Atsma, Tjerk Jan (2020) Antagonistic regulation of PRC1.1 stability by the TRIM27/USP7 axis allows for molecular targeting of the leukemic epigenome. thesis, Medicine.
Full text available on request.Abstract
Introduction: Acute myeloid leukaemia (AML) is a malignant disease of the bone marrow, characterized by the production of proliferative myeloblasts by quiescent leukemic stem cells (LCSs). These LSCs are resistant to chemotherapy, and frequently cause relapse of the disease. Therefore, it is of immediate interest to specifically eradicate LSCs. Polycomb Group (PcG) proteins are epigenetic modifiers that directly regulate self-renewal of LSCs. PcG proteins reside in multiple complexes, and one of these complexes, the Polycomb Repressive Complex 1.1 (PRC1.1), is essential LSC viability. To better understand the function of PRC1.1 in LSCs we characterized the composition of the PRC1.1 complex and identified two new subunits: The E3 ligase TRIM27 and deubiquitinase USP7. This research focuses on the role of TRIM27 and USP7 in PRC1.1, and their potential as therapeutic targets for the treatment of AML. Methods: Lentiviral transduction was used to express specific short hairpin RNAs and silence expression of TRIM27 and USP7 in the leukemic cell line K562. USP7 inhibitors were used to interfere with the catalytic activity of USP7. Subsequently, we studied the resulting effects on PRC1.1 complex stability, PRC1.1 chromatin binding, and expression of PRC1.1 target genes. Results: Incorporation of USP7 in PRC1.1 relies on TRIM27, and reversely, incorporation of TRIM27 requires USP7. In the absence of TRIM27 and USP7, PRC1.1 remains bound to its target genes, and maintains their epigenetic make-up and expression. In contrast, inhibition of USP7 activity results in dysfunction of PRC1.1. This effect is dependent on TRIM27. Discussion: Our data show that the TRIM27/USP7 axis antagonistically controls stability of the PRC1.1 complex. Inhibition of USP7 activity disturbs PRC1.1 function. Therefore, USP7 is a promising target to interfere with the leukemic epigenome, and potentially eradicate LSCs.
| Item Type: | Thesis (UNSPECIFIED) |
|---|---|
| Supervisor name: | van den Boom, Dr. V. and Schuringa, Prof. Dr. J.J. |
| Faculty: | Medical Sciences |
| Date Deposited: | 07 Aug 2023 11:15 |
| Last Modified: | 07 Aug 2023 11:15 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/3612 |
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