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Self-assembly and DNA binding of the blocking factor in X chromosome inactivation

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Nicodemi, Mario and Prisco, Antonella. (2007) Self-assembly and DNA binding of the blocking factor in X chromosome inactivation. PLoS Computational Biology, Vol.3 (No.11). pp. 2135-2142. ISSN 1553-734X

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Official URL: http://dx.doi.org/10.1371/journal.pcbi.0030210

Abstract

X chromosome inactivation (XCI) is the phenomenon occurring in female mammals whereby dosage compensation of
X-linked genes is obtained by transcriptional silencing of one of their two X chromosomes, randomly chosen during
early embryo development. The earliest steps of random X-inactivation, involving counting of the X chromosomes and
choice of the active and inactive X, are still not understood. To explain "counting and choice," the longstanding
hypothesis is that a molecular complex, a "blocking factor" (BF), exists. The BF is present in a single copy and can
randomly bind to just one X per cell which is protected from inactivation, as the second X is inactivated by default. In
such a picture, the missing crucial step is to explain how the molecular complex is self-assembled, why only one is
formed, and how it binds only one X. We answer these questions within the framework of a schematic Statistical
Physics model, investigated by Monte Carlo computer simulations. We show that a single complex is assembled as a
result of a thermodynamic process relying on a phase transition occurring in the system which spontaneously breaks
the symmetry between the X’s. We discuss, then, the BF interaction with X chromosomes. The thermodynamics of the
mechanism that directs the two chromosomes to opposite fates could be, thus, clarified. The insights on the selfassembling
and X binding properties of the BF are used to derive a quantitative scenario of biological implications
describing current experimental evidences on "counting and choice."

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics
Divisions:	Faculty of Science > Physics
Library of Congress Subject Headings (LCSH):	X chromosome, Gene silencing -- Computer simulation
Journal or Publication Title:	PLoS Computational Biology
Publisher:	Public Library of Science
ISSN:	1553-734X
Official Date:	9 November 2007
Volume:	Vol.3
Number:	No.11
Number of Pages:	8
Page Range:	pp. 2135-2142
Identification Number:	10.1371/journal.pcbi.0030210
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Italy. Ministero dell'istruzione, dell'università e della ricerca (MIUR), Fondo per gli Investimenti della Ricerca di Base (FIRB)
Grant number:	RBNE01S29H (MIUR-FIRB), Network MRTN-CT-2003–504712
References:	1. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190: 372–373. 2. Avner P, Heard E (2001) X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2: 59. 3. Lucchesi JC, Kelly WG, Panning B (2005) Chromatin remodeling in dosage compensation. Annu Rev Genet 39: 615. 4. Chow JC, Yen Z, Ziesche SM, Brown CJ (2005) Silencing of the mammalian X chromosome. Annu Rev Genomics Hum Genet 6: 69–92. 5. Lyon MF (2002) X-chromosome inactivation and human genetic disease. Acta Paediatr Suppl 91: 107–112. 6. Singh N, Ebrahimi FAW, Gimelbrant AA, Ensminger AW, Tackett MR, et al. (2003) Coordination of the random asynchronous replication of autosomal loci. Nat Genet 33: 339–341. 7. Ohlsson R, Tycko B, Sapienza C (1998) Monoallelic expression: ‘‘there can be only one.’’ Trends Genet 14: 435–438. 8. Lee JT (2005) Regulation of X-chromosome counting by Tsix and Xite sequences. Science 309: 768–771. 9. Lee JT, Strauss WM, Dausman JA, Jaenisch R (1996) A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell 86: 83–94. 10. Clerc P, Avner P (1998) Role of the region 39 to Xist exon 6 in the counting process of X chromosome inactivation. Nat Genet 19: 249–253. 11. Lee JT, Lu N (1999) Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99: 47–57. 12. Percec I, Plenge RM, Nadeau JH, Bartolomei MS, Willard HF (2002) Autosomal dominant mutations affecting X inactivation choice in the mouse. Science 296: 1136. 13. Gartler SM, Riggs AD (1983) Mammalian X-chromosome inactivation. Annu Rev Genet 17: 155–190. 14. Lyon MF (1972) X-chromosome inactivation and developmental patterns in mammals. Biol Rev Camb Philos Soc 47: 1. 15. Rastan S (1983) Non-random X-chromosome inactivation in mouse Xautosome translocation embryos location of the inactivation centre. J Embryol Exp Morphol 78: 1. 16. Marahrens Y, Loring J, Jaenisch R (1998) Role of the Xist gene in X chromosome choosing. Cell 92: 657. 17. Lee JT (2002) Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation. Nat Genet 32: 195–200. 18. Na Xu, Tsai C-L, Lee JT (2006) Transient homologous chromosome pairing marks the onset of X inactivation. Science 311: 1149. 19. Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, et al. (2006) Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol 8: 293. 20. Nicodemi M, Prisco A (2007) A symmetry breaking model for counting and choice in X-inactivation. Phys Rev Lett 98: 108104. 21. Watson JD, Baker TA, Bell SP, Gann A, Levine M, et al. (2003) Molecular biology of the gene. San Francisco: Benjamin Cummings. 22. Stanley HE (1971) Introduction to phase transitions and critical phenomena. Gloucestershire (United Kingdom): Clarendon Press. 23. Binder K (1997) Applications of Monte Carlo methods to statistical physics. Rep Prog Phys 60: 487. 24. Simmler MC, Cattanach BM, Rasberry C, Rouguelle C, Avner P (1993) Mapping the murine Xce locus with (CA)n repeats. Mamm Genome 4: 523– 530. 25. Vigneau S, Augui S, Navarro P, Avner P, Clerc P (2006) An essential role for the DXPas34 tandem repeat and Tsix transcription in the counting process of X chromosome inactivation. Proc Natl Acad Sci U S A 103: 7390–7395. 26. Morey C, Arnaud D, Avner P, Clerc P (2001) Tsix-mediated repression of Xist accumulation is not sufficient for normal random X inactivation. Hum Mol Genet 10: 1403. 27. Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT (2007) Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell 25: 43. 28. Cohen DE, Davidow L, Erwin JA, Xu N, Warshawsky D, et al. (2007) The DXPas34 repeat regulates random and imprinted X inactivation. Dev Cell 12: 57. 29. Heard E, Mongelard F, Arnaud D, Avner P (1999) Xist Yeast artificial chromosome transgenes functions as Xinactivation centers only in multicopy arrays and not as single copies. Mol Cell Biol 19: 3156–3166. 30. Herzing LB, Romer JT, Horn JM, Ashworth A (1997) Xist has properties of the X-chromosome inactivation centre. Nature 386: 272–275. 31. Csankovszki G, Panning B, Bates B, Pehrson JR, Jaenisch R (1999) Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nat Genet 22: 323. 32. Gribnau J, Luikenhuis S, Hochedlinger K, Monkhorst K, Jaenisch R (2005) X chromosome choice occurs independently of asynchronous replication timing. J Cell Biol 168: 365. 33. Luikenhuis S, Wutz A, Jaenisch R (2001) Antisense transcription through the Xist locus mediates Tsix function in embryonic stem cells. Mol Cell Biol 21: 8512. 34. Sado T, Wang Z, Sasaki H, Li E (2001) Regulation of imprinted Xchromosome inactivation in mice by Tsix. Development 128: 1275. 35. Morey C, Navarro P, Debrand E, Avner P, Rougeulle C, et al. (2004) The region 39 to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene. EMBO J 23: 594.
URI:	http://wrap.warwick.ac.uk/id/eprint/30920