scholarly journals Does DNA Methylation Matter in FSHD?

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 258 ◽  
Author(s):  
Valentina Salsi ◽  
Frédérique Magdinier ◽  
Rossella Tupler
Keyword(s):  
Dna Methylation ◽  
Developmental Disorder ◽  
Methylation Status ◽  
Disease Status ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Icf Syndrome ◽  
D4z4 Repeat ◽  
Molecular Features ◽  
Reliable Marker ◽  
Induced Pluripotent

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

scholarly journals Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shir Toubiana ◽  
Miriam Gagliardi ◽  
Mariarosaria Papa ◽  
Roberta Manco ◽  
Maty Tzukerman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Pharmacological Intervention ◽  
Icf Syndrome ◽  
Genome Wide ◽  
Mammalian Genomes ◽  
Induced Pluripotent ◽  
Methylation Patterns

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

Aberrant DNA Methylation in Childhood Acute Lymphoblastic Leukemia as a Potential Biomarker Reflecting Disease Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2637-2637
Author(s):  
Seung Yeon Kwon ◽  
Sung Chul Won ◽  
Hyo Sun Kim ◽  
Hei-Cheul Jeung ◽  
Sun Young Rha ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complete Resolution ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Disease Status ◽  
Childhood All ◽  
Remission Status ◽  
Potential Biomarker ◽  
Aberrant Dna Methylation

Abstract Abstract 2637 Poster Board II-613 Background: Aberrant DNA methylation of promoter-associated cystosine-guanine (CpG) islands is known to play an important role in leukemogenesis and has been reported to have association with poor prognosis in acute lymphoblastic leukemia (ALL). In adult, residual methylation at clinical remission status in patients with acute myeloid leukemia and Philadelphia chromosome-positive ALL showed significant association with poor prognosis in recent studies. We analyzed 47 patients with childhood ALL to evaluate the change of methylation status from the time of diagnosis to the time at morphologic remission. Methods: We analyzed the methylation status of CDH1, p16 and DAPK genes at the time of diagnosis and at the time of morphologic remission in 47 patients using methylation specific polymerase chain reaction method with genomic DNA extracted from bone marrow (BM) aspirates. All patients were treated with standard chemotherapy and after 4 weeks, every patient achieved morphologic complete remission. Methylation status of above three genes were also analyzed with the same method in 10 BM aspirate samples from healthy BM donor for comparison. Results: CDH1 was methylated in 30 (64%) patients, p16 in 2 (4%) patients and DAPK in 6 (13%) patients at the time of diagnosis. Thirty three (70%) patients had methylation at least one gene, and 5 (11%) had methylation of 2 genes. None of the healthy BM donors showed methylation of above genes. At the time of morphologic remission, all patients who had aberrant DNA methylation of any gene at the time of diagnosis had no detectable residual methylation showing complete resolution of aberrant DNA methylation of examined genes. Clinical prognostic factors including initial white blood cell count, immunophenotype and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1) did not show any association with initial methylation status. Age was the only factor which showed correlation with methylation status; patients under 2 year old showed significantly low frequency of methylation of above three genes (p <0.001). Conclusion: Since aberrant DNA methylation of CDH1, p16 and DAPK genes were found in 70% of pretreatment ALL patients and none in healthy BM donor showing complete resolution of methylation at morphologic remission status, we cautiously suggest aberrant DNA methylation as a potential biomarker reflecting disease status in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gene-associated methylation status of ST14 as a predictor of survival and hormone receptor positivity in breast Cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang-Hong Dai ◽  
Ying-Fu Wang ◽  
Po-Chien Shen ◽  
Cheng-Hsiang Lo ◽  
Jen-Fu Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Prognostic Value ◽  
Potential Role ◽  
Cox Model ◽  
Methylation Status ◽  
Specific Gene ◽  
Molecular Features ◽  
Gene Sets

