UNSW Embryology

Molecular Development - X Inactivation

© Dr Mark Hill (2011)

Acknowledgements

Introduction

The presence in females of 2 X chromosome raises the issue of gene dosage, in the case of mammals this is regulated by inactivating one of the X chromosomes (see X inactivation notes).

New 2011 Molecular Development - X Inactivation

In some other species compensation occurs by increasing the expression of X in males. The pattern of which X chromosome is inactivated in cells appears to be random, generating 50% cells expressing Father X, 50% cells expressing Mother X (mosaic pattern). The theory of random X inactivation was first suggested in mice in 1961.

This topic is also covered in Week 1 Notes

Epigenetic Mechanisms

A second form of X inactivation that occurs only in male meiotic spermatogenesis, meiotic sex chromosome inactivation (MSCI), is not covered in these current notes. MSCI is the process of transcriptional silencing of the X and Y chromosomes. (More? Meiotic sex chromosome inactivation. Turner JM. Development. 2007 May;134(10):1823-31.)

Recent Findings

A new model for random X chromosome inactivation. Starmer J, Magnuson T. Development. 2009 Jan;136(1):1-10. Epub 2008 Nov 26.

"X chromosome inactivation (XCI) reduces the number of actively transcribed X chromosomes to one per diploid set of autosomes, allowing for dosage equality between the sexes. In eutherians, the inactive X chromosome in XX females is randomly selected. ... Here, we introduce a new model of X chromosome inactivation that aims to account for the findings in recent studies, to promote a re-interpretation of existing data and to direct future experiments."

Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus. Li N, Carrel L. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17055-60.

"Although most genes on one X chromosome in mammalian females are silenced by X inactivation, some “escape” X inactivation and are expressed from both active and inactive Xs."

Popova BC, Tada T, Takagi N, Brockdorff N, Nesterova TB. Attenuated spread of X-inactivation in an X;autosome translocation. Proc Natl Acad Sci U S A. 2006 May 5

"X inactivation in female mammals involves transcriptional silencing of an entire chromosome in response to a cis-acting noncoding RNA, the X inactive-specific transcript (Xist). Xist can also inactivate autosomal sequences, for example, in X;autosome translocations; but here, silencing appears to be relatively inefficient. ... Our findings provide direct evidence that underlying chromosome/chromatin features can disrupt spreading of the primary inactivating signal."

 

 

X Inactivation (xist)

X- Chromosome

• Contains about 5% of the haploid genome.
• Genes encode house-keeping and specialized functions.
• Completely conserved in gene content between species.
• It does not encode sex determination or differentiation.
• In females one of the X-chromosomes is inactivated in each and every cell. [known since 1961]
• This inactivation occurs during embryogenesis.
• X Inactivation appears to be random in somatic cells. (mosaic pattern)
• The process starts at the "X inactivation centre" and spreads along the chromosome.
• The mechanism of inactivation was unknown.

X Inactivation (xist) History

• The theory of random X inactivation was first suggested in mice in 1961.
• The breakthrough was the discovery of the X inactive specific transcript (XIST). Brown et. al., (1991) Nature 349, 372-373.
• This gene is located within the "X inactivation centre" and only expressed by the inactive X chromosome.
• unlike other genes that encode protein XIST contained no "open reading frames" (ie no codons to encode amino acids).
• XIST is transcribed but not translated.
• XIST appears to act as RNA. Current thinking is that it binds to the X Chromosome and is involved in it's translocation to the nuclear periphery.
• It now appears that XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that maintains inactivity.

References:

• Gene action in the X-chromosome of the mouse (Mus musculus L.). LYON MF. Nature. 1961 Apr 22;190:372-3.
• A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HFNature 1991 Jan 3;349(6304):38-44 Abstract
• Localization of the X inactivation centre on the human X chromosome in Xq13. Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF Nature 1991 Jan 3;349(6304):82-4 Abstract
• X-chromosome inactivation in mammals. Heard E, Clerc P, Avner P Annu Rev Genet 1997;31:571-610 (review article) Abstract
• Epigenetic programming of differential gene expression in development and evolution. Monk M Dev Genet 1995;17(3):188-97 Abstract

Mechanisms

Epigenetic Mechanisms (Image: Nature 441, 143-145 (11 May 2006), with permission)

X Chromosome

• Contains about 5% of the haploid genome.
• Genes encode house-keeping and specialized functions.
• Conserved in gene content between species.
• It does not encode sex determination or differentiation.
• In females one of the X-chromosomes is inactivated in each and every cell. [known since 1961]
• This inactivation occurs during embryogenesis.
• X Inactivation appears to be random in somatic cells. (mosaic pattern)
• The process starts at the "X inactivation centre" and spreads along the chromosome.
• The mechanism of inactivation was unknown.
• X-Chromosome Inactivation

X Chromosome Inactivation

• The breakthrough was the discovery of the X inactive specific transcript (XIST). Brown et. al., (1991) Nature 349, 372-373.
• This gene is located within the "X inactivation centre" and only expressed by the inactive X chromosome.
• unlike other genes that encode protein XIST contained no "open reading frames" (ie no codons to encode amino acids).
• XIST is transcribed but not translated.
• XIST appears to act as RNA. Current thinking is that it binds to the X Chromosome and is involved in it's translocation to the nuclear periphery.
• It now appears that XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that maintains inactivity.

References

Reviews

New twists in X-chromosome inactivation. Erwin JA, Lee JT. Curr Opin Cell Biol. 2008 Jun;20(3):349-55. Epub 2008 May 26. Review.

X inactivation Xplained. Wutz A, Gribnau J. Curr Opin Genet Dev. 2007 Oct;17(5):387-93. Epub 2007 Sep 14. Review.

Wrzeska M, Rejduch B. Genomic imprinting in mammals. J Appl Genet. 2004;45(4):427-33. Review.

Articles

Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus. Li N, Carrel L. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17055-60.

Popova BC, Tada T, Takagi N, Brockdorff N, Nesterova TB. Attenuated spread of X-inactivation in an X;autosome translocation. Proc Natl Acad Sci U S A. 2006 May 5

Gene action in the X-chromosome of the mouse (Mus musculus L.). LYON MF. Nature. 1961 Apr 22;190:372-3.

Search PubMed: Search May 2006 "X Inactivation" 1431 reference articles of which 194 were reviews. Search term = X Inactivation

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