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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

Dates:

Date	Event
9 November 2007	Published

Volume:

Vol.3

Number:

No.11

Number of Pages:

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.