Abstract Background Genomic profiles of specific gene sets have been established to guide personalized treatment and prognosis for patients with breast cancer (BC). However, epigenomic information has not yet been applied in a clinical setting. ST14 encodes matriptase, a proteinase that is widely expressed in BC with reported prognostic value. Methods In this present study, we evaluated the effect of ST14 DNA methylation (DNAm) on overall survival (OS) of patients with BC as a representative example to promote the use of the epigenome in clinical decisions. We analyzed publicly available genomic and epigenomic data from 1361 BC patients. Methylation was characterized by the β-value from CpG probes based on sequencing with the Illumina Human 450 K platform. Results A high mean DNAm (β > 0.6779) across 34 CpG probes for ST14, as the gene-associated methylation (GAM) pattern, was associated with a longer OS after adjusting age, stage, histology and molecular features in Cox model (p value < 0.001). A high GAM status was also associated with a higher XBP1 expression level and higher proportion of hormone-positive BC (p value < 0.001). Pathway analysis revealed that altered GAM was related to matrisome-associated pathway. Conclusions Here we show the potential role of ST14 DNAm in BC prognosis and warrant further study.

scholarly journals Role of associated alleles and hypomethylation status in the clinical expression of facioscapulohumeral muscular dystrophy

2011 ◽  
Vol 152 (39) ◽  
pp. 1576-1585 ◽  
Author(s):  
Henriett Pikó ◽  
Mária Judit Molnár ◽  
Ágnes Herczegfalvi ◽  
Péter Mayer ◽  
Veronika Karcagi
Keyword(s):  
Muscular Dystrophy ◽  
Fragment Size ◽  
Restriction Analysis ◽  
Methylation Status ◽  
Prenatal Testing ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
D4z4 Repeat ◽  
Modifying Factors ◽  
Diagnostic Panel ◽  
Total Dna

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat region on 4q35. In addition, epigenetic modifying factors play a role in the complex pathomechanism of the disease. Aims: Introduction of a new diagnostic panel in Hungary for the extended molecular analysis of the disease which also provides new insights into the pathomechanism. Methods: In total, DNA samples of 185 clinically diagnosed FSHD patients and 71 asymptomatic relatives were analyzed by EcoRI and BlnI restriction digestion and Southern blot technique with probe p13-E11. Further investigations of the 4q35 alleles associated with the FSHD phenotype utilized qA and qB probes and a restriction analysis of the proximal D4Z4 unit by detecting a G/C SNP and the methylation status. Results: From the patients analyzed 115 had the D4Z4 repeat contraction, whereas from 71 asymptomatic family members five harbored the pathogenic fragment size. In eight families, prenatal testing had to be offered with an outcome of four affected fetuses. Methylation test was performed in 31 genetically confirmed FSHD patients and hypomethylation status was detected in all cases. All the 115 confirmed patients had 4qA alleles with the G polymorphism. Translocation events between 4q35 and the homologous 10q26 regions were also detected. Conclusion: Molecular diagnosis of FSHD became a routine approach in Hungary thus supporting the work of the clinicians, improving quality of life and genetic counseling of the affected families. The provided results from this research suggest that FSHD is associated with complex epigenetic disease mechanisms. Orv. Hetil., 2011, 152, 1576–1585.

scholarly journals Monosomy 18p is a risk factor for facioscapulohumeral dystrophy

2018 ◽  
Vol 55 (7) ◽  
pp. 469-478 ◽  
Author(s):  
Judit Balog ◽  
Remko Goossens ◽  
Richard J L F Lemmers ◽  
Kirsten R Straasheijm ◽  
Patrick J van der Vliet ◽  
...  
Keyword(s):  
Neurological Examination ◽  
Clinical Symptoms ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Cellular Systems ◽  
Deletion Syndrome ◽  
Facial Dysmorphism ◽  
D4z4 Repeat ◽  
Molecular Features ◽  
Digenic Inheritance ◽  
Primary Fibroblasts

Background18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2).ObjectivesSince 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD.MethodsTo test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination.ResultsPrimary fibroblasts hemizygous for SMCHD1 have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD.Conclusions18p deletions leading to haploinsufficiency of SMCHD1, together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD.

