Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic dysregulation in meningiomas.

ABSTRACT:

Background

Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue.

Methods

Whole-exome sequencing and methylation array profiling were performed on 12 dura/meningioma pairs (11 WHO grade I and 1 WHO grade II). Single-nucleotide polymorphism (SNP) genotyping and methylation array profiling were performed on an additional 19 meningiomas (9 WHO grade I, 5 WHO grade II, 4 WHO grade III).

Results

Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower-grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increasing histopathologic grade.

Conclusion

These findings support future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in meningioma formation as well as studies of the utility of polycomb inhibitors for the treatment of malignant meningiomas.

SUBMITTER: Wedemeyer MA

PROVIDER: S-EPMC9234763 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Epigenetic dysregulation in follicular lymphoma.

Project description:The adoption of next-generation sequencing technologies has led to a remarkable shift in our understanding of the genetic landscape of follicular lymphoma. While the disease has been synonymous with the t(14;18), the prevalence of alterations in genes that regulate the epigenome has been established as a pivotal hallmark of these lymphomas. Giant strides are being made in unraveling the biological consequences of these alterations in tumorigenesis opening up new opportunities for directed therapies.

| S-EPMC4864036 | biostudies-literature

Epigenetic Dysregulation of Myeloproliferative Neoplasms.

Project description:This article reviews the genetic data on epigenetic modifying mutations in myeloproliferative neoplasms and their clinical implications, preclinical studies exploring our current understanding of how mutations in epigenetic modifying proteins cooperate with myeloproliferative neoplasms drivers to promote disease progression, and recent advances in novel therapeutics supporting the role of targeting epigenetic pathways to treat fibrotic progression.

| S-EPMC7927771 | biostudies-literature

Epigenetic dysregulation of TET2 in human glioblastoma.

Project description:Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma.

| S-EPMC5995234 | biostudies-literature

Epigenetic dysregulation from chromosomal transit in micronuclei.

Project description:Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

| S-EPMC10322720 | biostudies-literature

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas.

Project description:Meningiomas are the most common primary central nervous system tumors. 20-30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.

| S-EPMC8303324 | biostudies-literature

Epigenetic dysregulation in the developing Down syndrome cortex.

Project description:Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.

| S-EPMC4990229 | biostudies-literature

Epigenetic Dysregulation in <i>MYCN</i>-Amplified Neuroblastoma.

Project description:Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the MYCN oncogene. Epigenetic factors play a pivotal role in normal neural crest and NB development, influencing gene expression patterns critical for tumorigenesis. This review delves into the multifaceted interplay between MYCN and known epigenetic modifications during NB genesis, shedding light on the intricate regulatory networks underlying the disease. We provide an extensive survey of known epigenetic mechanisms, encompassing DNA methylation, histone modifications, non-coding RNAs, super-enhancers (SEs), bromodomains (BET), and chromatin modifiers in MYCN-amplified (MNA) NB. These epigenetic changes collectively contribute to the dysregulated gene expression landscape observed in MNA NB. Furthermore, we review emerging therapeutic strategies targeting epigenetic regulators, including histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), and DNA methyltransferase inhibitors (DNMTi). We also discuss and summarize current drugs in preclinical and clinical trials, offering insights into their potential for improving outcomes for MNA NB patients.

| S-EPMC10707345 | biostudies-literature

Epigenetic Dysregulation at the Crossroad of Women's Cancer.

Project description:An increasingly number of women of all age groups are affected by cancer, despite substantial progress in our understanding of cancer pathobiology, the underlying genomic alterations and signaling cascades, and cellular-environmental interactions. Though our understanding of women's cancer is far more complete than ever before, there is no comprehensive model to explain the reasons behind the increased incidents of certain reproductive cancer among older as well as younger women. It is generally suspected that environmental and life-style factors affecting hormonal and growth control pathways might help account for the rise of women's cancers in younger age, as well, via epigenetic mechanisms. Epigenetic regulators play an important role in orchestrating an orderly coordination of cellular signals in gene activity in response to upstream signaling and/or epigenetic modifiers present in a dynamic extracellular milieu. Here we will discuss the broad principles of epigenetic regulation of DNA methylation and demethylation, histone acetylation and deacetylation, and RNA methylation in women's cancers in the context of gene expression, hormonal action, and the EGFR family of cell surface receptor tyrosine kinases. We anticipate that a better understanding of the epigenetics of women's cancers may provide new regulatory leads and further fuel the development of new epigenetic biomarkers and therapeutic approaches.

| S-EPMC6721458 | biostudies-literature

Rewiring the Epigenetic Networks in MLL-Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions.

Project description:Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL or KMT2A) are highly prevalent in pediatric oncology. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The resulting chimeric products of MLL gene rearrangements, i.e., MLL-fusion proteins (MLL-FPs), are capable of transforming hematopoietic stem/progenitor cells (HSPCs) into leukemic blasts. The ability of MLL-FPs to reprogram HSPCs toward leukemia requires the involvement of multiple chromatin effectors, including the histone 3 lysine 79 methyltransferase DOT1L, the chromatin epigenetic reader BRD4, and the super elongation complex. These epigenetic regulators constitute a complicated network that dictates maintenance of the leukemia program, and therefore represent an important cluster of therapeutic opportunities. In this review, we will discuss the role of MLL and its fusion partners in normal HSPCs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of MLL-r leukemias.

| S-EPMC6529847 | biostudies-literature

Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity.

Project description:B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated by autoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens and signals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells. Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switch DNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatory processes may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemic lupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generation sequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cell biology and its role in autoimmune development. Thus this review aims to summarize current research progress in epigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmune conditions such as lupus, rheumatoid arthritis and type 1 diabetes.

| S-EPMC6123482 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data