Embryonic Ectoderm Development (EED) as a Novel Target for Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Nicholas Cook ◽  
Jianping Chen ◽  
Jia Zhou ◽  
Daqing Wu
Keyword(s):  
Small Molecules ◽  
Histone H3 ◽  
Allosteric Site ◽  
Polycomb Repressive Complex 2 ◽  
Core Proteins ◽  
Recent Developments ◽  
Embryonic Ectoderm Development ◽  
Novel Target ◽  
Embryonic Ectoderm ◽  
New Strategies

: The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by the binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this mini review, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.

scholarly journals EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Shanshan Ai ◽  
Yong Peng ◽  
Chen Li ◽  
Fei Gu ◽  
Xianhong Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylases ◽  
Heart Function ◽  
Histone Mark ◽  
Gene Repression ◽  
Normal Heart ◽  
Proliferating Cells ◽  
Polycomb Repressive Complex 2 ◽  
Embryonic Ectoderm Development ◽  
Embryonic Ectoderm

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

scholarly journals EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6075-6080 ◽  
Author(s):  
Michel Wassef ◽  
Armelle Luscan ◽  
Setareh Aflaki ◽  
Dina Zielinski ◽  
Pascal W. T. C. Jansen ◽  
...  
Keyword(s):  
Tumor Type ◽  
Loss Of Function ◽  
Polycomb Repressive Complex 2 ◽  
Lymphoid Malignancies ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Chromatin Regulators ◽  
Recurrent Mutations ◽  
Embryonic Ectoderm Development ◽  
Embryonic Ectoderm

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2’s main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.

scholarly journals EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

2020 ◽  
Vol 6 (33) ◽  
pp. eaaz6477 ◽  
Author(s):  
Jiajia Wang ◽  
Lijun Yang ◽  
Chen Dong ◽  
Jincheng Wang ◽  
Lingli Xu ◽  
...  
Keyword(s):  
White Matter ◽  
Histone Methylation ◽  
Bmp Signaling ◽  
Polycomb Repressive Complex 2 ◽  
Morphogenetic Protein ◽  
Specific Manner ◽  
Embryonic Ectoderm Development ◽  
Cns Myelination ◽  
Embryonic Ectoderm

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

scholarly journals Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease

2019 ◽  
Vol 11 (494) ◽  
pp. eaau9087 ◽  
Author(s):  
Huan Liu ◽  
Jin He ◽  
Su Pin Koh ◽  
Yuping Zhong ◽  
Zhiqiang Liu ◽  
...  
Keyword(s):  
Bone Disease ◽  
Unique Feature ◽  
Histone H3 ◽  
Bone Lesions ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Osteolytic Lesions ◽  
Therapeutic Implications ◽  
Polycomb Repressive Complex 2 ◽  
Bone Changes

Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator–activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.

scholarly journals The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta

Epigenomes ◽  
2020 ◽  
Vol 4 (3) ◽  
pp. 20
Author(s):  
Ana M. Mesa ◽  
Cheryl S. Rosenfeld ◽  
Geetu Tuteja ◽  
Theresa I. Medrano ◽  
Paul S. Cooke
Keyword(s):  
Critical Role ◽  
Histone H3 ◽  
Gene Promoter ◽  
Epigenetic Changes ◽  
Promoter Regions ◽  
Polycomb Repressive Complex 2 ◽  
Gene Sets ◽  
Ezh2 Expression ◽  
And Function ◽  
Transcription Enhancer

Epigenetic modifications regulate normal physiological, as well as pathological processes in various organs, including the uterus and placenta. Both organs undergo dramatic and rapid restructuring that depends upon precise orchestration of events. Epigenetic changes that alter transcription and translation of gene-sets regulate such responses. Histone modifications alter the chromatin structure, thereby affecting transcription factor access to gene promoter regions. Binding of histones to DNA is regulated by addition or removal of subunit methyl and other groups, which can inhibit or stimulate transcription. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) and subsequently suppresses transcription of genes bound by such histones. Uterine EZH2 expression exerts a critical role in development and function of this organ with deletion of this gene resulting in uterine hyperplasia and expression of cancer-associated transcripts. Elucidating the roles of EZH2 in uterus and placenta is essential as EZH2 dysregulation is associated with several uterine and placental pathologies. Herein, we discuss EZH2 functions in uterus and placenta, emphasizing its physiological and pathological importance.

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