scholarly journals DIPG-12. TARGETING EPIGENETIC MODIFIERS TO INDUCE IMMUNE SIGNALING IN DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii289-iii289
Author(s):  
Ashley Tetens ◽  
Allison Martin ◽  
Antje Arnold ◽  
Orlandi Novak ◽  
Charles Eberhart ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Tumor Antigens ◽  
Hdac Inhibitors ◽  
Gene Expression Signature ◽  
Type I ◽  
Interferon Signaling ◽  
Dna Hypomethylation ◽  
Dna Methyltransferase Inhibitors ◽  
Genome Wide ◽  
Major Histocompatibility Complexes

Abstract DIPG is a universally fatal pediatric brainstem tumor with no effective therapy. Recent work has shown that over 80% of DIPG cases harbor the H3K27M mutation leading to global loss of the repressive H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression signature. We sought to exploit epigenetic vulnerabilities in DIPG through the use of DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. We find that treatment with low-dose 5-aza-2’-deoxycytidine (decitabine), alone and in combination with HDAC inhibitors, elicits profound genome-wide demethylation in DIPG patient-derived neurosphere cell lines, impairs proliferation, and induces apoptosis. We show that this treatment induces immune activation, with induction of type I interferon signaling, increased expression of major histocompatibility complexes, and expression of tumor antigens. These results suggest that the immunogenicity of DIPG may be modulated by epigenetic therapies, suggesting the possibility of novel combination approaches to immunotherapy of DIPG in the future.

Genetic vs. Epigenetic Disruption of the CEBPA Locus Yields Epigenomically and Biologically Distinct Leukemia Phenotypes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2117-2117 ◽  
Author(s):  
Maria E. Figueroa ◽  
Bas J. Wouters ◽  
Yushan Li ◽  
Peter Valk ◽  
Bob Lowenberg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Biological Difference ◽  
Significance Level ◽  
Dna Methyltransferase Inhibitors ◽  
Genome Wide ◽  
P38mapk Signaling ◽  
Cebpa Mutations

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints. In order to resolve some of this complexity, a recent microarray-based expression profiling study segregated cohorts of patients with common gene signatures. One of these signatures was associated with alterations of the CCAAT/enhancer-binding protein alpha (CEBPA) gene. Among these patients, a subset harbored CEBPA mutations, while the remainder failed to express CEBPA, which in a number of cases correlated with hypermethylation of its promoter. This latter subgroup of leukemias with silenced CEBPA presented with significant biological differences compared to CEBPA mutant patients, including expression of T-cell markers and activating mutations of NOTCH1 (Wouters BJ et. al., PMID:17671232). Since our preliminary data show that DNA methylation profiling is extremely accurate in identifying distinct biological phenotypes in AML and other tumors, we wondered whether genome-wide epigenetic analysis would identify the biological difference between these patients. In order to determine the DNA methylation profiles of these patients we performed HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR), a quantitative genome-wide DNA methylation method, using a 400,000 feature cutom-desinged microarray, representing 24,000 gene promoters with 50-mer oligonucleotides. We studied the complete previously identified cluster of AML cases presenting with a CEBPA expression signature, and compared and contrasted the DNA methylation profiles of cases carrying the CEBPA mutation and those presenting with CEBPA silencing. Remarkably, unsupervised (unbiased) clustering of DNA methylation profiles revealed that samples were readily segregated into two groups that overlapped perfectly with the presence or absence of the CEBPA mutation, indicating the presence of underlying genome-wide DNA methylation differences between these two groups. We next performed supervised analysis of the samples to compare the DNA methylation profiles of CEBPA mutated vs. CEBPA non-mutated samples. The analysis was performed using a moderated T test, and 291 genes promoters were identified as differentially methylated between the two groups at a significance level of p <0.001. Within this differentially methylated signature, we detected a clear predominance (90%) of hypermethylated genes in the CEBPA silenced group. The critical importance of CEBPA loss of function in mediating the phenotype of these tumors was underlined by the fact that multiple other members of the CEBPA network were likewise hypermethylated. Other than the CEBPA network, the two other most hypermethylated biological pathways involved p38MAPK signaling and PDGF/LCK signaling. Thus, we conclude i) that hypermethylation of the CEBPA promoter is not an isolated event, but rather part of a more widespread epigenetic regulation, and ii) that the original CEBPA signature group is composed of two distinct subgroups originating through two distinct mechanisms, a genetic one and an epigenetic one. The significance of these findings may be supported by the fact that the hypermethylated cohort of patients tended to show a worse prognosis than CEBPA mutant patients. These patients might be good candidates for DNA methyltransferase inhibitors in prospective clinical trials.

scholarly journals Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

2018 ◽  
Author(s):  
Aaron R Jeffries ◽  
Reza Maroofian ◽  
Claire G. Salter ◽  
Barry A. Chioza ◽  
Harold E. Cross ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Biological Aging ◽  
Growth Disorders ◽  
Sotos Syndrome ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Epigenetic Aging ◽  
Methylation Patterns

AbstractGermline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

scholarly journals Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive demethylation in mammals

2018 ◽  
Author(s):  
Christopher B. Mulholland ◽  
Atsuya Nishiyama ◽  
Joel Ryan ◽  
Ryohei Nakamura ◽  
Merve Yiğit ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Ectopic Expression ◽  
Dna Demethylation ◽  
Mammalian Development ◽  
Dna Hypomethylation ◽  
Tet Proteins ◽  
Genome Wide ◽  
Recent Emergence ◽  
High Conservation ◽  
Early Mammalian Development

AbstractGenome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.

scholarly journals Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype

2021 ◽  
Vol 118 (16) ◽  
pp. e2022760118
Author(s):  
David Y. Chen ◽  
Ian M. Ferguson ◽  
Krista A. Braun ◽  
Leslie A. Sutton ◽  
Nichole M. Helton ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Cellular Proliferation ◽  
De Novo ◽  
Mouse Skin ◽  
Gene Expression Signature ◽  
Epidermal Cells ◽  
Dominant Negative ◽  
Dna Hypomethylation ◽  
Increased Risk ◽  
Risk Of Cancer

DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3AR882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin.

