Tavares Cornejo, Manuel de Jesus; (2020) Disregulation of PRC2 function caused by the JAZF1-SUZ12 fusion protein. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Polycomb repressive complex 2 (PRC2) maintains developmental genes specific for other cell types in a repressed state through methylation of histone H3 lysine 27 and formation of a repressive chromatin state. PRC2 is frequently mutated or disregulated in cancer. In addition to binding to chromatin, PRC2 also binds RNA and this prevents its interaction with chromatin. In endometrial stromal sarcoma (ESS), chromosomal translocation fuses the first 128 amino acids of JAZF1 in place of the N-terminal 93 amino acids of the PRC2 subunit SUZ12. However, the effects this has on PRC2 function are unknown. Here, I show that the JAZF1- SUZ12 fusion protein prevents association of PRC2 with the accessory subunits JARID2, EPOP and PALI1. Moreover, I demonstrate that JAZF1-SUZ12 prevents the transfer of PRC2 from RNA to chromatin. Consistent with this defect being due to loss of EPOP and JARID2 interaction, PRC2 is also unable to transfer from RNA to chromatin in JARID2, EPOP or PALI1 deficient embryonic stem cells. Finally, I show that JAZF1-SUZ12 reduces the binding of PRC2 to its target genes and disrupts regulation of key developmental genes during differentiation of mouse embryonic stem cells. Thus, this work reveals molecular defects in PRC2 function caused by the JAZF1-SUZ12 fusion protein and suggests that changes in the balance between PRC2 RNA and chromatin binding may play a role in oncogenesis.

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