scholarly journals H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Dong Fang ◽  
Haiyun Gan ◽  
Liang Cheng ◽  
Jeong-Heon Lee ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Wilms Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Suppressor Genes ◽  
Mutant Proteins ◽  
Specific Tumor ◽  
Mutant Cells ◽  
Global Reduction

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

scholarly journals H3K27me3-mediated silencing of Wilms Tumor 1 supports the proliferation of brain tumor cells harboring the H3.3K27M mutation

2017 ◽  
Author(s):  
Dong Fang ◽  
Haiyun Gan ◽  
Liang Cheng ◽  
Jeong-Heon Lee ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Suppressor Gene ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Mutant Proteins ◽  
Brain Tumor Cells ◽  
Wilms Tumor 1 ◽  
Global Reduction

AbstractThe lysine 27 to methionine mutation of histone H3.3 (H3.3K27M) is detected in over 75% of diffuse intrinsic pontine glioma (DIPG). The H3.3K27M mutant proteins inhibit H3K27 methyltransferase complex PRC2, resulting in a global reduction of tri-methylation of H3K27 (H3K27me3). Paradoxically, high levels of H3K27me3 were also detected at hundreds of genomic loci. However, it is not known how and why H3K27me3 is redistributed in DIPG cells. Here we show that lower levels of H3.3K27M mutant proteins at some genomic loci contribute to the retention of H3K27me3 peaks. But more importantly, Jarid2, a PRC2-associated protein, strongly correlates the presence of H3K27me3 and relieves the H3.3K27M-mediated inhibition in vivo and in vitro. Furthermore, we show that H3K27me3-mediated silencing of tumor suppressor gene Wilms Tumor 1 (WT1) supports the proliferation of DIPG cells and reaction of WT1 inhibits DIPG proliferation. Together, these studies reveal mechanisms whereby H3K27me3 is retained in the environment of global loss of this mark, and how persistence of this mark contributes to DIPG tumorigenesis.

Two candidate tumor suppressor genes,MEOX2andSOSTDC1, identified in a 7p21 homozygous deletion region in a Wilms tumor

2009 ◽  
Vol 48 (12) ◽  
pp. 1037-1050 ◽  
Author(s):  
Junjiro Ohshima ◽  
Masayuki Haruta ◽  
Yasuhito Arai ◽  
Fumio Kasai ◽  
Yuiko Fujiwara ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Wilms Tumor ◽  
Homozygous Deletion ◽  
Suppressor Genes ◽  
Deletion Region ◽  
Candidate Tumor Suppressor

scholarly journals Identification of Molecular Biomarkers in Taiwanese Patients with Wilms Tumor Using a Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)-Based Approach

2020 ◽  
Author(s):  
Meng-Yao Lu ◽  
Wen-Chung Wang ◽  
Tai-Cheng Hou ◽  
Chen-Yun Kuo ◽  
Yen-Chein Lai
Keyword(s):  
Tumor Suppressor ◽  
Solid Tumor ◽  
Tumor Suppressor Genes ◽  
Mixed Type ◽  
Wilms Tumor ◽  
Promoter Regions ◽  
Suppressor Genes ◽  
Normal Tissues ◽  
Predominant Type ◽  
Dependent Probe

Abstract Background: Wilms tumor is a solid tumor that frequently occurs in children. Genetic or epigenetic aberrations in WT1 and WT2 loci are implicated in its etiology. Moreover, tumor suppressor genes are frequently silenced by methylation in this tumor. Methods: In the present study, we analyzed the methylation statuses of promoter regions of 24 different tumor suppressor genes using a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach in six Wilms tumors. Results: All six Wilms tumors showed methylation of RASSF1 specific to tumors, not in normal tissues. Moreover, methylated HIC1 was identified in stromal type Wilms tumors and methylated BRCA1 was identified in epithelial type Wilms tumors. Unmethylated CASP8, RARB, MLH1_167, APC, and CDKN2A were found only in blastemal predominant type Wilms tumors. Conclusions: Our results indicated that methylation of RASSF1 is the essential event in the tumorigenesis of Wilms tumor, which may inform its clinical and therapeutic management. In addition, mixed type Wilms tumors may be classified according to epithelial, stromal, and blastemal components via MS-MLPA-based approach.

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