Biology:X-chromosome reactivation

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X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells. Partial XCR may derepress one or more genes on the Xi, and the level of restored gene expression may not be as high as it would normally be on the active X chromosome (the Xa). Complete XCR restores the Xi to Xa and erases the epigenetic memory of XCI, meaning that inducing X-inactivation again will randomly select an X chromosome to silence, rather than deterministically silencing the original Xi.[1]

XCR is an emerging topic of interest for multiple reasons:[1]

  1. Reactivating silenced genes may be a therapy for X-linked diseases in heterozygous females, such as Rett syndrome,[2] or a therapy for cancer by reactivating silenced tumor suppressor genes
  2. XCR may be a contributing factor to human disorders, such as certain cancers
  3. Understanding the mechanisms of XCR will elucidate general gene regulation principles, and forge ahead in the study of gene silencing, epigenetic memory, and the role of long non-coding RNAs (lncRNAs)

History

History of X-inactivation

This section is an excerpt from X-inactivation#History[ edit ]

History of X-reactivation

Early in the study of XCI in early embryonic development, the original state of the two X chromosomes and the mechanism by which they differentiated into the Xa and Xi was unknown. One hypothesis was that the chromosomes were inactive until one was activated. The other, favored hypothesis that was eventually validated was that both maternal and paternal X chromosomes are active until some mechanism inactivates one chromosome.[3]

As early as 1981, the concept of X reactivation appears in the literature, with a paper on induced XCR in somatic cell hybrid clones by 5-azacitidine treatment,[4] and a paper on XCR in mouse oocytes.[5]

Experiments originally showed that eliminating the X-inactive specific transcript (Xist) gene, a gene that encodes a lncRNA that mediates XCI, in post-XCI somatic cells did not result in detectable Xi reactivation. Therefore, it was believed that XCI, once established in somatic cells, was irreversible and that Xist, while required to initiate XCI, was not required to sustain it.[6] However, newer investigations using modern technologies have found evidence that Xist RNA is involved in the maintenance of XCI. For example, Zhang, et al. found that “Deleting Xist results in a loss of nucleolar association and an inability to maintain Xi heterochromatin, leading to Xi reactivation at the single gene level.”[7]

Unlike XCI, XCR lacks an appropriate in vitro system for study, limiting current research to mouse embryos and in vitro stem cell reprogramming.[8]

Biological Occurrences

During Development

In mice, Xi reactivation is known to occur in three developmental stages:[9]

  1. In the oocyte after fertilization, the paternal X chromosome is reactivated, reversing male meiotic sex chromosome inactivation (MSCI).
  2. In the inner cell mass (ICM) of the epiblast after imprinted XCI in preimplantation development, the Xi is reactivated.
  3. In migrating primordial germ cells (PGCs), Xi reactivation establishes two Xa's in female germ cells before oogenesis. Unlike the other two, here genomic imprinting is erased.

It is known that in the inner cell mass (the embryo proper) of mice, XCI occurs randomly, while in the extra-embryonic tissues, imprinted XCI deterministically inactivates the paternal X. In early mouse embryos, the paternal X chromosome is already partially silenced at the zygote stage by imprinted XCI, suggesting that sex-chromosome dosage compensation exists from conception. Following re-activation of the paternal X in the ICM, complete and random XCI occurs post-implantation.[10][11]

Regarding female mouse germ cells, mature mammalian oocytes were observed to have two active X chromosomes by studies that recorded twice the expression levels from the oocytes from XX female mice as opposed to XO mice in the 1960s.[12] To determine whether XCI never occurred in these cells, or if the Xi was reactivated post-XCI, Kratzer and Chapman found that oogonia have an Xi and an Xa, but the Xi is gradually reactivated shortly before entering the meiotic cycle on the eleventh day.[5]

In human development, X chromosome reactivation also occurs in PGCs.[13] In the ICM of human embryos, however, X reactivation does not occur, because humans do not have imprinted XCI, so XCI has yet to happen in this stage of development.[14]

In Cancer

Because only one X chromosome is expressed, genetic mutations that lead to cancer are dominant when they occur on the Xa, and silent on the Xi. Increased dosage of X-linked genes, by whole or partial replication of the Xa or by whole or partial loss of XCI, is linked to oncogenesis. Translocations between the Xi and autosomal chromosomes can result in the silencing of autosomal tumor suppressors or reactivation of X-linked oncogenes. X-linked genes may escape inactivation, which potential oncogenic consequences. Impaired XCI and skewed X-inactivation may also be associated with oncogenesis.[15]