scholarly journals Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Yoshikazu Arai ◽  
Koji Hayakawa ◽  
Daisuke Arai ◽  
Rie Ito ◽  
Yusuke Iwasaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Cord Blood ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Methylation Status ◽  
Combined Exposure ◽  
Blood Samples ◽  
Low Concentrations ◽  
Induced Pluripotent

The regulation of transcription and genome stability by epigenetic systems are crucial for the proper development of mammalian embryos. Chemicals that disturb epigenetic systems are termed epimutagens. We previously performed chemical screening that focused on heterochromatin formation and DNA methylation status in mouse embryonic stem cells and identified five epimutagens: diethyl phosphate (DEP), mercury (Hg), cotinine, selenium (Se), and octachlorodipropyl ether (S-421). Here, we used human induced pluripotent stem cells (hiPSCs) to confirm the effects of 20 chemicals, including the five epimutagens, detected at low concentrations in maternal peripheral and cord blood samples. Of note, these individual chemicals did not exhibit epimutagenic activity in hiPSCs. However, because the fetal environment contains various chemicals, we evaluated the effects of combined exposure to chemicals (DEP, Hg, cotinine, Se, and S-421) on hiPSCs. The combined exposure caused a decrease in the number of heterochromatin signals and aberrant DNA methylation status at multiple gene loci in hiPSCs. The combined exposure also affected embryoid body formation and neural differentiation from hiPSCs. Therefore, DEP, Hg, cotinine, Se, and S-421 were defined as an “epimutagen combination” that is effective at low concentrations as detected in maternal peripheral and cord blood.

scholarly journals Establishment of Novel DNA Methylation-Based Prostate Cancer Subtypes and a Risk-Predicting Eight-Gene Signature

2021 ◽  
Vol 9 ◽  
Author(s):  
Enchong Zhang ◽  
Fujisawa Shiori ◽  
Oscar YongNan Mu ◽  
Jieqian He ◽  
Yuntian Ge ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Immune Cell ◽  
Methylation Status ◽  
Disease Status ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Cancer Subtypes ◽  
Cpg Sites ◽  
Selection Operator

Prostate cancer (PCa) is the most common malignant tumor affecting males worldwide. The substantial heterogeneity in PCa presents a major challenge with respect to molecular analyses, patient stratification, and treatment. Least absolute shrinkage and selection operator was used to select eight risk-CpG sites. Using an unsupervised clustering analysis, called consensus clustering, we found that patients with PCa could be divided into two subtypes (Methylation_H and Methylation_L) based on the DNA methylation status at these CpG sites. Differences in the epigenome, genome, transcriptome, disease status, immune cell composition, and function between the identified subtypes were explored using The Cancer Genome Atlas database. This analysis clearly revealed the risk characteristics of the Methylation_H subtype. Using a weighted correlation network analysis to select risk-related genes and least absolute shrinkage and selection operator, we constructed a prediction signature for prognosis based on the subtype classification. We further validated its effectiveness using four public datasets. The two novel PCa subtypes and risk predictive signature developed in this study may be effective indicators of prognosis.

scholarly journals OMIC-06. MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA VIA LOW-DEPTH WHOLE GENOME BISULFITE SEQUENCING

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i38-i38
Author(s):  
Dean Thompson ◽  
Jemma Castle ◽  
Debbie Hicks ◽  
Steve Clifford ◽  
Ed Schwalbe
Keyword(s):  
Dna Methylation ◽  
Bisulfite Sequencing ◽  
Methylation Status ◽  
Unmet Need ◽  
Whole Genome ◽  
Molecular Subgroups ◽  
International Consensus ◽  
Whole Genome Bisulfite Sequencing ◽  
Molecular Features ◽  
Genome Bisulfite Sequencing

