New twists in X-chromosome inactivation

Current Opinion in Cell Biology

Volumn 20, Issue 3, 2008, Pages 349-355

  Erwin, Jennifer A ^a,b   Lee, Jeannie T ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BRCA1 PROTEIN; DNA METHYLTRANSFERASE; UNTRANSLATED RNA;

CHROMATIN; DNA REPLICATION; EMBRYONIC STEM CELL; GENE CONTROL; GENE DELETION; GENE EXPRESSION REGULATION; GENE LOCATION; GENE REPRESSION; GENE SEQUENCE; GENE SILENCING; GENETIC TRANSCRIPTION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN MODIFICATION; REVIEW; X CHROMOSOME; X CHROMOSOME INACTIVATION;

ANIMALS; CHROMATIN ASSEMBLY AND DISASSEMBLY; CHROMOSOMES, HUMAN, X; DOSAGE COMPENSATION, GENETIC; EPIGENESIS, GENETIC; EVOLUTION, MOLECULAR; GENE SILENCING; HUMANS; REPRESSOR PROTEINS; RNA, UNTRANSLATED; X CHROMOSOME; X CHROMOSOME INACTIVATION;

MAMMALIA;

EID: 44649197671     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ceb.2008.04.007     Document Type: Review

References (75)

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34. Xu N., Tsai C.L., and Lee J.T. Transient homologous chromosome pairing marks the onset of X inactivation. Science 311 (2006) 1149-1152. By DNA FISH and 3C technology, this study shows that two female Xs pair and physically touch just before Xist upregulation. Pairing occurs exclusively at the Xic (not elsewhere on the X) and requires Xite and Tsix. X-X pairing can be blocked by deleting Tsix/Xite and by ectopic X-autosome interactions (through insertion of Xite/Tsix sequences onto autosomes) that compete away X-X interactions. These interactions block the initiation of XCI. It is proposed that X-X pairing provides the necessary crosstalk for counting and mutually exclusive choice.
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39. Chaumeil J., Le Baccon P., Wutz A., and Heard E. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20 (2006) 2223-2237. The authors demonstrate a repressive nuclear compartment dependent on Xist silencing. Interestingly, this compartment is composed of silenced intergenic DNA and formation is independent of genic silencing but requires the Repeat A element of Xist. Relocation of X-linked genes into a more interior portion of the compartment correlates with silencing. Active genes remain at the periphery of the compartment. This study demonstrates the presence of chromosomal subcompartments linked to gene expression states.
40. Clemson C.M., Hall L.L., Byron M., McNeil J., and Lawrence J.B. The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences. Proc Natl Acad Sci U S A 103 (2006) 7688-7693. Using RNA and DNA FISH, the authors demonstrate that the core of the Barr body in female human cells is composed of intergenic and repetitive DNA elements of the X chromosome. Genes which are subject to XCI are localized within the core of the silent compartment (near the inner periphery of the Xist RNA territory), while genes that escape XCI are localized at the outer edge of the compartment. This study demonstrates the presence of chromosomal subcompartments linked to gene expression states.
41. Wutz A., Rasmussen T.P., and Jaenisch R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet 30 (2002) 167-174
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43. Ganesan S., Silver D.P., Greenberg R.A., Avni D., Drapkin R., Miron A., Mok S.C., Randrianarison V., Brodie S., and Salstrom J. BRCA1 Supports XIST RNA Concentration on the Inactive X Chromosome. Cell 111 (2002) 393-405. This study makes the provocative observation that BRCA1 co-localizes with Xist RNA and may be required to target Xist RNA to the Xi. BRCA1-deficient tumor cells lack an Xi (Barr body). By adding BRCA1 back to deficient cells, the authors demonstrate a re-appearance of the Xist RNA foci. Similarly, depletion of BRCA1 by RNAi leads to a loss of proper Xist localization to the Xi. The authors propose that improper XCI is linked to breast cancer.
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45. ••]). They find that BRCA1 does not co-localize with the Xi and that depleting cells of BRCA1 by RNAi knockdown does not affect Xist localization. They further suggest that Xist and breast cancer are not causally linked in a simple way, if linked at all.
46. ••] and [45], the authors provide further supporting evidence that BRCA1 is involved in XIST localization to the Xi. By depleting BRCA1 either by RNAi or conditional deletion in mice, they demonstrate loss or decreased XIST localization onto Xi.
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48. Leeb M., and Wutz A. Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. J Cell Biol 178 (2007) 219-229. The authors delete Ring1B (a component of PRC1) in ES cells and determine that Xist is still capable of silencing nearby genes independent of PRC1. Also, PRC2 is still recruited upon Xist induction. This further supports the idea that PRC2 and PRC1 may be somewhat redundant.
49. ••].
50. ••] examine the results of an Eed deletion on XCI in mouse embryos. Together with previous work from the laboratory (Ref. [51]), these studies together show that Eed is required for imprinted XCI but not obviously for random XCI in the mouse. Surprisingly, for imprinted XCI, Eed seems to be necessary for maintaining silencing but not to establish it. Eed KO mice still suppress a paternal X-linked GFP transgene in peri-implantation embryos but cannot prevent its reactivation at later stages.
