scholarly journals Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad

2014 ◽  
Vol 21 (4) ◽  
pp. 567-577 ◽  
Author(s):  
Florian Haller ◽  
Evgeny A Moskalev ◽  
Fabio R Faucz ◽  
Sarah Barthelmeß ◽  
Stefan Wiemann ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Level ◽  
Gene Locus ◽  
Cpg Islands ◽  
Tumor Development ◽  
Rare Condition ◽  
Methylation Pattern ◽  
Dna Hypermethylation ◽  
Carney Triad ◽  
Alternate Mechanism

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney–Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

scholarly journals DNA Methylation and Genetic Aberrations in Gastric Cancer

Digestion ◽  
2020 ◽  
pp. 1-8
Author(s):  
Genki Usui ◽  
Keisuke Matsusaka ◽  
Yasunobu Mano ◽  
Masayuki Urabe ◽  
Sayaka Funata ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Tyrosine Kinases ◽  
Cpg Islands ◽  
Gene Mutations ◽  
Gastric Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Dna Hypermethylation ◽  
Genomic Amplification ◽  
Genetic Aberrations

<b><i>Background:</i></b> Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. <b><i>Summary:</i></b> Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows <i>CDKN2A</i> silencing, <i>PIK3CA</i> mutations, <i>PD-L1/2</i> overexpression, and lack of <i>TP53</i> mutations. MSI, exhibiting high DNA methylation, often has <i>MLH1</i> silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows <i>CDH1/RHOA</i> mutations or <i>CLDN18–ARHGAP</i> fusion. CIN is generally an intestinal-type GC and frequently has <i>TP53</i> mutations and genomic amplification of receptor tyrosine kinases. <b><i>Key Messages:</i></b> The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

Changes in methylation patterns of multiple genes from peripheral blood leucocytes of Alzheimer's disease patients

2013 ◽  
Vol 25 (2) ◽  
pp. 66-76 ◽  
Author(s):  
Yaping Hou ◽  
Huayun Chen ◽  
Qiong He ◽  
Wei Jiang ◽  
Tao Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Methylation Level ◽  
Target Genes ◽  
Normal Population ◽  
Cpg Islands ◽  
Methylation Pattern ◽  
Control Group ◽  
Specific Pcr

BackgroundEfforts aiming at identifying biomarkers and corresponding methods for early diagnosis of Alzheimer's disease (AD) might be the most appropriate strategy to initiate promising new treatments and/or prevention of ADObjectiveThe aim of our study is to assess the association of DNA methylation pattern of various leucocyte genes with AD pathogenesis in order to find potential biomarkers and corresponding methods for molecular diagnosis of AD.MethodsDNA methylation level of various genes in AD patients and normal population were compared by bisulphite sequencing PCR and methylation-specific PCR (MSP). Furthermore, real-time PCR was used to explore the effects of DNA methylation on the expression of target genes.ResultsResults showed significant hypermethylation of mammalian orthologue of Sir2 (SIRT1) gene in AD patients compared with normal population. Meanwhile, changes in methylation level of SIRT1 gene between different severities of AD were also found. Specific primers were designed from the SIRT1 CpG islands to differentiate AD and control group by MSP method. Besides, significant demethylation of β-amyloid precursor protein (APP) gene was observed in AD patients, whereas no difference was observed in other AD-related genes. Moreover, significant decrease in expression of SIRT1 gene and increase in expression of APP gene were also found in AD patients. In addition, the expression level of SIRT1/APP genes was associated with the severity, but not with the age or gender, of AD patients.Conclusion:SIRT1 and APP might be the interesting candidate biomarkers and valuable for clinical diagnosis or treatment of AD.

scholarly journals Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3098-3108 ◽  
Author(s):  
Thomas A. Paul ◽  
Juraj Bies ◽  
Donald Small ◽  
Linda Wolff
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Transcriptional Repression ◽  
Trichostatin A ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Methylation Pattern ◽  
Dna Hypermethylation ◽  
Polycomb Repression ◽  
On Chip