Identification of key mRNAs and lncRNAs involved in the effects of anti-TWEAK on Osteosarcoma

2020 ◽  
Vol 15 ◽  
Author(s):  
Mingxuan Yang ◽  
Liangtao Zhao ◽  
Xuchang Hu ◽  
Haijun Feng ◽  
Xuewen Kang
Keyword(s):  
Dna Replication ◽  
Signaling Pathway ◽  
Bioinformatics Analysis ◽  
Mapk Signaling ◽  
Migration And Invasion ◽  
Type I ◽  
Interferon Signaling ◽  
Nf Kappa B ◽  
Ppi Networks ◽  
Coexpression Networks

Background: Osteosarcoma (OS) is one of the most common primary malignant bone tumors in teenagers. Emerging studies demonstrated TWEAK and Fn14 were involved in regulating cancer cell differentiation, proliferation, apoptosis, migration and invasion. Objective: The present study identified differently expressed mRNAs and lncRNAs after anti-TWEAK treatment in OS cells using GSE41828. Methods: We identified 922 up-regulated mRNAs, 863 downregulated mRNAs, 29 up-regulated lncRNAs, and 58 down-regulated lncRNAs after anti-TWEAK treatment in OS cells. By constructing PPI networks, we identified several key proteins involved in anti-TWEAK treatment in OS cells, including MYC, IL6, CD44, ITGAM, STAT1, CCL5, FN1, PTEN, SPP1, TOP2A, and NCAM1. By constructing lncRNAs coexpression networks, we identified several key lncRNAs, including LINC00623, LINC00944, PSMB8-AS1, LOC101929787. Result: Bioinformatics analysis revealed DEGs after anti-TWEAK treatment in OS were involved in regulating type I interferon signaling pathway, immune response related pathways, telomere organization, chromatin silencing at rDNA, and DNA replication. Bioinformatics analysis revealed differently expressed lncRNAs after antiTWEAK treatment in OS were related to telomere organization, protein heterotetramerization, DNA replication, response to hypoxia, TNF signaling pathway, PI3K-Akt signaling pathway, Focal adhesion, Apoptosis, NF-kappa B signaling pathway, MAPK signaling pathway, FoxO signaling pathway. Conclusion: : This study provided useful information for understanding the mechanisms of TWEAK underlying OS progression and identifying novel therapeutic markers for OS.

scholarly journals Genome-wide identification and expression pattern analysis of lipoxygenase gene family in banana

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fan Liu ◽  
Hua Li ◽  
Junwei Wu ◽  
Bin Wang ◽  
Na Tian ◽  
...  
Keyword(s):  
High Temperature ◽  
Low Temperature ◽  
Pcr Analysis ◽  
Type I ◽  
Segmental Duplications ◽  
Expression Levels ◽  
Genome Wide ◽  
Encoded Proteins ◽  
Gene Structures ◽  
Lipoxygenase Gene Family

AbstractThe LOX genes have been identified and characterized in many plant species, but studies on the banana LOX genes are very limited. In this study, we respectively identified 18 MaLOX, 11 MbLOX, and 12 MiLOX genes from the Musa acuminata, M. balbisiana and M. itinerans genome data, investigated their gene structures and characterized the physicochemical properties of their encoded proteins. Banana LOXs showed a preference for using and ending with G/C and their encoded proteins can be classified into 9-LOX, Type I 13-LOX and Type II 13-LOX subfamilies. The expansion of the MaLOXs might result from the combined actions of genome-wide, tandem, and segmental duplications. However, tandem and segmental duplications contribute to the expansion of MbLOXs. Transcriptome data based gene expression analysis showed that MaLOX1, 4, and 7 were highly expressed in fruit and their expression levels were significantly regulated by ethylene. And 11, 12 and 7 MaLOXs were found to be low temperature-, high temperature-, and Fusarium oxysporum f. sp. Cubense tropical race 4 (FocTR4)-responsive, respectively. MaLOX8, 9 and 13 are responsive to all the three stresses, MaLOX4 and MaLOX12 are high temperature- and FocTR4-responsive; MaLOX6 and MaLOX17 are significantly induced by low temperature and FocTR4; and the expression of MaLOX7 and MaLOX16 are only affected by high temperature. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression levels of several MaLOXs are regulated by MeJA and FocTR4, indicating that they can increase the resistance of banana by regulating the JA pathway. Additionally, the weighted gene co-expression network analysis (WGCNA) of MaLOXs revealed 3 models respectively for 5 (MaLOX7-11), 3 (MaLOX6, 13, and 17), and 1 (MaLOX12) MaLOX genes. Our findings can provide valuable information for the characterization, evolution, diversity and functionality of MaLOX, MbLOX and MiLOX genes and are helpful for understanding the roles of LOXs in banana growth and development and adaptations to different stresses.

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