scholarly journals EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

2021 ◽  
Vol 22 (20) ◽  
pp. 11292
Author(s):  
Barbara Kunzler Souza ◽  
Natalia Hogetop Freire ◽  
Mariane Jaeger ◽  
Caroline Brunetto de Farias ◽  
Algemir L. Brunetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Brain Cancer ◽  
Adult Brain ◽  
Post Translational Modifications ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Cancer Types

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

scholarly journals EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

2021 ◽  
Author(s):  
Barbara Kunzler Souza ◽  
Natalia Hogetop Freire ◽  
Mariane Jaeger ◽  
Caroline Brunetto de Farias ◽  
Algemir Lunardi Brunetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Brain Cancer ◽  
Adult Brain ◽  
Normal Tissues ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Development And Differentiation

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development, and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), regulates changes in gene expression involved in embryonic development and differentiation of normal tissues. Overexpression of G9a has been observed in in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma multiforme (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. G9a inhibition dose-dependently reduces the viability of MB cells. Transcriptional levels of G9a are higher in MB tumors belonging to the SHH, Group 3, and Group 4, compared to Wnt tumors, and higher G9a gene expression may be a predictor of poor prognosis in patients with MB.

scholarly journals Long non-coding RNAs in brain tumors

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Keisuke Katsushima ◽  
George Jallo ◽  
Charles G Eberhart ◽  
Ranjan J Perera
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Brain Cancer ◽  
Regulation Of Gene Expression ◽  
Therapeutic Targets ◽  
Diagnostic Biomarkers ◽  
Cancer Pathogenesis ◽  
Current State ◽  
Non Coding Rnas ◽  
Post Transcriptional Regulation

Abstract Long non-coding RNAs (lncRNAs) have been found to be central players in the epigenetic, transcriptional and post-transcriptional regulation of gene expression. There is an accumulation of evidence on newly discovered lncRNAs, their molecular interactions and their roles in the development and progression of human brain tumors. LncRNAs can have either tumor suppressive or oncogenic functions in different brain cancers, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. Here, we summarize the current state of knowledge of the lncRNAs that have been implicated in brain cancer pathogenesis, particularly in gliomas and medulloblastomas. We discuss their epigenetic regulation as well as the prospects of using lncRNAs as diagnostic biomarkers and therapeutic targets in patients with brain tumors.

scholarly journals The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development

2015 ◽  
Vol 21 (10) ◽  
pp. 1199-1208 ◽  
Author(s):  
Ana Ortega-Molina ◽  
Isaac W Boss ◽  
Andres Canela ◽  
Heng Pan ◽  
Yanwen Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Expression Program ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Expression Program

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Seungil Paik ◽  
Francesca Maule ◽  
Marco Gallo
Keyword(s):  
Brain Tumors ◽  
Cell Fate ◽  
Three Dimensional ◽  
Genetic Alterations ◽  
Adult Brain ◽  
Post Translational Modifications ◽  
3D Genome ◽  
Differentiated Cells ◽  
Aberrant Dna Methylation ◽  
And Function

The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of “epigenomic erosion” to explain the transition from stem-like cells to differentiated cells in hierarchically organized brain cancers.

RNA profiling of neuroendocrine tumors (NETs) to define new targets and mechanisms of progression.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 302-302
Author(s):  
Namrata Vijayvergia ◽  
Suraj Peri ◽  
Karthik Devarajan ◽  
Jianming Pei ◽  
Yulan Gong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Drug Targets ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
Rna Profiling ◽  
Histone Lysine Methyltransferase ◽  
Canonical Pathways ◽  
Lysine Methyltransferase

302 Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]

Essential Cytoplasmic Role of the Histone Lysine Methyltransferase Setdb1 in Post-Transcriptional Regulation in Embryonic Stem Cells

2021 ◽  
Author(s):  
Roberta Rapone ◽  
Laurence Del Maestro ◽  
Costas Bouyioukos ◽  
Sonia Albini ◽  
Paola Cruz-Tapias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcriptional Regulation ◽  
Mrna Stability ◽  
Regulation Of Gene Expression ◽  
Embryonic Stem ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Post Transcriptional Regulation

Abstract Embryonic stem cells (ESCs) fate is regulated both at transcriptional and post-transcriptional levels. Indeed, several studies showed that, in addition to gene transcription, mRNA stability and protein synthesis are finely tuned and strongly control the ESCs pluripotency and fate changes. An increasing number of RNA-binding proteins (RBPs) involved in post-transcriptional and translational regulation of gene expression has been identified as regulators of ESC identity. The major lysine methyltransferase Setdb1 is essential for the self-renewal and viability of ESCs. Setdb1 was primarily known to methylate the lysine 9 of histone 3 (H3K9) in the nucleus, where it regulates chromatin functions. However, Setdb1 is also massively localized in the cytoplasm, including in mouse ESCs, where its role remains unknown. Here we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Functional assays further demonstrate that cSetdb1 regulates gene expression post-transcriptionally, affecting the abundance of mRNAs and the rate of newly synthetized proteins. A yeast-two-hybrid assay shows that cSetdb1 interacts with several regulators of mRNA stability and protein translation machinery, such as the ESCs-specific E3 ubiquitin ligase and mRNA silencer Trim71/Lin41. Finally, proteomic analyses reveal that cSetdb1 is required for the integrity of Trim71 complexes involved in mRNA metabolism and translation. Altogether, our data uncover the essential cytoplasmic function of a firstly supposed nuclear “histone” lysine methyltransferase, Setdb1, and provide new insights into the cytoplasmic/post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

