Molecular Development - X Inactivation

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Introduction

XIST expression in human embryonic stem cells[1]
Macaque Xi at interphase[2]

The presence in females of two X chromosome raises the issue of gene dosage, in the case of mammals this is regulated by inactivating one of the X chromosomes. To balance expression with the autosomal chromosomes the dosage imbalance is then adjusted by doubling expression of X-linked genes in both sexes.

In some other species compensation occurs by increasing the expression of X in males. The pattern of which X chromosome is inactivated in cells appears to be random, generating 50% cells expressing Father X, 50% cells expressing Mother X (mosaic pattern). The theory of random X inactivation was first suggested in mice in 1961.[3]

The process of inactivation relies on the Xist RNA, a 17 kb non-coding RNA, which accumulates on the future inactive X chromosome.

A second form of X inactivation that occurs only in male meiotic spermatogenesis, meiotic sex chromosome inactivation (MSCI), is not covered in these current notes. MSCI is the process of transcriptional silencing of the X and Y chromosomes.[4] X inactivation is not an encoded function and occurs randomly throughout female tissues, this represents a form of epigenetics.

Some species have several copies of sex chromosomes, for example the platypus karyotype (2 n = 52) consists of 21 autosomes and 10 sex chromosomes (5X's and 5Y's in male and 5 X-pairs in female). In mice, the paternal X chromosome is silenced. In rabbits, maternal or paternal selection occurs downstream of Xist expression.

Historic Embryology
Mary Lyon

Mary Lyon (1925-2014) was a UK geneticist who proposed in 1961 the theory of X inactivation, where one of the two X chromosomes in the cells of female mammals is randomly inactivated during early development. In deference to her, this process is also referred to as "Lyonisation". She also worked on other X-linked genetic diseases, such as Duchenne muscular dystrophy and haemophilia.


X Chromosome Links: X chromosome | X Inactivation | Trisomy X | Fragile X syndrome | Klinefelter syndrome | primordial germ cell | Female | epigenetics | Y chromosome | 2011 Group Project - Fragile X Syndrome | Category:X Chromosome
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Some Recent Findings

X Chromosome idiogram
  • The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist[5] "The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Template:Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes."
  • The Implication of Early Chromatin Changes in X Chromosome Inactivation[6]"During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing Xist and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon Xist coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing."
  • Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line[7] "Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy."
More recent papers  
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Search term: X inactivation | Xist

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • X-chromosome inactivation in female newborns conceived by assisted reproductive technologies[8] "A total of 185 female newborns, including 60 conceived by intracytoplasmic sperm injection (ICSI), 73 by in vitro fertilization (IVF), and 52 naturally conceived (NC). ...The assisted reproductive technologies of ICSI and IVF do not appear to affect XCI skewing." Assisted Reproductive Technology
  • Fifty years of X-inactivation research[9] "The third X-inactivation meeting 'Fifty years of X-inactivation research', which celebrated the fiftieth anniversary of Mary Lyon's formulation of the X-inactivation hypothesis, was an EMBO workshop held in Oxford, UK, in July 2011."
  • Analysis of active and inactive X chromosome architecture reveals the independent organization of 30 nm and large-scale chromatin structures[10] "Using a genetic model, we present a high-resolution chromatin fiber analysis of transcriptionally active (Xa) and inactive (Xi) X chromosomes packaged into euchromatin and facultative heterochromatin. Our results show that gene promoters have an open chromatin structure that is enhanced upon transcriptional activation but the Xa and the Xi have similar overall 30 nm chromatin fiber structures."
  • Variations of X chromosome inactivation occur in early passages of female human embryonic stem cells.[1] "Human embryonic stem cells (hESCs) derived from inner cell mass (ICM) of blastocyst stage embryos have been used as a model system to understand XCI initiation and maintenance. Previous studies of undifferentiated female hESCs at intermediate passages have shown three possible states of XCI; 1) cells in a pre-XCI state, 2) cells that already exhibit XCI, or 3) cells that never undergo XCI even upon differentiation. In this study, XCI status was assayed in ten female hESC lines between passage 5 and 15 to determine whether XCI variations occur in early passages of hESCs. Our results show that three different states of XCI already exist in the early passages of hESC. "
  • Random X inactivation and extensive mosaicism in human placenta[11] "Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals."
  • Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.[12] "...Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging."

XIST

The initiation of X chromosome inactivation requires cis accumulation of the large non-translated XIST RNA, which covers the X chromosome, followed by epigenetic changes on the future inactive X chromosome.

