Methylation Pattern of Repetitive Elements in Correlation with Genome Wide Global DNA Methylation in the Prognosis of Paediatric Tuberculosis

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.

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O6D.2 Evidence of dna methylation changes by carbon nanotubes in a translational study design

Occupational and Environmental Medicine ◽

10.1136/oem-2019-epi.154 ◽

2019 ◽

Vol 76 (Suppl 1) ◽

pp. A57.2-A57

Author(s):

Manosij Ghosh ◽

Deniz Öner ◽

Lode Godderis ◽

Peter Hoet

Keyword(s):

Dna Methylation ◽

Cross Sectional Study ◽

Methylation Pattern ◽

Global Dna Methylation ◽

Limited Information ◽

Cross Sectional ◽

Translational Study ◽

Exposed Workers

IntroductionWhile studies have addressed genotoxic effects of CNT, only limited information are available on epigenetic effects. We designed a study to investigate DNA methylation alterations in vitro, in vivo and in occupationally exposed workers.Material and methodsIn vitro studies were performed in 16-HBE and THP-1 cells. For the in vivo study, BALB/c mice were administered intratracheally with single-wall CNT (SWCNTs) and multi-wall (MWCNTs) at high (2.5 mg/kg) and low (0.25 mg/kg) doses. For the cross sectional study, 24 workers exposed to aggregates of MWCNT of 500 nm–100 µm with concentrations of 4.6–42.6 µg/m3 and 43 unexposed referents were recruited. Global DNA methylation and demethylation patterns were analysed by LC-MS/MS. Methylation of specific genes was measured by Pyromark 24® (Qiagen). Genome-wide assessment of DNA methylation was performed with Infinium HumanMethylation450 BeadChip Array.ResultsIn general, we did not find global DNA methylation alteration for both CNTs. In 16-HBE cells, differentially methylated and expressed genes (MWCNTs>SWCNTs) from p53 signalling, DNA damage repair and cell cycle pathways were observed. In THP-1 cells, CNTs induced promoter-specific methylation of genes involved in several signaling cascade, vascular endothelial growth factor and platelet activation pathways. In lungs of BALB/c mice CNTs affected methylation of ATM gene. Finally, analysis of gene-specific DNA methylation in exposed workers revealed significant changes for DNMT1, ATM, SKI, and HDAC4 promoter CpGs.ConclusionsEpigenetic changes seem to occur at sub cyto-genotoxic concentrations in vitro. Alteration in DNA methylation pattern could be a natural reaction of cells but could also silence critical genes and reprogram cellular functions.

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Global DNA Methylation Pattern of Fibroblasts in Idiopathic Pulmonary Fibrosis

DNA and Cell Biology ◽

10.1089/dna.2018.4557 ◽

2019 ◽

Vol 38 (9) ◽

pp. 905-914 ◽

Cited By ~ 4

Author(s):

Jong-Uk Lee ◽

Ji-Hye Son ◽

Eun-Young Shim ◽

Hyun Sub Cheong ◽

Seung-Woo Shin ◽

...

Keyword(s):

Dna Methylation ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Methylation Pattern ◽

Global Dna Methylation ◽

Dna Methylation Pattern

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Gut Microbiota Composition Is Associated With the Global DNA Methylation Pattern in Obesity

Frontiers in Genetics ◽

10.3389/fgene.2019.00613 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Bruno Ramos-Molina ◽

Lidia Sánchez-Alcoholado ◽

Amanda Cabrera-Mulero ◽

Raul Lopez-Dominguez ◽

Pedro Carmona-Saez ◽

...

Keyword(s):

Dna Methylation ◽

Gut Microbiota ◽

Methylation Pattern ◽

Global Dna Methylation ◽

Microbiota Composition ◽

Dna Methylation Pattern ◽

Gut Microbiota Composition

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Integration of Genome-Wide DNA Methylation and Transcription Uncovered Aberrant Methylation-Regulated Genes and Pathways in the Peripheral Blood Mononuclear Cells of Systemic Sclerosis

International Journal of Rheumatology ◽

10.1155/2018/7342472 ◽

2018 ◽

Vol 2018 ◽

pp. 1-19 ◽

Cited By ~ 8

Author(s):

Honglin Zhu ◽

Chengsong Zhu ◽

Wentao Mi ◽

Tao Chen ◽

Hongjun Zhao ◽

...

Keyword(s):

Dna Methylation ◽

Systemic Sclerosis ◽

Differentially Expressed ◽

Unknown Etiology ◽

Global Dna Methylation ◽

Aberrant Methylation ◽

Methylation Analysis ◽

Regulatory Pathways ◽

Genome Wide ◽

Dna Methylation Analysis

Objective. Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology. Aberrant gene expression and epigenetic modifications in circulating immune cells have been implicated in the pathogenesis of SSc. This study is to delineate the interaction network between gene transcription and DNA methylation in PBMC of SSc patients and to identify methylation-regulated genes which are involved in the pathogenesis of SSc. Methods. Genome-wide mRNA transcription and global DNA methylation analysis were performed on PBMC from 18 SSc patients and 19 matched normal controls (NC) using Illumina BeadChips. Differentially expressed genes (DEGs) and differentially methylated positions (DMPs) were integrative analyzed to identify methylation-regulated genes and associated molecular pathways. Results. Transcriptome analysis distinguished 453 DEGs (269 up- and 184 downregulated) in SSc from NC. Global DNA methylation analysis identified 925 DMPs located on 618 genes. Integration of the two lists revealed only 20 DEGs which harbor inversely correlated DMPs, including 12 upregulated (ELANE, CTSG, LTBR, C3AR1, CSTA, SPI1, ODF3B, SAMD4A, PLAUR, NFE2, ZYX, and CTSZ) and eight downregulated genes (RUNX3, PRF1, PRKCH, PAG1, RASSF5, FYN, CXCR6, and F2R). These potential methylation-regulated DEGs (MeDEGs) are enriched in the pathways related to immune cell migration, proliferation, activation, and inflammation activities. Using a machine learning algorism, we identified six out of the 20 MeDEGs, including F2R, CXCR6, FYN, LTBR, CTSG, and ELANE, which distinguished SSc from NC with 100% accuracy. Four genes (F2R, FYN, PAG1, and PRKCH) differentially expressed in SSc with interstitial lung disease (ILD) compared to SSc without ILD. Conclusion. The identified MeDEGs may represent novel candidate factors which lead to the abnormal activation of immune regulatory pathways in the pathogenesis of SSc. They may also be used as diagnostic biomarkers for SSc and clinical complications.

