Editing X-inactivation (section)

=== Cycle of X-chromosome activation in rodents ===
The paragraphs below have to do only with rodents and do not reflect XI in the majority of mammals.
X-inactivation is part of the activation cycle of the X chromosome throughout the female life. The egg and the fertilized zygote initially use maternal transcripts, and the whole embryonic genome is silenced until [[zygotic genome activation]]. Thereafter, all mouse cells undergo an early, [[Imprinting (genetics)|imprinted]] inactivation of the paternally-derived X chromosome in [[mammalian embryogenesis|4–8 cell stage]] [[embryo]]s.<ref>{{cite journal | vauthors = Takagi N, Sasaki M | title = Preferential inactivation of the paternally derived X chromosome in the extra embryonic membranes of the mouse | journal = Nature | volume = 256 | issue = 5519 | pages = 640–2 | date = August 1975 | pmid = 1152998 | doi = 10.1038/256640a0 | bibcode = 1975Natur.256..640T | s2cid = 4190616 }}</ref><ref>{{cite journal | vauthors = Cheng MK, Disteche CM | title = Silence of the fathers: early X inactivation | journal = BioEssays | volume = 26 | issue = 8 | pages = 821–4 | date = August 2004 | pmid = 15273983 | doi = 10.1002/bies.20082 | url = http://www3.interscience.wiley.com/cgi-bin/fulltext/109565168/PDFSTART | doi-access =  | url-access = subscription }}{{dead link|date=February 2019|bot=medic}}{{cbignore|bot=medic}}</ref><ref name="okamoto">{{cite journal | vauthors = Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E | title = Epigenetic dynamics of imprinted X inactivation during early mouse development | journal = Science | volume = 303 | issue = 5658 | pages = 644–9 | date = January 2004 | pmid = 14671313 | doi = 10.1126/science.1092727 | bibcode = 2004Sci...303..644O | s2cid = 26326026 }}</ref><ref name=":2">{{cite journal | vauthors = Deng Q, Ramsköld D, Reinius B, Sandberg R | title = Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells | journal = Science | volume = 343 | issue = 6167 | pages = 193–6 | date = January 2014 | pmid = 24408435 | doi = 10.1126/science.1245316 | bibcode = 2014Sci...343..193D | s2cid = 206552108 }}</ref> The [[extraembryonic tissue]]s (which give rise to the [[placenta]] and other tissues supporting the embryo) retain this early imprinted inactivation, and thus only the maternal X chromosome is active in these tissues.

In the early [[blastocyst]], this initial, imprinted X-inactivation is [[X-chromosome reactivation|reversed]] in the cells of the [[inner cell mass]] (which give rise to the embryo), and in these cells both X chromosomes become active again. Each of these cells then independently and randomly inactivates one copy of the X chromosome.<ref name=okamoto/> This inactivation event is irreversible during the lifetime of the individual, with the exception of the germline. In the female [[germline]] before meiotic entry, X-inactivation is reversed, so that after meiosis all haploid [[oocyte]]s contain a single active X chromosome.

==== Overview ====
The '''Xi''' marks the inactive, '''Xa''' the active X chromosome. '''X<sup>P</sup>''' denotes the paternal, and '''X<sup>M</sup>''' to denotes the maternal X chromosome. When the egg (carrying '''X<sup>M</sup>'''), is fertilized by a sperm (carrying a Y or an '''X<sup>P</sup>''') a diploid zygote forms. From zygote, through adult stage, to the next generation of eggs, the X chromosome undergoes the following changes:

# Xi<sup>P</sup> Xi<sup>M</sup> zygote → undergoing [[zygotic genome activation]], leading to:
# '''Xa<sup>P</sup>''' '''Xa<sup>M</sup>'''  → undergoing '''imprinted''' (paternal) '''X-inactivation''', leading to:
# Xi<sup>P</sup> '''Xa<sup>M</sup>'''  → undergoing '''X-activation''' in the early [[blastocyst]] stage, leading to:
# '''Xa<sup>P</sup> Xa<sup>M</sup>'''  → undergoing '''random X-inactivation''' in the embryonic lineage (inner cell mass) in the blastocyst stage, leading to:
# Xi<sup>P</sup> '''Xa<sup>M</sup>''' OR '''Xa<sup>P</sup>''' Xi<sup>M</sup> → undergoing '''X-reactivation''' in [[primordial germ cells]] before [[meiosis]], leading to:
# '''Xa<sup>M</sup>''' '''Xa<sup>P</sup>''' diploid germ cells in meiotic arrest. As the meiosis I only completes with [[ovulation]], human germ cells exist in this stage from the first weeks of development until puberty. The completion of meiosis leads to:
# '''Xa<sup>M</sup>''' AND '''Xa<sup>P</sup>''' haploid germ cells (eggs).

The X activation cycle has been best studied in mice, but there are multiple studies in humans. As most of the evidence is coming from mice, the above scheme represents the events in mice. The completion of the meiosis is simplified here for clarity. Steps 1–4 can be studied in in vitro fertilized embryos, and in differentiating stem cells; X-reactivation happens in the developing embryo, and subsequent (6–7) steps inside the female body, therefore much harder to study.