The physical region at the nucleus periphery where the inactive X chromosome is located in a female cell is described as the Barr body.[13]

X inactivation Xist.jpg Human female fibroblast line (47,XXX) XIST expression.jpg
The above figure shows confocal images from a combined RNA-DNA FISH experiment for Xist in female mouse fibroblast cells (Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse.[14] XIST expression in two cell nuclei using RNA FISH probes for the human XIST RNA (green) in the human female fibroblast line GM04626 (karyotype: 47,XXX).[15] As there are 3 copies of the X chromosome in each cell, there are 2 inactive X chromosomes as shown by Xist staining.
Links: OMIM - Xist

X Inactivation Model

Model for XIST RNA spread from X inactivation center.jpg

Model for XIST RNA spread from X inactivation center[16]

Above model showing how heterochromatin of the Xi could transition between metaphase and interphase to be organized into the two nonoverlapping heterochromatin territories and to explain how XIST RNA could rapidly spread in cis outward from the X inactivation center (XIC) along only part of the Xi.

Barr Body

Neutrophil EM01.jpg

A female human neutrophil - Barr body (White arrowhead)[17]

This neutrophil comes from a female donor and one inactivated x chromosome can be found as an extranuclear stretch of heterochromatin. These structures are termed Barr bodies, and in neutrophils “drum sticks.”


X Inactivation (xist) History

Mary Lyon

The theory of random X inactivation was first suggested in mice in 1961.[3] The breakthrough was the discovery of the X inactive specific transcript (XIST).[18] This gene is located within the "X inactivation centre" and only expressed by the inactive X chromosome. Unlike other genes that encode protein XIST contained no "open reading frames" (ie no codons to encode amino acids).

XIST is transcribed but not translated. XIST appears to act as RNA. Current thinking is that it binds to the X Chromosome and is involved in it's translocation to the nuclear periphery. It now appears that XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that maintains inactivity.


Links: Mary Lyon - X Inactivation

Tsix

A gene antisense to Xist, hence the name which is Xist backwards, in embryonic stem cells Xist repression occurs and Tsix is upregulated. This is part of the overall process of maintaining pluripotency in these cells. Tsix upregulation depends on the recruitment of another pluripotent marker Rex1, and of the associated factors Klf4 and c-Myc, by the DXPas34 minisatellite associated with the Tsix promoter.[19]

DXPas34 is made up of 34bp repeats containing Ctcf motifs and is located within a CpG-rich region in the 5-prime end of the mouse Tsix gene. This region also has bidirectional promoter activity, produced overlapping forward and reverse transcripts, and is necessary for both random and imprinted X inactivation in mice. The human sequence also has a 14 kb insertion not found in mouse Tsix.


Links: OMIM - Tsix

Meiotic Sex Chromosome Inactivation

Both the X and Y chromosome are transcriptionally silenced during spermatogenesis, at primary spermatocyte stage onward, by a process called meiotic sex chromosome inactivation (MSCI). This second form of X inactivation takes place in the male, during spermatogenesis, as germ cells enter meiosis. This is thought to be a form of meiotic silencing of unsynapsed chromatin that silences chromosomes that fail to pair with their homologous partners.[4]


Links: Meiosis | Y Chromosome

Placenta

Placenta potential imprinted genes

In the mouse placenta, X inactivation is imprinted and the paternal X chromosome is always inactive. In the human placenta, initial studies appear to show a pattern of random X inactivation.[11] They also identified a preferential expression of maternal alleles, indicating that, although imprinted X chromosome inactivation has been lost during evolution, a proliferative advantage may remain for cells that inactivate the paternal X (Xp) in human placenta.


Links: Placenta Development | Mouse Development

Cancer

Recently meta-analysis of postnatal up-regulation of XIST has been shown to associate with poor prognosis in human cancers.[20][21]


