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Revealing the Mechanism of Xist-mediated Silencing

Citation

Chen, Chun-Kan (2018) Revealing the Mechanism of Xist-mediated Silencing. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z94J0C9J. http://resolver.caltech.edu/CaltechTHESIS:11032017-102218314

Abstract

Xist initiates XCI by spreading across the future inactive X-chromosome, excluding RNA polymerase II, recruiting the polycomb repressive complex and its associated repressive chromatin modifications, and repositioning active genes into a transcriptionally silenced nuclear compartment. While much is known about the events that occur during XCI, the mechanism by which Xist carries out these various roles remains unclear. Here we identify ten proteins that directly associate with Xist, and we further show that three of these proteins are required for Xist-mediated transcriptional silencing. One of these proteins, SHARP, which is known to interact with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of PolII from the inactive X. We show that both SMRT and HDAC3 are required for Xist-mediated silencing and RNA polymerase II exclusion. Another of these proteins, LBR, is required for repositioning actively transcribed genes into the Xist-silenced compartment. We further show that Xist, through its interaction with LBR, a protein that is anchored in the inner nuclear membrane, would effectively reposition Xist-coated DNA to the nuclear lamina, thereby changing the accessibility of other genes on the X-chromosome to enable Xist to spread to active genes across the entire chromosome to silence chromosome-wide transcription. Together, these results present an integrative picture of how Xist can scaffold multiple proteins to orchestrate the complex functions required for the establishment of the inactive X-chromosome.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:lncRNA; Xist; X chromosome inactivation
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Molecular Biology and Biochemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Guttman, Mitchell
Thesis Committee:
  • Elowitz, Michael B. (chair)
  • Guttman, Mitchell
  • Wold, Barbara J.
  • Aravin, Alexei A.
Defense Date:1 November 2017
Funders:
Funding AgencyGrant Number
NIH NRSA training grantT32GM07616
Record Number:CaltechTHESIS:11032017-102218314
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:11032017-102218314
DOI:10.7907/Z94J0C9J
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nature14443DOIArticle adapted for Chapter 2 and 3.
http://dx.doi.org/10.1126/science.aae0047DOIArticle adapted for Chapter 4.
ORCID:
AuthorORCID
Chen, Chun-Kan0000-0002-1194-9137
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10551
Collection:CaltechTHESIS
Deposited By: Chun-Kan Chen
Deposited On:30 Nov 2017 21:36
Last Modified:21 Aug 2018 19:56

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