Gain of an X chromosome,[16] Klinefelter syndrome,[17] and XX male syndrome[18] are risk factors linked to male breast cancer. In females, there is no evidence that trisomy X or tetrasomy X females are at higher risk of cancer.[15]

Breast cancer and ovarian cancer, particularly more aggressive strains, commonly lack an Xi and have two Xa's.[19] Breast cancer cells commonly have two identical Xa's, possibly from duplication of the original Xa and loss of the original Xi.[20] Gains of X chromosomes have been observed in many other cancers, including leukemia,[21] prostate cancer,[22][23] and intracranial germ cell cancers.[24] Potential mechanisms leading to this overexpression of X-linked genes include chromosome segregation errors, defects in general heterochromatin maintenance, and defects in Xi-specific silencing factors, the latter two of which would partially reactivate the Xi.[19]

In Stem Cell Reprogramming

The presence of two Xa's is a measure of the pluripotency, or ability to differentiate into many different cell types, of embryonic stem cells.[25] Cell hybrid experiments fusing somatic cells and stem cells in vitro resulted in reactivation of the entire Xi.[26][27][28][29]Reprogramming of mouse and human fibroblast cells to induced pluripotent stem cells (iPSCs) reactivates the Xi found in the original fibroblasts. If re-differentiated and XCI occurs again, the selection of the Xi is not randomized and the X that was the Xi in the starting fibroblast is inactivated, evidencing the incompleteness of X reactivation.[30] Reprogramming can be accomplished by nuclear cloning, cell fusion with pluripotent cells, or expression of pluripotency factors.[9] Factors implicated in XCI maintenance include origin recognition complex 2 (Orc2), heterochromatin protein 1 (HP1a),[31] macroH2A1,[32] and Bmil.[9] Disruption of Orc2 or HP1a function have both been shown to lead to partial Xi reactivation.[31]

Mechanism

The mechanisms of Xi reactivation remains unknown, including whether they share a common pathway or if different contexts leverage completely different pathways.[9] It is thought that for XCR to be repressed, silencing of Xist expression is required but not sufficient.[33] The erasure of chromatin modifications that maintain the heterochromatin of the Xi significantly contributes to XCR. H3K27me3 and macroH2A, and their associated mechanisms of DNA methylation and histone deacetylation, act as a barriers to XCR in the ICM.[14] Deleting Xist RNA, demethylating DNA, and inhibiting histone hypoacetylation together increases reactivation in primary mouse embryonic fibroblasts on the gene level in a stochastic manner.[34][35]

X reactivation can be induced and tolerated in mouse extra-embryonic tissues.[9] For example, a mutation of the Polycomb protein EED leads to a lack of Xist RNA coating on the Xi and X reactivation in differentiated trophoblast stem cells.[36]

Xist repression in XCR is thought to be induced by Tsix RNA.[37] Tsix deletion appears to decrease the efficiency of XCR in the ICM in vivo, but not in iPSC reprogramming.[38]

Timing of Gene Expression

Studies have elucidated some of the progression of XCR in the reversal of imprinted XCI in the mouse ICM,[39] of random XCI in iPSC reprogramming,[40] and in germ cell development.[41] XCR proceeds gradually, with sets of genes regaining expression at the early, mid, or late stage of XCR. At the initiation of X reactivation, early genes are transcriptionally activated and Xist repression starts. The reactivation of these early genes happens before complete Xist silencing, suggesting the latter is not necessary for the reactivation of some genes.[40] As XCR progresses, intermediate and late genes are transcriptionally activated, Xist RNA is lost, H3K27me3 is lost, and Tsix is reactivated. During this process, in genome topology there may possibly be acquisition of topologically associating domains (TADs), which are units of genome organization in 3D space, and loss of mega-domains. At completion, there is complete transcriptional reactivation of genes on the Xi, loss of epigenetic memory, DNA hypomethylation, fully established TADs, and if XCI is re-instated, the choice of Xi will be random.[1]