51. Wang J., Mager J., Chen Y., Schneider E., Cross J.C., Nagy A., and Magnuson T. Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet 28 (2001) 371-375
52. ••].
53. ••].
54. ••] search for XIC sequences in the opossum (marsupial) and find that, while protein coding regions flanking the XIC are well conserved throughout vertebrates, the ncRNA genes of the XIC are missing. In fact, the region around XIC shows broken synteny with that of eutherian mammals. Thus, marsupial mammals are apparently lacking XIST/TSIX and may undergo imprinted XCI using a different mechanism.
55. Duret L., Chureau C., Samain S., Weissenbach J., and Avner P. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312 (2006) 1653-1655. By comparative genomics, the authors make the interesting finding that eutherian Xist may have evolved from the protein-coding gene with no known function in gene silencing. It is proposed that Xist resulted from pseudogenization of Lnx6. However, Xist/Tsix and other ncRNAs of the Xic apparently evolved in eutherians for the first time. They propose imprinted XCI in marsupials utilize a different mechanism from eutherian imprinted XCI.
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60. ••]). The existence of MSCI and PMSC in marsupials is consistent with the hypothesis that imprinted paternal X silencing may be directly derived from the silent germline X.
61. ••]). The existence of MSCI and PMSC in marsupials is consistent with the hypothesis that imprinted paternal X silencing may be directly derived from the silent germline X.
62. ••].
63. ••].
64. ••] make the surprising finding that sex chromosome silencing does not end with meiosis. By a combination of immunstaining with chromatin markers, RNA FISH, RT-PCR, and microarray analysis, the authors show that the X and Y continue to behave differently in early and late-stage spermatids. By expression profiling, it is estimated that ∼85% of X-linked genes remain transcriptionally suppressed. The sex chromosomes are marked by H3-K9me2, HP1, and H2A.Z. These studies are consistent with the idea that imprinted silencing of the paternal X may in part be derived from a previously inactivated X in the paternal germline (Ref. [68]).
65. Shiu P.K., Raju N.B., Zickler D., and Metzenberg R.L. Meiotic silencing by unpaired DNA. Cell 107 (2001) 905-916
66. Turner J.M., Mahadevaiah S.K., Fernandez-Capetillo O., Nussenzweig A., Xu X., Deng C.X., and Burgoyne P.S. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37 (2005) 41-47
67. McCarrey J.R., Watson C., Atencio J., Ostermeier G.C., Marahrens Y., Jaenisch R., and Krawetz S.A. X-chromosome inactivation during spermatogenesis is regulated by an Xist/Tsix-independent mechanism in the mouse. Genesis 34 (2002) 257-266
68. Turner J.M., Mahadevaiah S.K., Elliott D.J., Garchon H.J., Pehrson J.R., Jaenisch R., and Burgoyne P.S. Meiotic sex chromosome inactivation in male mice with targeted disruptions of Xist. J Cell Sci 115 (2002) 4097-4105
69. Huynh K., and Lee J.T. Inheritance of a pre-inactivated paternal X chromosome in the mouse. Nature 426 (2003) 857-862
70. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 16 (2002) 6-21
71. Hellman A., and Chess A. Gene body-specific methylation on the active X chromosome. Science 315 (2007) 1141-1143. Using allele specific methylation analysis on over 1000 loci of the human X chromosome, the authors and make the unexpectedly discovery that DNA methylation is concentrated on the Xa, contrary to the previous notion that the Xi is hypermethylated relative to Xa. On the Xa, CpG methylation occurs at gene bodies, while promoters are relatively unmethylated. These results suggest a role of DNA methylation on the Xa.
72. Mlynarczyk-Evans S., Royce-Tolland M., Alexander M.K., Andersen A.A., Kalantry S., Gribnau J., and Panning B. X chromosomes alternate between two states prior to random X-inactivation. PLoS Biol 4 (2006) e159. The authors describe a cytological mark that differentiates the two Xa in undifferentiated female ES cells. In a high percentage of cells, the two Xa look different, with one showing two hybridization signals at the Xic and the other showing only one. The underlying cause of this is unknown; however, the marks appear to predict the future active and inactive states of the chromosome.
73. Augui S., Filion G.J., Huart S., Nora E., Guggiari M., Maresca M., Stewart A.F., and Heard E. Sensing X chromosome pairs before X inactivation via a novel X-pairing region of the Xic. Science 318 (2007) 1632-1636. The authors identify a region several hundred kilobases upstream of Xist that pairs even before the onset of XCI. The authors claim this region allows for sensing of the two X chromosomes independently of Tsix/Xite and affects whether Xist is expressed. Evidence is presented that pairing can occur even in the absence of the previously identified 65 kb critical region. The putative element lies within the Xpct coding gene.
74. ••].
75. ••] present evidence that dosage compensation involves two mechanisms, one on the Xi that silences X-genes and the other on Xa to ensure that X-linked gene expression is on par with the autosomal average. Thus, dosage compensation in mammals may involve an X-upregulating mechanism like the one described in the fruitfly. Molecular players in the mammalian mechanism are not currently known.