1. X-chromosome inactivation: molecular mechanism and genetic consequences
By: Ambaye, S. & Mujahed, H

2. Intoduction What makes a child a boy or a girl ?
X-Chromosome and Y-chromosome
are different.
Males and Females should
have the same amount
X-chromsome genes
product.

3. Intoduction Dosage Compensation
A mechanism to equalize the dosage of X- chromosome gene products by means of inactivating one of female X-chromosomes in mammels.
In Drosophila dosage Compensation accompleished by two fold transcriptional upregulation male X chromosome.

4. The existence of XCI was first suggested by Mary Lyon in 1961.
For this reason this suggestion was known as the `Lyon hypothesis,'

5. Molecular mechanisms of X inactivation
X-chromosome contains X Inactivation Center (XIC) which located in long arm.
XIC contains an unusual gene called inactive X (Xi)-specific transcripts (XIST).
XIST expresses a noncoding functional 17 (kb) RNA molecule.
XIST expressed only when more than one X- chromosome found in same cell.

6. Molecular mechanisms of X inactivation
(Migeon, 1994)

7. Molecular mechanisms of X inactivation
XIST
(Brown, C. J. et al. 1991)

8. Molecular mechanisms of X inactivation
XIST transcripts remains in the nucleus.
While Xist is being transcribed, blocking factors prevent the association with X chromosome.

9. Molecular mechanisms of X inactivation
Blocking factores are released, Xist RNA is stablized and upregulated.

10. Molecular mechanisms of X inactivation
Before inactivation the X chromosome coated with stabilized Xist RNA.

11. Molecular mechanisms of X inactivation
Genes on the X chromosome are silenced following Xist RNA coating using an unknown mechanism.

12. Molecular mechanisms of X inactivation
 Chromatin modifications, including histone deacetylation and methylation of promoters of X- linked.
(Avner, P., & Heard, 2001)

13. Genetic Imprinting and X Inactivation
X-chromosome inactivation ocurres by two ways: Random and imprented.
Differes in:
Developmental timing.
Mechanism.

14. Genetic Imprinting
 Paternal X-chromosome is preferentially silenced in the placenta.
Extensive methylation of CpG islands on paternal X-chromosome.
Suggested to take a place during spermatogenesis.

15. Genetic Imprinting
Summary of Fthl17 gene family expression in preimplantation stage embryos.
Summary of Fthl17 gene family expression in preimplantation stage embryos. The Fthl17 genes are imprinted and expressed from the paternal X chromosome as early as the two-cell stage. A significant difference in gene expression between male and female embryos appears at the time of zygotic genome activation (ZGA).
Kobayashi S et al. Nucl. Acids Res. 2010;nar.gkq113
© The Author(s) Published by Oxford University Press.

16. Random X Inactivation
One of the two X-chromosomes is randomly inactivated in the early female embryo developmental stage.
Cells ensure that one
of the Xs still active.

17. Random X Inactivation

18. Consequences of X chromosome inactivation
The result is that the effective dosages of products of X-linked genes are equal in males and females.
The X chromosome is large and with many genes, whereas the Y chromosome
is much smaller and carries
orthologs of only a few of the
X-linked genes.

19. Consequences of X chromosome inactivation
Inactivation in females results in cellular mosaicsim, one population of cells expresses the maternal allele; the other expresses the paternal one.

20. Consequences of X chromosome inactivation
Females benefit from the presence of heterozygous populations of cells.
In case of X-linked mutations that are detrimental and even lethal, sons may not be affected of the mutant gene they express.
Also growth competition between the mosaic populations can result in elimination of cells that express the mutant allele.

21. Consequences of X chromosome inactivation
X inactivation can create problems when cells with the mutation have a growth advantage (e.g: cancer cells).
Elimination of normal cells occurs as the result of chromosomal abnormalities that arise by chance.
As a consequence, females may manifest diseases usually found only in males

22. “It has been six weeks now
“It has been six weeks now. Six weeks of tireless, frenzied activity since that sperm jostled its way into that egg. So little time spent in this warm, dark, womby home, and so much achieved”
David Bainbridge, The X In Sex

23. Referenses
Avner, P. and Heard, E. (2001). X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2, Brown, C. J., Ballabio, A., Rupert, J. L., Lafreniere, R. G., Grompe, M., Tonlorenzi, R. and Willard, H. F. (1991). A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, Migeon, B. R. (1994). X-chromosome inactivation: molecular mechanisms and genetic consequences. Trends Genet 10, Yang, C., Chapman, A. G., Kelsey, A. D., Minks, J., Cotton, A. M. and Brown, C. J. (2011). X-chromosome inactivation: molecular mechanisms from the human perspective. Hum Genet.