin in higher eukaryotes, is positioned to be a deeply effective target for evolutionary change. Future investigations into assembly, maintenance and the many other functions of heterochromatin will shed light on the processes of gene and chromosome regulation. }}
</ref> some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by the cell as damaged or viral DNA, triggering [[cell cycle]] arrest, [[DNA repair]] or destruction of the fragment, such as by [[endonuclease]]s in bacteria.

Some regions of chromatin are very densely packed with fibers that display a condition comparable to that of the chromosome at [[mitosis]]. Heterochromatin is generally clonally inherited; when a cell divides, the two daughter cells typically contain heterochromatin within the same regions of DNA, resulting in [[epigenetic inheritance]]. Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (in ''cis'') at these boundary domains. This gives rise to expression levels that vary from cell to cell,<ref>
{{cite journal | vauthors = Fisher AG, Merkenschlager M | title = Gene silencing, cell fate and nuclear organisation | journal = Current Opinion in Genetics & Development | volume = 12 | issue = 2 | pages = 193–7 | date = April 2002 | pmid = 11893493 | doi = 10.1016/S0959-437X(02)00286-1 }}
</ref> which may be demonstrated by [[position-effect variegation]].<ref>
{{cite journal
|title=Cytogenetic and molecular aspects of position effect variegation in Drosophila melanogaster
|author=Zhimulev, I.F.
|date=December 1986
|journal=[[Chromosoma]]
|volume=94
|issue=6
|pages=492–504
|doi=10.1007/BF00292759
|s2cid=24439936
|issn=1432-0886|display-authors=etal|author-link=:ru:Жимулёв, Игорь Фёдорович
}}
</ref> [[Insulator (genetics)|Insulator]] sequences may act as a barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus,<ref>
{{cite journal | vauthors = Burgess-Beusse B, Farrell C, Gaszner M, Litt M, Mutskov V, Recillas-Targa F, Simpson M, West A, Felsenfeld G | display-authors = 6 | title = The insulation of genes from external enhancers and silencing chromatin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = Suppl 4 | pages = 16433–7 | date = December 2002 | pmid = 12154228 | pmc = 139905 | doi = 10.1073/pnas.162342499 | bibcode = 2002PNAS...9916433B | doi-access = free }}
</ref> and loci in two ''[[Saccharomyces]]'' spp.<ref>
{{cite journal | vauthors = Allis CD, Grewal SI | title = Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries | journal = Science | volume = 293 | issue = 5532 | pages = 1150–5 | date = August 2001 | pmid = 11498594 | doi = 10.1126/science.1064150 | s2cid = 26350729 }}
</ref><ref>
{{cite journal | vauthors = Donze D, Kamakaka RT | title = RNA polymerase III and RNA polymerase II promoter complexes are heterochromatin barriers in Saccharomyces cerevisiae | journal = The EMBO Journal | volume = 20 | issue = 3 | pages = 520–31 | date = February 2001 | pmid = 11157758 | pmc = 133458 | doi = 10.1093/emboj/20.3.520 }}
</ref>).

==Constitutive heterochromatin==
{{main article|Constitutive heterochromatin}}
All cells of a given species package the same regions of DNA in [[constitutive heterochromatin]], and thus in all cells, any genes contained within the constitutive heterochromatin will be poorly [[Gene expression|expressed]]. For example, all human chromosomes [[Chromosome 1 (human)|1]], [[Chromosome 9 (human)|9]], [[Chromosome 16 (human)|16]], and the [[Y chromosome|Y-chromosome]] contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.

{{anchor|FacultativeHeterochromatin}}

==Facultative heterochromatin==
[[File:Human karyotype with bands and sub-bands.png|thumb|Schematic [[karyotype|karyogram]] of a [[human]], showing an overview of the [[human genome]] using [[G banding]], which is a method that includes [[Giemsa stain]]ing, wherein the lighter staining regions are generally more euchromatic, whereas darker regions generally are more heterochromatic.{{further|Karyotype}}]]
The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within are poorly expressed) may be packaged in euchromatin in another cell (and the genes within are no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with [[morphogenesis]] or [[Cellular differentiation|differentiation]]. An example of facultative heterochromatin is [[X-inactivation|X chromosome inactivation]] in female mammals: one [[X chromosome]] is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed.