scholarly journals Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function

2010 ◽  
Vol 207 (5) ◽  
pp. 915-922 ◽  
Author(s):  
Bernhard Lehnertz ◽  
Jeffrey P. Northrop ◽  
Frann Antignano ◽  
Kyle Burrows ◽  
Sima Hadidi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
T Helper ◽  
Trichuris Muris ◽  
Th Cells ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
And Function

Accumulating evidence suggests that the regulation of gene expression by histone lysine methylation is crucial for several biological processes. The histone lysine methyltransferase G9a is responsible for the majority of dimethylation of histone H3 at lysine 9 (H3K9me2) and is required for the efficient repression of developmentally regulated genes during embryonic stem cell differentiation. However, whether G9a plays a similar role in adult cells is still unclear. We identify a critical role for G9a in CD4+ T helper (Th) cell differentiation and function. G9a-deficient Th cells are specifically impaired in their induction of Th2 lineage-specific cytokines IL-4, IL-5, and IL-13 and fail to protect against infection with the intestinal helminth Trichuris muris. Furthermore, G9a-deficient Th cells are characterised by the increased expression of IL-17A, which is associated with a loss of H3K9me2 at the Il17a locus. Collectively, our results establish unpredicted and complex roles for G9a in regulating gene expression during lineage commitment in adult CD4+ T cells.

scholarly journals Histone Lysine Methyltransferase SDG8 Is Involved in Brassinosteroid-Regulated Gene Expression in Arabidopsis thaliana

2014 ◽  
Vol 7 (8) ◽  
pp. 1303-1315 ◽  
Author(s):  
Xiaolei Wang ◽  
Jiani Chen ◽  
Zhouli Xie ◽  
Sanzhen Liu ◽  
Trevor Nolan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Regulated Gene Expression

scholarly journals ATIM-02. A NEW SOURCE OF NEOANTIGENS FOR PEDIATRIC AND ADULT BRAIN CANCER VACCINES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Stephen Albert Johnston ◽  
Milene Peterson ◽  
Chris Diehnelt ◽  
Luhui Shen
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Brain Tumors ◽  
Mouse Model ◽  
Brain Cancer ◽  
Cancer Vaccines ◽  
Rich Source ◽  
Adult Brain ◽  
Tumor Type ◽  
Therapeutic Vaccines

Abstract The paucity of mutations in pediatric and adult brain tumors has limited the ability to design therapeutic personal cancer vaccines. However, we have discovered that, in contrast to mutations in DNA, RNA is a rich source of frameshift neoantigens produced by mis-splicing of exons or indels from transcription through micro satellites. We have found that in GBM there are an average of 4000 such FS neoantigens per patient and in DIPG an average of at least 500 FS neoantigens/patient. Approximately 20% of these neoantigens are frequently recurrent across different patients. This has allowed us to design pre-synthesized vaccines for each tumor type. The vaccines consist of 20 -30 FS epitopes that are predicted to be present in at least 20% of all patient’s tumor. Each patient would have a 90% chance of having at least 50% of the peptides in their tumor. This type of “FAST” vaccine is much less expensive than a personal vaccine, any patient could be treated and there would be no delay in producing the vaccine. We have directly compared the efficacy of a FAST and personal vaccines in a mouse model of breast cancer. We find that both approaches have comparable protection though there are some interesting differences. We suggest that FAST vaccines may be a useful approach to developing therapeutic vaccines for brain cancers. We also demonstrate that an array of the 400K possible FS neoantigen peptides can be used to assay which neoantigens the patient has developed antibodies to. This array was useful in discovering the FAST vaccine components and could also be used to determine the pre-existing overlap of a FAST vaccine with the patient’s immune response.

scholarly journals The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw7965 ◽  
Author(s):  
Cristina Molnar ◽  
Jan Peter Heinen ◽  
Jose Reina ◽  
Salud Llamazares ◽  
Emilio Palumbo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Quantitative Proteomics ◽  
Human Cancer ◽  
Malignant Neoplasms ◽  
Male And Female ◽  
Phd Finger ◽  
Male Predominance ◽  
Finger Protein ◽  
Cancer Types

The notable male predominance across many human cancer types remains unexplained. Here, we show that Drosophila l(3)mbt brain tumors are more invasive and develop as malignant neoplasms more often in males than in females. By quantitative proteomics, we have identified a signature of proteins that are differentially expressed between male and female tumor samples. Prominent among them is the conserved chromatin reader PHD finger protein 7 (Phf7). We show that Phf7 depletion reduces sex-dependent differences in gene expression and suppresses the enhanced malignant traits of male tumors. Our results identify potential regulators of sex-linked tumor dimorphism and show that these genes may serve as targets to suppress sex-linked malignant traits.

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