As a Potential Therapy

The human X chromosome contains a disproportionate number of genes associated with intellectual disability.[42] X-linked disorders in heterozygous female patients are a unique subject of study because they carry an X chromosome with the mutated disorder allele and an X chromosome with a healthy wild-type allele.[43] XCI randomly selects on X chromosome as the Xi, leaving the genes on the other X, the Xa, to be expressed.[44] Therefore, heterozygous female patients are a mosaic of healthy and diseased cells. In non-cell-autonomous X-linked disorders, such as hemophilia A,[45] the healthy cells can compensate for the diseased cells. In other disorders such as Kabuki syndrome, the mutation affects the cell such that cells carrying the healthy allele are more common (a skewed XCI pattern), reducing the severity of the disease.[46] However, in X-linked disorders where the healthy cells are insufficient to restore wild-type function, X chromosome reactivation may be a potential therapy. By reactivating the Xi in diseased cells, the previously unexpressed wild-type allele can regain some level of expression and restore function. Disorders that could hypothetically be treated by X reactivation include Rett syndrome,[47][48] CDKL5 deficiency disorder,[49] Fragile X syndrome, etc.[50][51][52]

Potential Risks and Concerns

XCI serves a central function in sex-chromosome dosage compensation. Xi reactivation currently doesn't target specific genes, but rather targets the entire chromosome, running the risk of overexpression of other X-linked genes and subsequent side effects. Treatments also may not be able to specifically target the Xi chromosome, instead causing genome-wide disruption of epigenetic patterns.[9]

XCI is essential for early embryonic development. For example, female mouse embryos that inherited a paternal germline Xist deletion had trophoblast cells where both X chromosomes were fully expressed, resulting in a lethal phenotype.[53] Pre-XCI Xist deletion in mouse zygotes can be tolerated to the extent that the embryos can be carried to term, but none survive past weaning as a result of issues with organ development.[54] However, these concerns may be mitigated by the fact that applications of X reactivation are more focused on post-XCI cells, past the early developmental stages.

Xi loss or Xi reactivation is associated with certain cancers. Xist deletion in the blood compartment of mice has been shown to cause hematologic cancers, suggesting an important role for Xist RNA and for XCI in cancer suppression.[55] In addition, while Xist deletion can be tolerated in the epithelial cells and the gut, the mouse becomes more susceptible to stress-induced gut cancer, suggesting Xist and XCI are protective against chronic stress.[56] Xist deletion in mouse brains have seen no negative effects in some studies.[57] The variation among organs and cell-types for tolerance of partial X reactivation currently appears to recommend a local approach targeting individual organs for X reactivation. For example, in neurodevelopmental disorders, X reactivation may be targeted to the brain and central nervous system.[58]

Research

In developing a treatment to reactivate the Xi, screens to identify single factors that inhibit XCI have listed many potential pharmacological targets to consider for further study.[59][60] However, XCI is complex and maintained by a diverse set of proteins[31] and multiple mechanisms, such as DNA methylation, histone hypoacetylation, and the role of Xist RNA.[34] More effective X reactivation may require a synergistic combination of factors, and studies have considered combinations of decitabine with Aurora kinase inhibitors,[61] Xist antisense oligonucleotides (ASOs),[62] and DNA TOP2A/TOP2B knockdown.[63] Some experimental synergistic combinations of drugs have outperformed any single factor for levels of X reactivation.[58]

