Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia

Oittinen, Mikko; Popp, Alina; Kurppa, Kalle; Lindfors, Katri; Mäki, Markku; Viiri, Keijo

doi:10.1002/stem.2479

Cited by 34 publications

(42 citation statements)

References 56 publications

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“…A variety of transcriptional and post-transcriptional mechanisms impart tight regulation on the Wnt/β-catenin signaling pathway 21 . Recently, PRC2-mediated regulation of Wnt signaling has been shown to control cell growth across multiple tissues 23 , 24 ; however, it is not clear how the Wnt signaling pathway is epigenetically regulated and little is known about the role of PRC2 in regulating these pathways.…”

Section: Introductionmentioning

confidence: 99%

Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis

et al. 2018

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Polycomb repressive complex 2 (PRC2) accessory proteins play substoichiometric, tissue-specific roles to recruit PRC2 to specific genomic loci or increase enzymatic activity, while PRC2 core proteins are required for complex stability and global levels of trimethylation of histone 3 at lysine 27 (H3K27me3). Here, we demonstrate a role for the classical PRC2 accessory protein Mtf2/Pcl2 in the hematopoietic system that is more akin to that of a core PRC2 protein. Mtf2−/− erythroid progenitors demonstrate markedly decreased core PRC2 protein levels and a global loss of H3K27me3 at promoter-proximal regions. The resulting de-repression of transcriptional and signaling networks blocks definitive erythroid development, culminating in Mtf2−/− embryos dying by e15.5 due to severe anemia. Gene regulatory network (GRN) analysis demonstrated Mtf2 directly regulates Wnt signaling in erythroblasts, leading to activated canonical Wnt signaling in Mtf2-deficient erythroblasts, while chemical inhibition of canonical Wnt signaling rescued Mtf2-deficient erythroblast differentiation in vitro. Using a combination of in vitro, in vivo and systems analyses, we demonstrate that Mtf2 is a critical epigenetic regulator of Wnt signaling during erythropoiesis and recast the role of polycomb accessory proteins in a tissue-specific context.

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Section: Introductionmentioning

confidence: 99%

Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis

et al. 2018

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“…36 However, the gene activation gained by downregulation of H3K27me3 is global and thus associated with uncontrolled risks, as suggested by other tumor models. 49 In addition, our study suggests that particular effects of deregulation might even become reinforced by this type of treatment. Considering that in most cases the cause of the hypermethylation is unknown, these results suggest that treatment surveillance is important to avoid related side effects.…”

Section: Discussionmentioning

confidence: 68%

Targeting DNA hypermethylation: Computational modeling of DNA demethylation treatment of acute myeloid leukemia

et al. 2017

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In acute myeloid leukemia (AML) DNA hypermethylation of gene promoters is frequently observed and often correlates with a block of differentiation. Treatment of AML patients with DNA methyltransferase inhibitors results in global hypomethylation of genes and, thereby, can lead to a reactivation of the differentiation capability. Unfortunately, after termination of treatment both hypermethylation and differentiation block return in most cases. Here, we apply, for the first time, a computational model of epigenetic regulation of transcription to: i) provide a mechanistic understanding of the DNA (de-) methylation process in AML and; ii) improve DNA demethylation treatment strategies. By in silico simulation, we analyze promoter hypermethylation scenarios referring to DNMT dysfunction, decreased H3K4me3 and increased H3K27me3 modification activity, and accelerated cell proliferation. We quantify differences between these scenarios with respect to gene repression and activation. Moreover, we compare the scenarios regarding their response to DNMT inhibitor treatment alone and in combination with inhibitors of H3K27me3 histone methyltransferases and of H3K4me3 histone demethylases. We find that the different hypermethylation scenarios respond specifically to therapy, suggesting that failure of remission originates in patient-specific deregulation. We observe that inappropriate demethylation therapy can result even in enforced deregulation. As an example, our results suggest that application of high DNMT inhibitor concentration can induce unwanted global gene activation if hypermethylation originates in increased H3K27me3 modification. Our results underline the importance of a personalized therapy requiring knowledge about the patient-specific mechanism of epigenetic deregulation.

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“…PRC2 is theorized to suppress Wnt signaling and thereby affect multiple biological processes, such as skeletal muscle differentiation [114], skeletal growth [115], adipogenesis [116], erythropoiesis [117], and intestinal homeostasis [118]. This suppression of Wnt signaling is mediated through a variety of targets within the Wnt pathway, including genes such as Wnt1, Wnt6, Wnt10a, Wnt10b, and Lef1.…”

Section: Prc2 Loss and Wnt Signalingmentioning

confidence: 99%

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Zhang

Murray

et al. 2020

Genes

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

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Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia

Cited by 34 publications

References 56 publications

Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis

Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis

Targeting DNA hypermethylation: Computational modeling of DNA demethylation treatment of acute myeloid leukemia

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

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