Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

AbstractThe cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

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Racial Disparities in Epigenetic Aging of the Right vs Left Colon

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa206 ◽

2020 ◽

Author(s):

Matthew Devall ◽

Xiangqing Sun ◽

Fangcheng Yuan ◽

Gregory S Cooper ◽

Joseph Willis ◽

...

Keyword(s):

Dna Methylation ◽

African Americans ◽

Racial Differences ◽

Age Of Onset ◽

Left Colon ◽

Right Colon ◽

Normal Colon ◽

Epigenetic Aging ◽

Epigenetic Age Acceleration ◽

The Right

Abstract There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared to individual-matched left colon (1.51 years; 95% CI = 0.62 to 2.40 years; two-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; two-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.

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To Determine Pivotal Genes Driven by Methylated DNA in Obstructive Sleep Apnea Hypopnea Syndrome

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/5520325 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Yan Li ◽

Yajuan Zhang

Keyword(s):

Dna Methylation ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Molecular Mechanisms ◽

Sleep Apnea Syndrome ◽

Respiratory Dysfunction ◽

Obstructive Sleep ◽

Hypopnea Syndrome ◽

First Time ◽

Erbb2 Signaling

Obstructive sleep apnea syndrome (OSAHS) is a widespread respiratory dysfunction that has attracted more and more attention in recent years. Recently, a large number of studies have shown that abnormal DNA methylation epigenetically silences genes necessary for the pathogenesis of human diseases. However, the exact mechanism of abnormal DNA methylation in OSAHS is still elusive. In this study, we downloaded the OSAHS data from the GEO database. Our data for the first time revealed 520 hypermethylated genes and 889 hypomethylated genes in OSAHS. Bioinformatics analysis revealed that these abnormal methylated genes exhibited an association with the regulation of angiogenesis, apoptosis, Wnt, and ERBB2 signaling pathways. PPI network analysis displayed the interactions among these genes and validated several hub genes, such as GPSM2, CCR8, TAS2R20, TAS2R4, and TAS2R5, which were related to regulating liganded Gi-activating GPCR and the transition of mitotic metaphase/anaphase. In conclusion, our study offers a new hint of understanding the molecular mechanisms in OSAHS progression and will provide OSAHS with newly generated innovative biomarkers.

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Validation and characterization of a DNA methylation alcohol biomarker across the life course

10.1101/591404 ◽

2019 ◽

Cited By ~ 1

Author(s):

Paul Darius Yousefi ◽

Rebecca Richmond ◽

Ryan Langdon ◽

Andrew Ness ◽

Chunyu Liu ◽

...

Keyword(s):

Dna Methylation ◽

Parents And Children ◽

Average Alcohol ◽

Alcohol Biomarker ◽

Audit Score ◽

Potential Applications ◽

The Life Course ◽

Offspring Generation ◽

First Time

AbstractRecently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterize the drivers of this DNAm-Alc for the first time in independent populations. In N=1,049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of AUDIT score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding we examined how earlier vs. concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions. The stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.

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Search for Pharmacoepigenetic Correlations in Type 2 Diabetes Under Sulfonylurea Treatment

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0043-121265 ◽

2018 ◽

Vol 127 (04) ◽

pp. 226-233 ◽

Cited By ~ 1

Author(s):

Makrina Karaglani ◽

Georgia Ragia ◽

Maria Panagopoulou ◽

Ioanna Balgkouranidou ◽

Evangelia Nena ◽

...

Keyword(s):

Dna Methylation ◽

Gene Promoter ◽

Katp Channels ◽

Protective Role ◽

Gene Promoters ◽

Specific Pcr ◽

Abcc8 Gene ◽

First Time ◽

E23k Polymorphism

AbstractSulfonylureas are insulin secretagogues which act in pancreatic β cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR. KCNJ11 methylation was detected in 19/88 (21.6%) of hypoglycemic and in 23/83 (27.7%) of non-hypoglycemic patients (p=0.353), while ABCC8 methylation in 6/83 (7.2%) of non-hypoglycemic and none (0/88) of the hypoglycemic patients (p=0.012). Methylation in at least one promoter (KCNJ11 or ABCC8) was significantly associated with non-hypoglycemic patients who are carriers of KCNJ11 EK allele (p=0.030). Our data suggest that ABCC8 but not KCNJ11 methylation is associated to hypoglycemic events in sulfonylureas-treated T2DM patients. Furthermore, it is demonstrated that the KCNJ11 E23K polymorphism in association to either of the two genes’ DNA methylation may have protective role against sulfonylurea-induced hypoglycemia.

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Juvenile Hemochromatosis: A Case Report and Review of the Literature

Pharmaceuticals ◽

10.3390/ph13080195 ◽

2020 ◽

Vol 13 (8) ◽

pp. 195

Author(s):

Akiyoshi Takami ◽

Yasuaki Tatsumi ◽

Katsuhisa Sakai ◽

Yasumichi Toki ◽

Katsuya Ikuta ◽

...

