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

Rothberg, Janet L. Manias; Maganti, Harinad; Jrade, Hani; Porter, Christopher J.; Palidwor, Gareth; Cafariello, Christopher; Battaion, Hannah L.; Khan, Safwat T.; Perkins, Theodore J.; Paulson, Robert F.; Ito, Caryn Y.; Stanford, William L.

doi:10.1038/s41421-018-0022-5

Cited by 46 publications

(51 citation statements)

References 60 publications

(82 reference statements)

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“…We found that Wnt signaling was affected upon the loss of Mtf2. This is consistent with recent evidence that Mtf2 null mice demonstrated impairment in definitive erythroid development, and that Wnt was regulated by MTF2 during erythropoiesis 25 . We also found other signaling pathways (e.g.…”

Section: Discussionsupporting

confidence: 93%

“…Reports on the phenotypic developmental consequences of losing PRC2 subunits during development have been diverse. The loss of Mtf2 has been shown to be embryonic lethal by E15.5, with observations of severe anemia and growth retardation [43][44][45] . On the contrary, Jarid2 null mice exhibited early embryonic lethality (as early as E10.5) [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Mtf2 and Jarid2 mutants further revealed the requirement for accessory subunits during embryonic development, with mutants experiencing embryonic lethality (before E15. 5 for Mtf2 and E18.5 for Jarid2 mutants) 25,26 .…”

Section: Introductionmentioning

confidence: 99%

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Loss of PRC2 subunits primes lineage choice during exit of pluripotency

Loh

Perino

Bark

et al. 2020

Preprint

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AbstractPolycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. There are two distinct PRC2 complexes, PRC2.1 and PRC2.2, which contain respectively MTF2 and JARID2 in ES cells. Very little is known about the roles of these auxiliary PRC2 subunits during the exit of pluripotency. In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived from Mtf2 and Jarid2 null embryonic stem cells (ESCs). We observed that the loss of Mtf2 resulted in enhanced and faster differentiation towards cell fates from all germ layers, while the Jarid2 null cells were predominantly directed towards early differentiating precursors and neuro-ectodermal fates. Interestingly, we found that these effects are caused by derepression of developmental regulators that were poised for activation in pluripotent cells and gained H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories were relatively similar to those of wild type cells. Together, our results uncovered a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, providing a threshold for lineage choice during the exit of pluripotency.HighlightsEnhanced and faster differentiation into all three germ layers in Mtf2 null embryoid bodiesJarid2 null cells enriched for early differentiating precursors and neuro-ectodermal cell fatesMTF2 is critical for the balance of activation and repression of key developmental regulatorsPRC2 coordinates lineage choice and execution of the lineage-specific program by thresholding of lineage-priming

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Loss of PRC2 subunits primes lineage choice during exit of pluripotency

Loh

Perino

Bark

et al. 2020

Preprint

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“…In embryonic stem cells (ESC), MTF2 functions as a prototypical PRC2 accessory protein to recruit PRC2 to the extended pluripotency network gene promoters, leading to increased H3K27me3 methylation and repression of the pluripotency network to enable ESC differentiation (6). In contrast, in hematopoietic cells, MTF2 behaves more similarly to a core PRC2 component because its loss reduces SUZ12 and EZH1/2 expression and global H3K27me3 levels (8).…”

Section: Introductionmentioning

confidence: 99%

Targeting the MTF2–MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy

et al. 2018

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Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that metal response element binding transcription factor 2/polycomblike 2 (MTF2/PCL2) plays a fundamental role in the polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2-deficient CD34CD38 cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell-cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML. MTF2 deficiency predicts refractory AML at diagnosis. MTF2 represses MDM2 in hematopoietic cells and its loss in AML results in chemoresistance. Inhibiting p53 degradation by overexpressing MTF2 or by using MDM2 inhibitors sensitizes MTF2-deficient refractory AML cells to a standard induction-chemotherapy regimen. .

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

Cited by 46 publications

References 60 publications

Loss of PRC2 subunits primes lineage choice during exit of pluripotency

Loss of PRC2 subunits primes lineage choice during exit of pluripotency

Targeting the MTF2–MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy

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

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