References

  1. ↑ 1.0 1.1 1.2 "Recent Advances in Understanding the Reversal of Gene Silencing During X Chromosome Reactivation". Frontiers in Cell and Developmental Biology 7: 169. 2019. doi:10.3389/fcell.2019.00169. PMID 31552244. 
  2. ↑ "New Rett Therapies May Stem From X-chromosome Reactivation Findings" (in en-US). October 2019. https://rettsyndromenews.com/news/discovering-the-mechanisms-behind-x-chromosome-reactivation-could-eventually-lead-to-targeted-therapies-researchers-say/. 
  3. ↑ "X-chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro". Nature 271 (5643): 329–333. January 1978. doi:10.1038/271329a0. PMID 563984. Bibcode: 1978Natur.271..329M. 
  4. ↑ "Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation". Science 211 (4480): 393–396. January 1981. doi:10.1126/science.6164095. PMID 6164095. Bibcode: 1981Sci...211..393M. 
  5. ↑ 5.0 5.1 "X chromosome reactivation in oocytes of Mus caroli". Proceedings of the National Academy of Sciences of the United States of America 78 (5): 3093–3097. May 1981. doi:10.1073/pnas.78.5.3093. PMID 6942418. Bibcode: 1981PNAS...78.3093K. 
  6. ↑ "A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation" (in English). Molecular Cell 5 (4): 695–705. April 2000. doi:10.1016/S1097-2765(00)80248-8. PMID 10882105. 
  7. ↑ "Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing" (in English). Cell 129 (4): 693–706. May 2007. doi:10.1016/j.cell.2007.03.036. PMID 17512404. 
  8. ↑ "Early reactivation of clustered genes on the inactive X chromosome during somatic cell reprogramming". Stem Cell Reports 17 (1): 53–67. January 2022. doi:10.1016/j.stemcr.2021.11.008. PMID 34919813. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Reactivation of the inactive X chromosome in development and reprogramming". Cellular and Molecular Life Sciences 70 (14): 2443–2461. July 2013. doi:10.1007/s00018-012-1174-3. PMID 23052214. 
  10. ↑ "Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos". Nature 426 (6968): 857–862. December 2003. doi:10.1038/nature02222. PMID 14661031. Bibcode: 2003Natur.426..857H. 
  11. ↑ "Epigenetic dynamics of imprinted X inactivation during early mouse development". Science 303 (5658): 644–649. January 2004. doi:10.1126/science.1092727. PMID 14671313. Bibcode: 2004Sci...303..644O. 
  12. ↑ "Mammalian oocytes: X chromosome activity". Science 163 (3871): 1078–1079. March 1969. doi:10.1126/science.163.3871.1078. PMID 5764873. Bibcode: 1969Sci...163.1078E. 
  13. ↑ "Forget the Parents: Epigenetic Reprogramming in Human Germ Cells" (in English). Cell 161 (6): 1248–1251. June 2015. doi:10.1016/j.cell.2015.05.039. PMID 26046435. 
  14. ↑ 14.0 14.1 "Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development". Nature 472 (7343): 370–374. April 2011. doi:10.1038/nature09872. PMID 21471966. Bibcode: 2011Natur.472..370O. https://hal.archives-ouvertes.fr/hal-01019321/file/okamoto2011.pdf. 
  15. ↑ 15.0 15.1 "X-chromosome genetics and human cancer". Nature Reviews. Cancer 4 (8): 617–629. August 2004. doi:10.1038/nrc1413. PMID 15286741. 
  16. ↑ "Karyotypic findings in two cases of male breast cancer" (in English). Cancer Genetics and Cytogenetics 121 (2): 190–193. September 2000. doi:10.1016/S0165-4608(00)00254-5. PMID 11063806. 
  17. ↑ "Carcinoma of the male breast and Klinefelter's syndrome: is there an association?". CA 37 (4): 246–251. 1987-07-01. doi:10.3322/canjclin.37.4.246. PMID 3111653. 
  18. ↑ "XX male: a rare cause of short stature, infertility, gynaecomastia and carcinoma of the breast". International Journal of Clinical Practice 57 (9): 844–845. November 2003. doi:10.1111/j.1742-1241.2003.tb10625.x. PMID 14686579. https://pubmed.ncbi.nlm.nih.gov/14686579/. 
  19. ↑ 19.0 19.1 "The disappearing Barr body in breast and ovarian cancers". Nature Reviews. Cancer 7 (8): 628–633. August 2007. doi:10.1038/nrc2172. PMID 17611545. 
  20. ↑ "Two identical active X chromosomes in human mammary carcinoma cells" (in English). Cancer Genetics and Cytogenetics 46 (2): 271–280. June 1990. doi:10.1016/0165-4608(90)90112-N. PMID 1971194. 
  21. ↑ "Acquired gain of an X chromosome as the sole abnormality in the blast crisis of chronic neutrophilic leukemia" (in English). Cancer Genetics and Cytogenetics 134 (1): 84–87. April 2002. doi:10.1016/S0165-4608(01)00603-3. PMID 11996803. 