References

  1. 1.0 1.1 Dvash T, Lavon N & Fan G. (2010). Variations of X chromosome inactivation occur in early passages of female human embryonic stem cells. PLoS ONE , 5, e11330. PMID: 20593031 DOI.
  2. McLaughlin CR & Chadwick BP. (2011). Characterization of DXZ4 conservation in primates implies important functional roles for CTCF binding, array expression and tandem repeat organization on the X chromosome. Genome Biol. , 12, R37. PMID: 21489251 DOI.
  3. 3.0 3.1 LYON MF. (1961). Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature , 190, 372-3. PMID: 13764598
  4. 4.0 4.1 Turner JM. (2007). Meiotic sex chromosome inactivation. Development , 134, 1823-31. PMID: 17329371 DOI.
  5. van Bemmel JG, Galupa R, Gard C, Servant N, Picard C, Davies J, Szempruch AJ, Zhan Y, Żylicz JJ, Nora EP, Lameiras S, de Wit E, Gentien D, Baulande S, Giorgetti L, Guttman M, Hughes JR, Higgs DR, Gribnau J & Heard E. (2019). The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist. Nat. Genet. , 51, 1024-1034. PMID: 31133748 DOI.
  6. Żylicz JJ, Bousard A, Žumer K, Dossin F, Mohammad E, da Rocha ST, Schwalb B, Syx L, Dingli F, Loew D, Cramer P & Heard E. (2018). The Implication of Early Chromatin Changes in X Chromosome Inactivation. Cell , , . PMID: 30595450 DOI.
  7. Sangrithi MN & Turner JMA. (2018). Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line. Bioessays , , . PMID: 29756331 DOI.
  8. Wu EX, Stanar P & Ma S. (2014). X-chromosome inactivation in female newborns conceived by assisted reproductive technologies. Fertil. Steril. , 101, 1718-23. PMID: 24726222 DOI.
  9. Gendrel AV & Heard E. (2011). Fifty years of X-inactivation research. Development , 138, 5049-55. PMID: 22069183 DOI.
  10. Naughton C, Sproul D, Hamilton C & Gilbert N. (2010). Analysis of active and inactive X chromosome architecture reveals the independent organization of 30 nm and large-scale chromatin structures. Mol. Cell , 40, 397-409. PMID: 21070966 DOI.
  11. 11.0 11.1 Moreira de Mello JC, de Araújo ES, Stabellini R, Fraga AM, de Souza JE, Sumita DR, Camargo AA & Pereira LV. (2010). Random X inactivation and extensive mosaicism in human placenta revealed by analysis of allele-specific gene expression along the X chromosome. PLoS ONE , 5, e10947. PMID: 20532033 DOI.
  12. Schoeftner S, Blanco R, Lopez de Silanes I, Muñoz P, Gómez-López G, Flores JM & Blasco MA. (2009). Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations. Proc. Natl. Acad. Sci. U.S.A. , 106, 19393-8. PMID: 19887628 DOI.
  13. BARR ML & CARR DH. (1962). Correlations between sex chromatin and sex chromosomes. Acta Cytol. , 6, 34-45. PMID: 13865187
  14. Reinius B, Shi C, Hengshuo L, Sandhu KS, Radomska KJ, Rosen GD, Lu L, Kullander K, Williams RW & Jazin E. (2010). Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse. BMC Genomics , 11, 614. PMID: 21047393 DOI.
  15. Thorogood NP & Brown CJ. (2010). Active chromatin marks are retained on X chromosomes lacking gene or repeat silencing despite XIST/Xist expression in somatic cell hybrids. PLoS ONE , 5, e10787. PMID: 20520737 DOI.
  16. Chadwick BP & Willard HF. (2004). Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proc. Natl. Acad. Sci. U.S.A. , 101, 17450-5. PMID: 15574503 DOI.
  17. Brinkmann V & Zychlinsky A. (2012). Neutrophil extracellular traps: is immunity the second function of chromatin?. J. Cell Biol. , 198, 773-83. PMID: 22945932 DOI.
  18. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R & Willard HF. (1991). A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature , 349, 38-44. PMID: 1985261 DOI.
  19. Navarro P, Oldfield A, Legoupi J, Festuccia N, Dubois A, Attia M, Schoorlemmer J, Rougeulle C, Chambers I & Avner P. (2010). Molecular coupling of Tsix regulation and pluripotency. Nature , 468, 457-60. PMID: 21085182 DOI.
  20. Liu JL, Zhang WQ, Zhao M & Huang MY. (2019). Upregulation of long noncoding RNA XIST is associated with poor prognosis in human cancers. J. Cell. Physiol. , 234, 6594-6600. PMID: 30341910 DOI.
  21. Chen J, Yang X, Gong D, Cui Y, Hu J, Li H, Liu P, Li C, Cheng X, Liu L, Chen H & Zu X. (2019). Long noncoding RNA X-inactive specific transcript as a prognostic factor in cancer patients: A meta-analysis based on retrospective studies. Medicine (Baltimore) , 98, e14095. PMID: 30653128 DOI.

Reviews

Berletch JB, Yang F & Disteche CM. (2010). Escape from X inactivation in mice and humans. Genome Biol. , 11, 213. PMID: 20573260 DOI.


Agrelo R & Wutz A. (2010). X inactivation and disease. Semin. Cell Dev. Biol. , 21, 194-200. PMID: 19815084 DOI.


Bondy CA & Cheng C. (2009). Monosomy for the X chromosome. Chromosome Res. , 17, 649-58. PMID: 19802705 DOI.

Articles

Morey C & Avner P. (2011). The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever. PLoS Genet. , 7, e1002212. PMID: 21811421 DOI.


Dvash T, Lavon N & Fan G. (2010). Variations of X chromosome inactivation occur in early passages of female human embryonic stem cells. PLoS ONE , 5, e11330. PMID: 20593031 DOI.

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Cite this page: Hill, M.A. (2019, July 16) Embryology Molecular Development - X Inactivation. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_X_Inactivation

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