QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 26 November 2008
doi: 10.1242/dev.025908

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Starmer, J. Articles by Magnuson, T. Search for Related Content PubMed PubMed Citation Articles by Starmer, J. Articles by Magnuson, T. Social Bookmarking                         What's this?

A new model for random X chromosome inactivation

¹ Department of Genetics and the Carolina Center for the Genome Sciences, and University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

View larger version (31K): [in this window] [in a new window]   Fig. 1. Three models of X chromosome inactivation. (A) The blocking factor model. (a) Diploid autosomes work together to create a single blocking factor (blue shape), which can bind to only one X chromosome, preventing it from inactivating. (b) Nicodemi and Prisco used computer simulations to show that if the autosomes produce a swarm of blocking factors (blue dots) that can bind to each other and to the X chromosome, then all of the blocking factor molecules will accumulate on a single X. (B) The two factor model. Autosomes produce blocking factors and X chromosomes produce transacting competence factors (red shape). Blocking factors bind to competence factors with a two to one stoichiometry and then bind to one X chromosome; the remaining competence factor binds to the other X, which inactivates. (C) The sensing and choice model. After cells start to differentiate, the two Xpr regions (yellow) pair and upregulate Xist (red) on both X chromosmes. The Tsix/Xite region (blue) pairs and chooses which chromosome to inactivate, and represses Xist on the other. The X chromosome that represses Xist remains active (green), and the other becomes inactive (red).

View larger version (28K): [in this window] [in a new window]   Fig. 2. Stochastic model of X chromosome inactivation. (A) The various components of the stochastic model. (B,a) Prior to cell differentiation, the stochastic model proposes that the autosomes produce a trans-acting factor (purple stars) that induces Tsix expression on both X chromosomes (blue shape). (b) Tsix, when bound by autosomal trans-acting factors, represses Xist transcription (red shape). (c) After differentiation, an X-linked locus (yellow triangle) produces a trans-acting factor (red circles) that attempts to upregulate Xist. (d) Competition between Tsix- and Xist-promoting factors creates a probability for each X chromosome to inactivate. Cells that do not inactivate either X chromosome will continue to produce the factor that promotes Xist upregulation in subsequent cell cycles. Cells that inactivate both X chromosomes will either die, or reactivate one. The percentages shown here reflect the proportions of each XCI configuration observed 7 days after differentiation. Xa, active X chromosome; Xi, inactive X chromosome.

View larger version (15K): [in this window] [in a new window]   Fig. 3. Part of the mouse X chromosome inactivation center and sequence replacements and deletions within it. Sequences used to replace portions of the XIC are shown above the diagram, which shows their relative locations. The effects of these replacements are listed in Table 3. Below the diagram, the dotted lines show XIC regions that have been deleted. The effects of these deletions are listed in Table 2.

View larger version (21K): [in this window] [in a new window]   Fig. 4. A problem with the two factor model. After XCI, XTsixCpG:XTsixCpG ES cells make three cell populations: one with a single active X (Xa) chromosome and a single inactive X (Xi) chromosome; one with two Xa chromosomes; and one with two Xi chromosomes. (A) Cells with normal XCI result from blocking factor (BF) binding to one X chromosome and the competence factor (C) binding to the other. (B) Cells with two Xa chromosomes and two Xi chromosomes result from BF and C binding to the same X chromosome. However, it is not clear how having both BF and C bound to a single X chromosome results in these two different populations of cells.

View larger version (24K): [in this window] [in a new window]   Fig. 5. The feedback model of X chromosome inactivation. (A) A description of the components required for the model. (B,a) The active X chromosomes produce a trans-acting signal, A, that saturates specific sites on the autosomes. (b) Once saturated, the autosomes produce a swarm of inactivation signals, I. These signals bind to each other and to XCI inhibitors on the X chromosomes. Once all of the XCI inhibitors on an X chromosome are sufficiently bound by I, the XCI initiator induces inactivation. (c) With only one active X chromosome producing A, the autosomes are no longer saturated with A and stop producing I.

View larger version (24K): [in this window] [in a new window]   Fig. 6. Three different paths to X inactivation. (A) In a normal X chromosome, all of the XCIrepress loci must be turned off by I. (B) In a mutant X chromosome where some of the XCIrepress loci have been removed, only a small amount of I is required to initiate XCI. Because these chromosomes have a lower threshold to overcome before initiating XCI, there is a higher probability that they will inactivate. (C) In a mutant X chromosome where all of the XCIrepress loci have been removed, XCI will initiate without any I.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

Twitter