===== Timing =====

The timing of each process depends on the species, and in many cases the precise time is actively debated. [The whole part of the human timing of X-inactivation in this table is highly questionable and should be removed until properly substantiated by empirical data]
{| class="wikitable"
|+Approximate timing of major events in the X chromosome activation cycle
|
|'''Process'''
|'''Mouse'''
|'''Human'''
|-
|1
|Zygotic genome activation
|2–4 cell stage<ref name=":4">{{cite journal | vauthors = Xue Z, Huang K, Cai C, Cai L, Jiang CY, Feng Y, Liu Z, Zeng Q, Cheng L, Sun YE, Liu JY, Horvath S, Fan G | title = Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing | language = En | journal = Nature | volume = 500 | issue = 7464 | pages = 593–7 | date = August 2013 | pmid = 23892778 | pmc = 4950944 | doi = 10.1038/nature12364 | bibcode = 2013Natur.500..593X }}</ref>
|2–8 cell stage<ref name=":4" />
|-
|2
|Imprinted (paternal) X-inactivation
|4–8 cell stage<ref name=":2" /><ref name=":3">{{cite journal|vauthors=Borensztein M, Syx L, Ancelin K, Diabangouaya P, Picard C, Liu T, Liang JB, Vassilev I, Galupa R, Servant N, Barillot E, Surani A, Chen CJ, Heard E|date=March 2017|title=Xist-dependent imprinted X inactivation and the early developmental consequences of its failure|journal=Nature Structural & Molecular Biology|language=En|volume=24|issue=3|pages=226–233|doi=10.1038/nsmb.3365|pmc=5337400|pmid=28134930}}</ref>
|Unclear if it takes place in humans<ref name=":5">{{cite journal | vauthors = Deng X, Berletch JB, Nguyen DK, Disteche CM | title = X chromosome regulation: diverse patterns in development, tissues and disease | language = En | journal = Nature Reviews. Genetics | volume = 15 | issue = 6 | pages = 367–78 | date = June 2014 | pmid = 24733023 | pmc = 4117651 | doi = 10.1038/nrg3687 }}</ref>
|-
|3
|X-activation
|Early blastocyst stage
|Early blastocyst stage
|-
|4
|Random X-inactivation in the embryonic lineage (inner cell mass)
|Late blastocyst stage
|Late blastocyst stage, after implantation<ref name=":5" />
|-
|5
|X-reactivation in primordial germ cells before meiosis
|
|From before developmental week 4 up to week 14<ref>{{cite journal | vauthors = Vértesy Á, Arindrarto W, Roost MS, Reinius B, Torrens-Juaneda V, Bialecka M, Moustakas I, Ariyurek Y, Kuijk E, Mei H, Sandberg R, van Oudenaarden A, Chuva de Sousa Lopes SM | display-authors = 6 | title = Parental haplotype-specific single-cell transcriptomics reveal incomplete epigenetic reprogramming in human female germ cells | language = En | journal = Nature Communications | volume = 9 | issue = 1 | pages = 1873 | date = May 2018 | pmid = 29760424 | pmc = 5951918 | doi = 10.1038/s41467-018-04215-7 | bibcode = 2018NatCo...9.1873V }}</ref><ref>{{cite journal | vauthors = Guo F, Yan L, Guo H, Li L, Hu B, Zhao Y, Yong J, Hu Y, Wang X, Wei Y, Wang W, Li R, Yan J, Zhi X, Zhang Y, Jin H, Zhang W, Hou Y, Zhu P, Li J, Zhang L, Liu S, Ren Y, Zhu X, Wen L, Gao YQ, Tang F, Qiao J | display-authors = 6 | title = The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells | journal = Cell | volume = 161 | issue = 6 | pages = 1437–52 | date = June 2015 | pmid = 26046443 | doi = 10.1016/j.cell.2015.05.015 | doi-access = free }}</ref>
|}

===== Inheritance of inactivation status across cell generations =====

The descendants of each cell which inactivated a particular X chromosome will also inactivate that same chromosome. This phenomenon, which can be observed in the coloration of [[tortoiseshell cat]]s when females are [[heterozygous]] for the [[sex linkage|X-linked]] pigment gene, should not be confused with [[mosaic (genetics)|mosaicism]], which is a term that specifically refers to differences in the [[genotype]] of various cell populations in the same individual; X-inactivation, which is an [[epigenetics|epigenetic]] change that results in a different phenotype, is ''not'' a change at the [[genotype|genotypic]] level. For an individual cell or lineage the inactivation is therefore [[Skewed X-inactivation|skewed]] or '[[Skewed X-inactivation|non-random]]', and this can give rise to mild symptoms in female 'carriers' of [[X-linked]] genetic disorders.<ref>{{cite journal | vauthors = Puck JM, Willard HF | title = X inactivation in females with X-linked disease | journal = The New England Journal of Medicine | volume = 338 | issue = 5 | pages = 325–8 | date = January 1998 | pmid = 9445416 | doi = 10.1056/NEJM199801293380611 }}</ref>