  22. ↑ "Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy". The American Journal of Pathology 147 (6): 1608–1614. December 1995. PMID 7495286. 
  23. ↑ "Sensitive detection of chromosome copy number aberrations in prostate cancer by fluorescence in situ hybridization". The American Journal of Pathology 145 (3): 624–630. September 1994. PMID 8080044. 
  24. ↑ "Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors". Journal of Neuropathology and Experimental Neurology 61 (6): 531–538. June 2002. doi:10.1093/jnen/61.6.531. PMID 12071636. 
  25. ↑ "The lesser known story of X chromosome reactivation: a closer look into the reprogramming of the inactive X chromosome". Cell Cycle 11 (2): 229–235. January 2012. doi:10.4161/cc.11.2.18998. PMID 22234239. 
  26. ↑ "Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro" (in English). Cell 34 (3): 1053–1062. October 1983. doi:10.1016/0092-8674(83)90563-9. PMID 6627391. 
  27. ↑ "Nanog promotes transfer of pluripotency after cell fusion". Nature 441 (7096): 997–1001. June 2006. doi:10.1038/nature04914. PMID 16791199. Bibcode: 2006Natur.441..997S. 
  28. ↑ "Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells". Current Biology 11 (19): 1553–1558. October 2001. doi:10.1016/s0960-9822(01)00459-6. PMID 11591326. 
  29. ↑ "Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming". Nature Communications 7 (1): 12354. August 2016. doi:10.1038/ncomms12354. PMID 27507283. Bibcode: 2016NatCo...712354C. 
  30. ↑ "Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation". Cell Stem Cell 20 (1): 87–101. January 2017. doi:10.1016/j.stem.2016.10.006. PMID 27989770. 
  31. ↑ 31.0 31.1 31.2 "Diverse factors are involved in maintaining X chromosome inactivation". Proceedings of the National Academy of Sciences of the United States of America 108 (40): 16699–16704. October 2011. doi:10.1073/pnas.1107616108. PMID 21940502. Bibcode: 2011PNAS..10816699C. 
  32. ↑ "Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase". Proceedings of the National Academy of Sciences of the United States of America 102 (21): 7635–7640. May 2005. doi:10.1073/pnas.0408918102. PMID 15897469. 
  33. ↑ "Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming". Nature Communications 7 (1): 12354. August 2016. doi:10.1038/ncomms12354. PMID 27507283. Bibcode: 2016NatCo...712354C. 
  34. ↑ 34.0 34.1 "Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation". The Journal of Cell Biology 153 (4): 773–784. May 2001. doi:10.1083/jcb.153.4.773. PMID 11352938. 
  35. ↑ "Allele-specific analysis of cell fusion-mediated pluripotent reprograming reveals distinct and predictive susceptibilities of human X-linked genes to reactivation". Genome Biology 18 (1): 2. January 2017. doi:10.1186/s13059-016-1136-4. PMID 28118853. 
  36. ↑ "The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation". Nature Cell Biology 8 (2): 195–202. February 2006. doi:10.1038/ncb1351. PMID 16415857. 
  37. ↑ "Lineage-specific function of the noncoding Tsix RNA for Xist repression and Xi reactivation in mice". Genes & Development 25 (16): 1702–1715. August 2011. doi:10.1101/gad.16997911. PMID 21852535. 
  38. ↑ "Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming". Molecular Cell 52 (6): 805–818. December 2013. doi:10.1016/j.molcel.2013.10.023. PMID 24268575. 
  39. ↑ "Contribution of epigenetic landscapes and transcription factors to X-chromosome reactivation in the inner cell mass". Nature Communications 8 (1): 1297. November 2017. doi:10.1038/s41467-017-01415-5. PMID 29101321. Bibcode: 2017NatCo...8.1297B. 
  40. ↑ 40.0 40.1 "Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming". Genome Research 29 (10): 1659–1672. October 2019. doi:10.1101/gr.249706.119. PMID 31515287. 
  41. ↑ "X chromosome reactivation initiates in nascent primordial germ cells in mice". PLOS Genetics 3 (7): e116. July 2007. doi:10.1371/journal.pgen.0030116. PMID 17676999. 
  42. ↑ "X-linked genes and mental functioning". Human Molecular Genetics 14 Spec No 1 (suppl_1): R27–R32. April 2005. doi:10.1093/hmg/ddi112. PMID 15809269. 