Among the molecular components that appear to regulate the spreading of heterochromatin are the [[Polycomb-group proteins]] and non-coding genes such as [[Xist]]. The mechanism for such spreading is still a matter of controversy.<ref>{{cite journal | vauthors = Talbert PB, Henikoff S | title = Spreading of silent chromatin: inaction at a distance | journal = Nature Reviews. Genetics | volume = 7 | issue = 10 | pages = 793–803 | date = October 2006 | pmid = 16983375 | doi = 10.1038/nrg1920 | s2cid = 1671107 }}
</ref>  The polycomb repressive complexes [[polycomb repressive complex 1|PRC1]] and [[PRC2]] regulate [[chromatin]] compaction and gene expression and have a fundamental role in developmental processes.  PRC-mediated [[epigenetics|epigenetic]] aberrations are linked to [[genome instability]] and malignancy and play a role in the [[DNA damage (naturally occurring)|DNA damage]] response, [[DNA repair]] and in the fidelity of [[DNA replication|replication]].<ref name="pmid28758948">{{cite journal | vauthors = Veneti Z, Gkouskou KK, Eliopoulos AG | title = Polycomb Repressor Complex 2 in Genomic Instability and Cancer | journal = International Journal of Molecular Sciences | volume = 18 | issue = 8 | pages = 1657 | date = July 2017 | pmid = 28758948 | pmc = 5578047 | doi = 10.3390/ijms18081657 | doi-access = free }}</ref>

==Yeast heterochromatin==
''[[Saccharomyces cerevisiae]]'', or budding yeast, is a model [[eukaryote]] and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin, ''S. cerevisiae'' has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR), the rDNA (encoding ribosomal RNA), and the sub-telomeric regions.
Fission yeast (''[[Schizosaccharomyces pombe]]'') uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the [[RNAi]] pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.

In the fission yeast ''Schizosaccharomyces pombe'', two RNAi complexes, the RITS complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in a [[siRNA]]-dependent manner on chromosomes, at the site of heterochromatin assembly. [[RNA polymerase II]] synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly.<ref>{{cite journal | vauthors = Kato H, Goto DB, Martienssen RA, Urano T, Furukawa K, Murakami Y | title = RNA polymerase II is required for RNAi-dependent heterochromatin assembly | journal = Science | volume = 309 | issue = 5733 | pages = 467–9 | date = July 2005 | pmid = 15947136 | doi = 10.1126/science.1114955 | bibcode = 2005Sci...309..467K | s2cid = 22636283 }}</ref><ref>{{cite journal | vauthors = Djupedal I, Portoso M, Spåhr H, Bonilla C, Gustafsson CM, Allshire RC, Ekwall K | title = RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing | journal = Genes & Development | volume = 19 | issue = 19 | pages = 2301–6 | date = October 2005 | pmid = 16204182 | pmc = 1240039 | doi = 10.1101/gad.344205 }}</ref> Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of ''Schizosaccharomyces pombe'' may occur in other eukaryotes.<ref name= Vavasseur>{{cite book |chapter-url=http://www.horizonpress.com/rnareg|author= Vavasseur|year=2008 |chapter=Heterochromatin Assembly and Transcriptional Gene Silencing under the Control of Nuclear RNAi: Lessons from Fission Yeast |title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity |publisher=Caister Academic Press |isbn=978-1-904455-25-7|display-authors=etal}}</ref> A large RNA structure called [[RevCen]] has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.<ref name="Dju09">{{cite journal | vauthors = Djupedal I, Kos-Braun IC, Mosher RA, Söderholm N, Simmer F, Hardcastle TJ, Fender A, Heidrich N, Kagansky A, Bayne E, Wagner EG, Baulcombe DC, Allshire RC, Ekwall K | display-authors = 6 | title = Analysis of small RNA in fission yeast; centromeric siRNAs are potentially generated through a structured RNA | journal = The EMBO Journal | volume = 28 | issue = 24 | pages = 3832–44 | date = December 2009 | pmid = 19942857 | pmc = 2797062 | doi = 10.1038/emboj.2009.351 }}</ref>

== See also ==
* [[Centric heterochromatin]]

== References ==<!-- ZoolSci24:588. -->
{{reflist|30em}}

== External links ==
* {{BUHistology|20102loa}}
* {{cite journal | vauthors = Avramova ZV | title = Heterochromatin in animals and plants. Similarities and differences | journal = Plant Physiology | volume = 129 | issue = 1 | pages = 40–9 | date = May 2002 | pmid = 12011336 | pmc = 1540225 | doi = 10.1104/pp.010981 }}
* {{cite journal | vauthors = Caron H, van Schaik B, van der Mee M, Baas F, Riggins G, van Sluis P, Hermus MC, van Asperen R, Boon K, Voûte PA, Heisterkamp S, van Kampen A, Versteeg R | display-authors = 6 | title = The human transcriptome map: clustering of highly expressed genes in chromosomal domains | journal = Science | volume = 291 | issue = 5507 | pages = 1289–92 | date = February 2001 | pmid = 11181992 | doi = 10.1126/science.1056794 | bibcode = 2001Sci...291.1289C | doi-access = free }}
* {{cite news |title=Scientists discover an important new driver of aging |first1= Ariana Eunjung |last1=Cha |first2= Lenny |last2=Bernstein |date=April 30, 2015 |access-date = 4 May 2015 |newspaper=New York Times |url=https://www.washingtonpost.com/news/to-your-health/wp/2015/04/30/scientists-discover-an-important-new-driver-of-aging/}}

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[[Category:Molecular genetics]]
[[Category:Nuclear organization]]