Abstract DNA hypermethylation of the p15INK4b tumor suppressor gene is commonly observed in acute myeloid leukemia (AML). Repressive histone modifications and their associated binding proteins have been implicated in the regulation of DNA methylation and the transcriptional repression of genes with DNA methylation. We have used high-density chromatin immunoprecipitation-on-chip to determine the histone modifications that normally regulate p15INK4b expression in AML cells and how these marks are altered in cells that have p15INK4b DNA methylation. In AML patient blasts without p15INK4b DNA methylation, a bivalent pattern of active (H3K4me3) and repressive (H3K27me3) modifications exist at the p15INK4b promoter. AML patient blasts with p15INK4b DNA methylation lose H3K4me3 at p15INK4b and become exclusively marked by H3K27me3. H3K27me3, as well as EZH2, extends throughout p14ARF and p16INK4a, indicating that polycomb repression of p15INK4b is a common feature in all AML blasts irrespective of the DNA methylation status of the gene. Reactivation of p15INK4b expression in AML cell lines and patient blasts using 5-aza-2′-deoxycytidine (decitabine) and trichostatin A increased H3K4me3 and maintained H3K27me3 enrichment at p15INK4b. These data indicate that AML cells with p15INK4b DNA methylation have an altered histone methylation pattern compared with unmethylated samples and that these changes are reversible by epigenetic drugs.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Author(s):  
Jean S Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurelie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression. It is now well established that tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) of methylation marks in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark known to be deposited during progression of the transcription machinery and to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of increased DNA methylation in the MAGEA6/GABRA3 locus. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo- and hypermethylation. In several of these loci, DNA hypermethylation affected tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands

2021 ◽  
Vol 5 (1) ◽  
pp. e202101228
Author(s):  
Xiaokang Wang ◽  
Wojciech Rosikiewicz ◽  
Yurii Sedkov ◽  
Tanner Martinez ◽  
Baranda S Hansen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Cpg Islands ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Genome Wide ◽  
Associated Proteins ◽  
Tet Enzymes ◽  
Tet Protein ◽  
First Time

DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.

scholarly journals High Resolution Genome Wide DNA Methylation Analysis in a Large Trial Group Reveals a Novel Epigenetically Defined Subgroup of Myeloma Patients Characterized By Developmental Gene Hypermethylation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2189-2189
Author(s):  
Martin F Kaiser ◽  
Alexander Murison ◽  
Charlotte Pawlyn ◽  
Eileen M Boyle ◽  
David C Johnson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Resolution ◽  
Methylation Pattern ◽  
Gene Set Enrichment Analysis ◽  
Epigenetic Changes ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Epigenetic Programming ◽  
Genome Wide ◽  
Dna Methylation Pattern