  43. ↑ "X-linked diseases: susceptible females" (in English). Genetics in Medicine 22 (7): 1156–1174. July 2020. doi:10.1038/s41436-020-0779-4. PMID 32284538. 
  44. ↑ "A new model for random X chromosome inactivation". Development 136 (1): 1–10. January 2009. doi:10.1242/dev.025908. PMID 19036804. 
  45. ↑ "Past, present and future of hemophilia: a narrative review". Orphanet Journal of Rare Diseases 7 (1): 24. May 2012. doi:10.1186/1750-1172-7-24. PMID 22551339. 
  46. ↑ "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome" (in English). American Journal of Human Genetics 90 (1): 119–124. January 2012. doi:10.1016/j.ajhg.2011.11.021. PMID 22197486. 
  47. ↑ "Rett syndrome: a complex disorder with simple roots". Nature Reviews. Genetics 16 (5): 261–275. May 2015. doi:10.1038/nrg3897. PMID 25732612. 
  48. ↑ "Rett syndrome: insights into genetic, molecular and circuit mechanisms". Nature Reviews. Neuroscience 19 (6): 368–382. June 2018. doi:10.1038/s41583-018-0006-3. PMID 29740174. 
  49. ↑ "Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation" (in English). American Journal of Human Genetics 75 (6): 1079–1093. December 2004. doi:10.1086/426462. PMID 15492925. 
  50. ↑ "Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling" (in English). American Journal of Human Genetics 97 (2): 343–352. August 2015. doi:10.1016/j.ajhg.2015.07.004. PMID 26235985. 
  51. ↑ "De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations" (in English). American Journal of Human Genetics 98 (2): 373–381. February 2016. doi:10.1016/j.ajhg.2015.12.015. PMID 26833328. 
  52. ↑ "De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy". Journal of Medical Genetics 53 (12): 850–858. December 2016. doi:10.1136/jmedgenet-2016-103909. PMID 27358180. 
  53. ↑ "Xist-deficient mice are defective in dosage compensation but not spermatogenesis". Genes & Development 11 (2): 156–166. January 1997. doi:10.1101/gad.11.2.156. PMID 9009199. 
  54. ↑ "Female mice lacking Xist RNA show partial dosage compensation and survive to term". Genes & Development 30 (15): 1747–1760. August 2016. doi:10.1101/gad.281162.116. PMID 27542829. 
  55. ↑ "Xist RNA is a potent suppressor of hematologic cancer in mice" (in English). Cell 152 (4): 727–742. February 2013. doi:10.1016/j.cell.2013.01.034. PMID 23415223. 
  56. ↑ "Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut". Proceedings of the National Academy of Sciences of the United States of America 117 (8): 4262–4272. February 2020. doi:10.1073/pnas.1917203117. PMID 32041873. Bibcode: 2020PNAS..117.4262Y. 
  57. ↑ "A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders". Proceedings of the National Academy of Sciences of the United States of America 115 (4): E668–E675. January 2018. doi:10.1073/pnas.1715124115. PMID 29282321. Bibcode: 2018PNAS..115E.668C. 
  58. ↑ 58.0 58.1 "Selective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome" (in English). Trends in Genetics 38 (9): 920–943. September 2022. doi:10.1016/j.tig.2022.01.007. PMID 35248405. 
  59. ↑ "Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression". Proceedings of the National Academy of Sciences of the United States of America 114 (7): 1619–1624. February 2017. doi:10.1073/pnas.1621356114. PMID 28143937. Bibcode: 2017PNAS..114.1619S. 
  60. ↑ "Genetic and pharmacological reactivation of the mammalian inactive X chromosome". Proceedings of the National Academy of Sciences of the United States of America 111 (35): 12591–12598. September 2014. doi:10.1073/pnas.1413620111. PMID 25136103. Bibcode: 2014PNAS..11112591B. 
  61. ↑ "A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation". Proceedings of the National Academy of Sciences of the United States of America 113 (50): 14366–14371. December 2016. doi:10.1073/pnas.1617597113. PMID 28182563. Bibcode: 2016PNAS..11314366L. 
  62. ↑ "Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells". Stem Cell Reports 17 (3): 693–706. March 2022. doi:10.1016/j.stemcr.2022.01.008. PMID 35148843. 
  63. ↑ "Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation". Science 349 (6245): aab2276. July 2015. doi:10.1126/science.aab2276. PMID 26089354. 



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