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Genome-wide dynamic changes of DNA methylation of repetitive elements in human embryonic stem cells and fetal fibroblasts

Genomics ◽

10.1016/j.ygeno.2011.10.004 ◽

2012 ◽

Vol 99 (1) ◽

pp. 10-17 ◽

Cited By ~ 24

Author(s):

Jianzhong Su ◽

Xiujuan Shao ◽

Hongbo Liu ◽

Shengqiang Liu ◽

Qiong Wu ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Repetitive Elements ◽

Dynamic Changes ◽

Genome Wide ◽

Fetal Fibroblasts

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Profiling the genome-wide DNA methylation pattern of porcine ovaries using reduced representation bisulfite sequencing

Scientific Reports ◽

10.1038/srep22138 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 18

Author(s):

Xiao-Long Yuan ◽

Ning Gao ◽

Yan Xing ◽

Hai-Bin Zhang ◽

Ai-Ling Zhang ◽

...

Keyword(s):

Dna Methylation ◽

Bisulfite Sequencing ◽

Methylation Pattern ◽

Reduced Representation ◽

Genome Wide ◽

Reduced Representation Bisulfite Sequencing ◽

Dna Methylation Pattern

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Global DNA methylation changes in Cucurbitaceae inter-species grafting

Cropp Breeding and Applied Biotechnology ◽

10.1590/1984-70332015v15n2n20 ◽

2015 ◽

Vol 15 (2) ◽

pp. 112-116 ◽

Cited By ~ 13

Author(s):

Evangelia Avramidou ◽

Aliki Kapazoglou ◽

Filippos A. Aravanopoulos ◽

Aliki Xanthopoulou ◽

Ioannis Ganopoulos ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Markers ◽

Disease Resistance ◽

Molecular Mechanisms ◽

Genetic Material ◽

Methylation Pattern ◽

Global Dna Methylation ◽

Long Distance ◽

Epigenetic Effect ◽

Selection Of

Grafting has been used to improve yield, fruit quality and disease resistance in a range of tree and vegetable species. The molecular mechanisms underpinning grafting responses have only recently started to be delineated. One of those mechanisms involves long distance transfer of genetic material from rootstock to scion alluding to an epigenetic component to the grafting process. In the research presented herein we extended published work on heritable changes in the DNA methylation pattern of Solanaceae scion genomes, in Cucurbitaceae inter-species grafting. Specifically, we examined global DNA methylation changes in scions of cucumber, melon and watermelon heterografted onto pumpkin rootstocks using MSAP analysis. We observed a significant increase of global DNA methylation in cucumber and melon scions pointing to an epigenetic effect in Cucurbitaceae heterografting. Exploitation of differential epigenetic marking in different rootstock-scion combinations could lead to development of epi-molecular markers for generation and selection of superior quality grafted vegetables.

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Use of Two Complementary Bioinformatic Approaches to Identify Differentially Methylated Regions in Neonatal Sepsis

The Open Bioinformatics Journal ◽

10.2174/1875036202114010144 ◽

2021 ◽

Vol 14 (1) ◽

pp. 144-152

Author(s):

Paula Navarrete ◽

María José Garzón ◽

Sheila Lorente-Pozo ◽

Salvador Mena-Mollá ◽

Máximo Vento ◽

...

Keyword(s):

Dna Methylation ◽

Neonatal Sepsis ◽

Late Onset ◽

Underlying Disease ◽

Methylation Pattern ◽

Differentially Methylated Regions ◽

Genome Wide ◽

Bioinformatic Approaches ◽

Using Data ◽

Underlying Mechanisms

Background: Neonatal sepsis is a heterogeneous condition affecting preterm infants whose underlying mechanisms remain unknown. The analysis of changes in the DNA methylation pattern can contribute to improving the understanding of molecular pathways underlying disease pathophysiology. Methylation EPIC 850K BeadChip technology is an excellent tool for genome-wide methylation analyses and the detection of differentially methylated regions (DMRs). Objective: The aim is to identify DNA methylation traits in complex diseases, such as neonatal sepsis, using data from Methylation EPIC 850K BeadChip arrays. Methods: Two different bioinformatic methods, DMRcate (a supervised approach) and mCSEA (an unsupervised approach), were used to identify DMRs using EPIC data from leukocytes of neonatal septic patients. Here, we describe with detail the implementation of both methods as well as their applicability, briefly discussing the results obtained for neonatal sepsis. Results: Differences in methylation levels were observed in neonatal sepsis patients. Moreover, differences were identified between the two subsets of the disease: Early-Onset neonatal Sepsis (EOS) and Late-Onset Neonatal Sepsis (LOS). Conclusion: This approach by using DMRcate and mCSA helped us to gain insight into the intricate mechanisms that may drive EOS and LOS development and progression in newborns.

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