Skip to main content
Open Access Publications from the University of California


UCLA Electronic Theses and Dissertations bannerUCLA

Elucidation of Initiation and Maintenance Mechanisms of X Chromosome Inactivation


X chromosome inactivation is a program of gene silencing on one of two female mammalian X chromosomes to equalize X-linked gene expression to XY male counterparts. This developmentally-regulated chromatin change is initiated on either the maternal or paternal X chromosome early in embryonic development and, once established, is maintained on the chosen chromosome for the lifetime of the female. The onset of X chromosome inactivation is regulated by the long noncoding transcript Xist and an open question is the field is how embryonic developmental cues trigger expression of Xist and onset of X chromosome inactivation. The correlation of pluripotency with repression of Xist in the mouse system has led to a model where pluripotency transcription factors repress X chromosome inactivation by binding to a region within the first intron of Xist gene. Thus differentiation would release the repression of Xist. We rigorously tested this intron1 hypothesis in a transgenic mouse model and refute that intron1 binding is responsible for the developmental regulation of X chromosome inactivation.

A second set of studies focused on the maintenance phase of X chromosome inactivation with the goal of discovering novel chromatin factors that contribute to the remarkable stability of gene silencing on the entire X chromosome. We took an unbiased screening approach, designing a high throughput assay with primary mouse cells bearing reporters on the inactive X, and screened genome-wide siRNA and chemical libraries. We report that knockdown of chromatin-associated protein Atf7ip or its previously characterized interactors reactivates silenced genes of the inactive X chromosome. From chemical screening, we found that the compound Resveratrol can lead to reactivation of silenced genes as part of a novel drug combination. We show evidence that Resveratrol inhibits the dNTP biosynthetic enzyme ribonucleotide reductase in this context. This finding has spurred a collaboration investigating Resveratrol as part of a rationale drug combination for cancer therapy. In summary, these studies demonstrate that X chromosome inactivation is powerful and flexible model for the interrogation of mammalian chromatin regulation mechanisms with relevance for disease therapy.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View