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Mutational Analysis of Xist and the X-inactivation Center

  • Author(s): Goodrich, Leeanne
  • Advisor(s): Panning, Barbara
  • et al.
Abstract

In placental mammals, dosage compensation of the sex chromosomes is

achieved through inactivation of one X chromosome in female cells. This X

chromosome inactivation (XCI) requires tight developmental regulation to ensure all but

one X chromosome is silenced.

At the center of this process is Xist, a long non-coding RNA. Upon differentiation

of a female cell, Xist spreads in cis to coat and silence the inactive X chromosome.

While upregulation of Xist, has been shown to be sufficient for X inactivation to occur,

no one has thoroughly investigated whether Xist is necessary for the establishment of X

chromosome inactivation. In this thesis I provide evidence that Xist is not required for

dosage compensation of the X chromosome during epiblast-like cell differentiation. This

result suggests Xist-independent silencing mechanisms for this essential process may

be in place.

A 1-2 Mb region of the X chromosome, termed the X-inactivation center (Xic) is

necessary in two copies for XCI to occur, indicating it is necessary for cells to count the

number of X chromosomes present. I delete one copy of the putative 2 Mb Xic in male

and female mouse embryonic stem cells and present evidence that this deletion is not

well tolerated, suggesting that this region requires finer resolution mapping to identify

the minimal element required for counting.

Finally, I finish with a review which elaborates on studies that enlighten our

understanding of activators and repressors that control XCI. Our findings challenge

existing dogmas in the field and provide the foundation for future work focused on

uncovering the molecular mechanisms behind Xist-independent silencing of the X

chromosome.

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