Abstract Introduction Multiple myeloma is a clinically highly heterogeneous disease, which is reflected by both a complex genome and epigenome. Dynamic epigenetic changes are involved at several stages of myeloma biology, such as transformation and disease progression. Our previous genome wide epigenetic analyses identified prognostically relevant DNA hypermethylation at specific tumor suppressor genes (Kaiser MF et al., Blood 2013), indicating that specific epigenetic programming influences clinical behavior. This clinically relevant finding prompted further investigation of the epigenomic structure of myeloma and its interaction with genetic aberrations. Material and Methods Genome wide DNA methylation of CD138-purified myeloma cells from 464 patients enrolled in the NCRI Myeloma XI trial at presentation were analyzed using the high resolution 450k DNA methylation array platform (Illumina). In addition, 4 plasma cell leukemia (PCL) cases (two t(11;14) and two (4;14)) and 7 myeloma cell lines (HMCL) carrying different translocations were analysed. Analyses were performed in R Bioconductor packages after filtering and removal of low quality and non-uniquely mapping probes. Results Variation in genome wide DNA methylation was analyzed using unsupervised hierarchical clustering of the 10,000 most variable probes, which revealed epigenetically defined subgroups of disease. Presence of recurrent IGH translocations was strongly associated with specific epigenetic profiles. All 60 cases with t(4;14) clustered into two highly similar sub-clusters, confirming that overexpression of the H3K36 methyltransferase MMSET in t(4;14) has a defined and specific effect on the myeloma epigenome. Interestingly, HMCLs KMS-11 and LP-1, which carry t(4;14), MM1.S, a t(14;16) cell line with an E1099K MMSET activating mutation as well as two PCLs with t(4;14) all clustered in one sub-clade. The majority (59/85) of t(11;14) cases showed global DNA hypomethylation compared to t(4;14) cases and clustered in one subclade, indicating a epigenetic programming effect associated with CCND1, with a subgroup of t(11;14) cases showing a variable DNA methylation pattern. In addition to translocation-defined subgroups, a small cluster of samples with a distinct epigenetic profile was identified. In total 7 cases with a shared specific DNA methylation pattern (median inter-sample correlation 0.4) were identified. The group was characterized by DNA hypermethylation (4,341 hypermethylated regions vs. 750 hypomethylated regions) in comparison to all other cases. Intersection of regions hypermethylated in this subgroups with ENCODE datasets revealed mapping to poised enhancers and promoters in H1-hESC, indicating functionally relevant epigenetic changes. Gene set enrichment analysis (KEGG) demonstrated enrichment of developmental pathway genes, e.g. Hedgehog signaling (adj p=5x10exp-13), amongst others and all four HOX clusters were differentially methylated in this group. Of note, three of seven cases in this subgroup carried a t(11;14) and all t(11;14) or t(11;14)-like HMCLs clustered closely together with these patient cases, but not with the cluster carrying the majority of t(11;14) myeloma or t(11;14) PCLs. This potentially indicates that t(11;14) HMCL could be derived from a subgroup of patients with specific epigenetic characteristics. Conclusion Our results indicate that the recurrent IGH translocations are fundamentally involved in shaping the myeloma epigenome through either direct upregulation of epigenetic modifiers (e.g. MMSET) or through insufficiently understood mechanisms. However, developmental epigenetic processes seem to independently contribute to the complexity of the epigenome in some cases. This work provides important insights into the spectrum of epigenetic subgroups of myeloma and helps identify subgroups of disease that may benefit from specific epigenetic therapies currently being developed. Disclosures Walker: Onyx Pharmaceuticals: Consultancy, Honoraria.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean S. Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurélie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Transcriptional Elongation ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

AbstractTumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Loora Laan ◽  
Joakim Klar ◽  
Maria Sobol ◽  
Jan Hoeber ◽  
Mansoureh Shahsavani ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Cpg Islands ◽  
Methylation Pattern ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Epigenetic Changes ◽  
450K Array ◽  
Neurodevelopmental Abnormalities ◽  
Induced Pluripotent

Abstract Background Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages. Results Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling. Conclusions The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.

scholarly journals Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/T-lymphoid features

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2795-2804 ◽  
Author(s):  
Maria E. Figueroa ◽  
Bas J. Wouters ◽  
Lucy Skrabanek ◽  
Jacob Glass ◽  
Yushan Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Cpg Islands ◽  
Specific Gene ◽  
Molecular Heterogeneity ◽  
Dna Hypermethylation ◽  
Genome Wide

Abstract Acute myeloid leukemia is a heterogeneous disease from the molecular and biologic standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients who shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, whereas the rest presented with silencing of this gene and coexpression of certain T-cell markers. DNA methylation studies revealed that these 2 groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA-silenced leukemias also displayed marked hypermethylation compared with normal CD34+ hematopoietic cells, whereas CEBPA mutant cases showed only mild changes in DNA methylation compared with these normal progenitors. Biologically, CEBPA-silenced leukemias presented with a decreased response to myeloid growth factors in vitro.

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