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Title: Role of CIZ1 in maintenance of epigenetic state
Author: Stewart, Emma Rachael
ISNI:       0000 0004 8499 1365
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2019
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The ability to transcriptionally repress genes is essential for cell survival. X chromosome inactivation is a widely used model for studying establishment and maintenance of facultative heterochromatin. This process requires Xist lncRNA and recruitment of chromatin modifiers including polycomb repressive complexes (PRC1/2), which lay down the classical epigenetic marks H2AK119Ub1 and H3K27me3. The nuclear matrix (NM) is the insoluble nuclear substructure which remains following extraction of soluble proteins, lipids, chromatin and, in some protocols, RNA. This thesis focuses on CIZ1, a NM protein known for its role in DNA replication. A CIZ1-null mouse model has shown CIZ1 loss results in fully penetrant female-specific lymphoproliferative disorder, and CIZ1-null primary embryonic fibroblasts (PEFs) display loss of Xist localisation and epigenetic mark enrichment from the inactive X chromosome (Xi). I have optimised a protocol capable of profiling how proteins are anchored within the nucleus and generated a model of NM structure at the Xi. I demonstrate that CIZ1 is normally anchored via attachment to RNA but becomes part of the core protein NM during Xi replication, coincident with Xi relocation from the nuclear periphery to the nucleolus and back. Compromised Xi relocation in CIZ1-null PEFs is accompanied by increased solubility of PRC2 catalytic subunit EZH2, and genome-wide deregulation of polycomb-regulated genes. Compromised Xi relocation, solubilisation of EZH2 and polycomb target deregulation are also observed in WT cells following adaption to long term culture, suggesting this CIZ1-dependent process is typically compromised in cell lines. CIZ1 loss also appears to lead to DREAM complex target deregulation and expression of unannotated transcripts in activated CIZ1-null lymphocytes. The data are consistent with CIZ1 having a role in how enzyme and template meet, likely contributing to the maintenance of epigenetic landscape in PEFs, and offers a pathway that could explain the widespread links between CIZ1 and cancer.
Supervisor: Coverley, Dawn ; White, Bob Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available