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Title: Epigenetic regulation of postnatal subventricular zone development
Author: Sun, Bin
ISNI:       0000 0004 6063 2798
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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The postnatal/adult subventricular zone (SVZ) harbours neural stem cells (NSC), which produce neurons that migrate to the olfactory bulbs. SVZ NSC share several biological features with glia, especially reactive astrocytes. However, it is not clear how SVZ NSC simultaneously maintain self-renewal stem cell properties and the potential for generating daughter cells that differentiate into neurons. Multiple cyclin-dependent kinase inhibitors (CDKIs), including p16, p19 and p21 have been identified as indispensable for maintaining stem cell potential, in both cyclin dependent and independent manners. However, how these CDKIs are coordinated remains poorly defined. One possible regulator of CDKIs is the canonical Polycomb Repressive Complex 2 (PRC2) that consists of Eed, Suz12, and Ezh2. Ezh2 functions to methylate lysine 27 of histone 3 (H3K27me3) and consequently suppresses target gene expression. Whereas PRC2 serves to balance self-renewal versus differentiation and neuron versus glial fate choices in early and late embryogenesis, respectively, our understanding of its role in the neonatal and adult SVZ is incomplete. In this thesis, I discovered that the PRC2 core subunit Eed, but not Ezh2, was expressed in SVZ NSC. Eed directly repressed p16 and p19, but indirectly fine-tuned p21 expression in SVZ NSC. Conditional deletion or knockdown of Eed in vivo led to loss of constitutive SVZ stemness and blocked NSC activation. This was partly due to selective activation of the PRC2 targets, Cdkn2a and Gata6; in contrast Ezh2 loss of function only activated Cdkn2a but not Gata6. In the SVZ, Gata6 overexpression was sufficient to limit the neurogenic ability of NSC and also inhibited p21 post-transcriptional expression. I also showed that although reactive astrocytes in the cerebral cortex can acquire stem cell properties in response to brain injury, Eed was not involved in this process. Taken together, I identified novel and divergent regulation of SVZ CDKIs by separate subcomponents of PRC2, and showed that these are essential for SVZ NSC maintenance. Whilst this regulatory pathway was specific in the neurogenic niche it had little influence on parenchymal astrocytes. In a relatively small side project, I screened and identified several long non- coding RNAs (lncRNA) that were highly expressed in the adult rodent SVZ. The lncRNA Paupar, which is transcribed upstream from the Pax6 antisense strand, was enriched in the postnatal SVZ and regulated Pax6 and Ezh2 expression. In vivo, Paupar knockdown showed it is necessary for stem cell maintenance and thus regulates postnatal neurogenesis. To conclude, I discovered two interacting epigenetic regulators that control postnatal SVZ NSC and neurogenesis.
Supervisor: Szele, Francis Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available