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- Nylund, Patrick
(författare)
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Targeting molecular mechanisms for epigenetic silencing in multiple myeloma : Implications for biology and precision medicine
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a heterogeneous haematological cancer where malignant plasma cells clonally expand within the bone marrow. The transcriptional repressor PRC2 and its catalytic subunit EZH2 play a major role in MM, as PRC2 re-targeting results in a MM-specific gene silencing profile. In paper I, we explored the metabolic response to EZH2 inhibition (EZH2i). A global loss of H3K27me3 was found in all EZH2i-treated MM cell lines. EZH2i-sensitive cell lines acquired a unique metabolic signature, following the upregulation of a cluster of miRNAs which target methionine cycling-associated genes and are silenced by H3K27me3. These miRNAs were not upregulated in resistant cell lines, due to additional DNA methylation-mediated silencing.Therefore, in paper II we sought to evaluate the combinatorial effect of DNA demethylation agents and EZH2 inhibitors. Here, we provided a comprehensive map of the reconfiguration of the epigenome in primary MM samples. Furthermore, we demonstrated a direct protein-protein interaction between DNMT1 and EZH2 and showed that co-inhibition of these enzymes has an enhanced effect in synergistically activating genes regulating apoptosis and cell cycling. PRC2 lacks sequence specificity but contains a lncRNA binding pocket. In paper III, we hypothesized that PRC2 targeting to specific genomic regions could be mediated by lncRNAs in the context of MM. Coupling RIP- and RNA-seq, we identified a physical interaction between the lncRNA PVT1 and EZH2, as well as 270 genes potentially targeted by the EZH2-PVT1 axis. In addition, we found that independent inhibition of EZH2 and PVT1 resulted in the upregulation of the tumour suppressor genes ZBTB7C, RNF144A and CCDC136, suggesting a functional interdependency between these two epigenetic regulators. In paper IV we investigated the effects of dual G9a/DNMT inhibition in MM cells, resulting in suppressed expression of MM-associated oncogenes and increased tumour cell death. By coupling ChIP-seq, DNA methylation arrays and RNA-seq, we identified a group of genes silenced by G9a and/or DNMTs that when activated, blocked MM proliferative potential by activating genes with tumour suppressor function. In summary, this thesis highlights the strong interconnection between the dysregulation of epigenetic/metabolic regulatory mechanisms and MM pathogenesis, providing insights into how these mechanisms can be targeted to promote anti-MM effects.
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| 2. |
- Nylund, Patrick, et al.
(författare)
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The complex nature of lncRNA-mediated chromatin dynamics in multiple myeloma
- 2023
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Extensive genome-wide sequencing efforts have unveiled the intricate regulatory potential of long non-protein coding RNAs (lncRNAs) within the domain of haematological malignancies. Notably, lncRNAs have been found to directly modulate chromatin architecture, thereby impacting gene expression and disease progression by interacting with DNA, RNA, and proteins in a tissue- or condition-specific manner. Furthermore, recent studies have highlighted the intricate epigenetic control of lncRNAs in cancer. Consequently, this provides a rationale to explore the possibility of therapeutically targeting lncRNAs themselves or the epigenetic mechanisms that govern their activity. Within the scope of this review, we will assess the current state of knowledge regarding the epigenetic regulation of lncRNAs and how, in turn, lncRNAs contribute to chromatin remodelling in the context of multiple myeloma.
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