Keyword(s):

Autosomal Recessive ◽

Age Of Onset ◽

Relevant Literature ◽

Autosomal Recessive Disorder ◽

Age Difference ◽

Outpatient Basis ◽

Review Of The Literature ◽

Hepcidin Expression ◽

Juvenile Hemochromatosis ◽

First Time

Juvenile hemochromatosis (JH), type 2A hemochromatosis, is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2), which encodes hemojuvelin, an essential regulator of the hepcidin expression, causing liver fibrosis, diabetes, and heart failure before 30 years of age, often with fatal outcomes. We report two Japanese sisters of 37 and 52 years of age, with JH, who showed the same homozygous HJV I281T mutation and hepcidin deficiency and who both responded well to phlebotomy on an outpatient basis. When all reported cases of JH with homozygous HJV mutations in the relevant literature were reviewed, we found—for the first time—that JH developed in females and males at a ratio of 3:2, with no age difference in the two groups. Furthermore, we found that the age of onset of JH may depend on the types of HJV mutations. In comparison to patients with the most common G320V/G320V mutation, JH developed earlier in patients with L101P/L101P or R385X/R385X mutations and later in patients with I281T/I281T mutations.

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Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver

Nutrients ◽

10.3390/nu12020277 ◽

2020 ◽

Vol 12 (2) ◽

pp. 277 ◽

Cited By ~ 1

Author(s):

Noémie Gensous ◽

Francesco Ravaioli ◽

Chiara Pirazzini ◽

Roberto Gramignoli ◽

Ewa Ellis ◽

...

Keyword(s):

Dna Methylation ◽

Caloric Restriction ◽

Ribosomal Rna ◽

Tissue Specificity ◽

Rdna Locus ◽

Nutritional Interventions ◽

Age Related ◽

Dna Methylation Profile ◽

Main Determinants ◽

First Time

A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.

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Identification of two novel variants in GAA underlying infantile-onset Pompe disease in two Pakistani families

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0477 ◽

2020 ◽

Vol 33 (4) ◽

pp. 553-556

Author(s):

Aman Ullah ◽

Bibi Zubaida ◽

Huma Arshad Cheema ◽

Muhammad Naeem

Keyword(s):

Pompe Disease ◽

Age Of Onset ◽

Pathogenic Variants ◽

Whole Exome ◽

Sequence Variations ◽

Heterozygous Variant ◽

Novel Variants ◽

Carrier Identification ◽

First Time ◽

Pakistani Families

AbstractBackgroundPompe disease (PD) is an autosomal recessive metabolic myopathy with an average incidence of one in 40,000 live births. It has a variable age of onset and can be diagnosed within the first 3 months. Heart involvement and muscle weakness are its primary manifestations.Case presentationWe describe two families affected by PD with two rare, novel variants. To date, pathogenic variants in acid α-glucosidase (GAA) alone have accounted for all cases of the disease. Both families were screened for pathogenic sequence variations. This study presents the implications of regulatory or modifier sequences in the disease pathogenesis for the first time. A homozygous missense p.Arg854Gln variant in family A and a single heterozygous variant (p.Asn925His) in family B were found to be segregating according to the disease phenotype. The variants were not detected in our in-house database comprising 50 whole-exome sequences of healthy individuals from a local unrelated Pakistani population. In silico analyses predicted that the variants would have deleterious effects on the protein structure.ConclusionsThe variants likely underlie the infantile-onset PD (IOPD) in these Pakistani families. The study expands the mutation spectrum of GAA associated with IOPD and highlights the insufficiency of screening the GAA coding sequence to determine the cause of IOPD. The work should be helpful in carrier identification, improving genetic counselling, and prenatal diagnosis.

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A dated molecular perspective of eucalypt taxonomy, evolution and diversification

Australian Systematic Botany ◽

10.1071/sb18015 ◽

2019 ◽

Cited By ~ 5

Author(s):

Andrew H. Thornhill ◽

Michael D. Crisp ◽

Carsten Külheim ◽

Kristy E. Lam ◽

Leigh A. Nelson ◽

...

Keyword(s):

Dna Sequences ◽

Molecular Study ◽

Late Eocene ◽

Early Oligocene ◽

Eastern Australia ◽

Statistical Support ◽

Rapid Diversification ◽

Penalised Likelihood ◽

Inland Water Bodies ◽

First Time

The eucalypts, which include Eucalyptus, Angophora and Corymbia, are native to Australia and Malesia and include over 800 named species in a mixture of diverse and depauperate lineages. We assessed the fit of the eucalypt taxonomic classification to a phylogeny of 711 species scored for DNA sequences of plastid matK and psbA–trnH, as well as nuclear internal transcribed spacer and external transcribed spacer. Two broadly similar topologies emerge from both maximum likelihood and Bayesian analyses, showing Angophora nested within Corymbia, or Angophora sister to Corymbia. The position of certain species-poor groups on long branches fluctuated relative to the three major Eucalyptus subgenera, and positions of several closely related species within those subgenera were unstable and lacked statistical support. Most sections and series of Eucalyptus were not recovered as monophyletic. We calibrated these phylogenies against time, using penalised likelihood and constraints obtained from fossil ages. On the basis of these trees, most major eucalypt subgenera arose in the Late Eocene and Early Oligocene. All Eucalyptus clades with taxa occurring in south-eastern Australia have crown ages <20million years. Several eucalypt clades display a strong present-day geographic disjunction, although these clades did not have strong phylogenetic statistical support. In particular, the estimated age of the separation between the eudesmids (Eucalyptus subgenus Eudesmia) and monocalypts (Eucalyptus subgenus Eucalyptus) was consistent with extensive inland water bodies in the Eocene. Bayesian analysis of macroevolutionary mixture rates of net species diversification accelerated in five sections of Eucalyptus subgenus Symphyomyrtus, all beginning 2–3million years ago and associated with semi-arid habitats dominated by mallee and mallet growth forms, and with open woodlands and forests in eastern Australia. This is the first time that a calibrated molecular study has shown support for the rapid diversification of eucalypts in the recent past, most likely driven by changing climate and diverse soil geochemical conditions.

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