Abstract Introduction International consensus recognises four molecular subgroups of medulloblastoma, each with distinct molecular features and clinical outcomes. The current gold-standard for subgroup assignment is DNA methylation microarray. There is an unmet need to develop platform-independent subgrouping assays which are both non-proprietary and compatible with rapidly-expanding WGS capacity in healthcare. Whole Genome Bisulfite Sequencing (WGBS) enables the assessment of genome-wide methylation status at single-base resolution. Previously, WGBS adoption has been limited by cost and sample quality/quantity requirements. Its application for routine detection of medulloblastoma subgroups has not previously been reported. Methodology Two datasets were utilised; 36 newly-sequenced low-depth (10x coverage) and 34 publicly-available high-depth (30x) WGBS medulloblastomas, all with matched DNA methylation microarray data. We compared platform concordance and identified molecular subgroups. Machine-learning WGBS-based subgroup classifiers were optimised and compared between platforms. Aneuploidy and mutation detection using WGBS was optimised and compared to microarray-derived estimates where possible. Finally, comprehensive subgroup-specific DNA methylation signatures were identified. Results We optimised a pipeline for processing, quality control and analysis of low-depth WGBS data, suitable for routine molecular subgrouping and aneuploidy assessment. We demonstrated the suitability of fresh-frozen and FFPE DNA for WGBS, and, using downsampling, showed that subgroup calling is robust at coverages as low as 2x. We identified differentially methylated regions that, due to poor representation, could not be detected using methylation microarrays. Molecular subgroups of medulloblastoma assigned using WGBS were concordant with array-based definitions, and WGBS-derived classifier performance measures exceeded microarray-derived classifiers. Conclusion We describe a platform-independent assay for molecular subgrouping of medulloblastoma using WGBS. It performs equivalently to current array-based methods at comparable cost ($405 vs $596) and provides a proof-of-concept for its routine clinical adoption using standard WGS technology. Finally, the full methylome enabled elucidation of additional biological heterogeneity that has hitherto been inaccessible.

scholarly journals RARE-54. MOLECULAR ANALYSIS OF ROSETTE-FORMING GLIONEURONAL TUMOR AT MIDBRAIN; REPORT OF TWO CASES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii454-iii454
Author(s):  
Hajime Handa
Keyword(s):  
Dna Methylation ◽  
Histological Analysis ◽  
Clinical Course ◽  
Methylation Status ◽  
Glioneuronal Tumor ◽  
Rt Pcr ◽  
Methylation Array ◽  
Molecular Features ◽  
Occipital Transtentorial Approach ◽  
Dna Methylation Array

Abstract Rosette-forming glioneuronal tumor (RGNT) is a tumor that primarily arises at posterior fossa. We experienced two rare cases of RGNT located at midbrain and investigated their molecular features. Case 1 is a 23-year-old female, and Case 2 is an 18-year-old male. Both cases were surgically removed by the occipital transtentorial approach. Histological analysis demonstrated a biphasic pattern of neurocytic and glial components. The former consisted of neurocytic rosettes and perivascular pseudorosettes, and the latter was GFAP positive, corresponding to the diagnosis of RGNT. Both cases have an excellent clinical course without receiving chemotherapy or radiation therapy. Small residual tumors of both cases shrunk and maintained for 27 and 12 months, respectively. Case 1 underwent DNA methylation array and a subsequent DNA methylation-based classifier, indicating that the case matched RGNT with a 0.99 calibrated score. Also, we identified FGFR1 K656 mutation. Pyrosequence analysis of other genes such as IDH1 R132, IDH2 R172, BRAF T599, BRAF V600, H3F3A K27, H3F3A G34, HIST1H3B K27, TERT C228, FGFR1 N546 had no mutations. RT-PCR of KIAA1549-BRAF fusion was not detected. DNA methylation status of Case 2 is under investigation. Pyorosequence analysis identified TERT C228 mutation but did not identify other mutations such as FGFR1 N546 and K656. Midbrain RGNT corresponds to the histological and molecular features of RGNT. RGNT needs to be differentially diagnosed in the case of a midbrain tumor.

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