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Mammalian X chromosome inactivation
1Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
Novartis Foundation Symposium
|May 27, 1998
Summary
X chromosome inactivation requires the Xist gene, encoding untranslated RNA, which is essential for initiating and propagating inactivation. Xist RNA stabilization, not promoter regulation, drives this crucial process.
Area of Science:
- Mammalian genetics
- Epigenetics
- Developmental biology
Background:
- X chromosome inactivation (XCI) is a key process in mammalian females to equalize gene dosage between sexes.
- The Xist gene, located at the X inactivation centre (Xic), plays a critical role in initiating and maintaining XCI.
- Understanding the regulatory mechanisms of Xist is crucial for comprehending XCI.
Purpose of the Study:
- To investigate the necessity of Xist RNA for XCI initiation and propagation.
- To determine the minimal DNA fragment sufficient to confer XCI activity.
- To elucidate the regulatory mechanism controlling Xist expression during XCI.
Main Methods:
- Gene targeting to truncate Xist RNA.
- Yeast artificial chromosome (YAC) transgenesis to deliver Xist and flanking regions.
- Analysis of XCI initiation, propagation, and maintenance in engineered models.
Main Results:
- Truncation of Xist RNA is lethal and prevents X chromosome inactivation, confirming Xist RNA's essential role.
- A 450 kb DNA fragment containing Xist is sufficient to act as an inactivation centre, mediating initiation, propagation, and maintenance.
- X inactivation is regulated by post-translational stabilization of Xist RNA, not by Xist promoter activity.
Conclusions:
- Xist RNA is indispensable for the initiation, propagation, and maintenance of X chromosome inactivation in mammals.
- The Xist gene and its regulatory elements within a defined region are sufficient to drive the entire XCI process.
- X inactivation is primarily controlled by the post-transcriptional stabilization of Xist RNA, highlighting a post-translational regulatory mechanism.