scholarly journals Tools and applications for integrative analysis of DNA methylation in social insects

2021 ◽  
Author(s):  
Claire Morandin ◽  
Volker P. Brendel
Keyword(s):  
Dna Methylation ◽  
Quality Control ◽  
De Novo ◽  
Data Quality Control ◽  
Sequencing Data ◽  
Physiological Control ◽  
Genetic Determination ◽  
Cpg Sites ◽  
And Function ◽  
Honeybee Genome

DNA methylation is a common epigenetic signaling tool and an important biological process which is widely studied in a large array of species. The presence, level, and function of DNA methylation varies greatly across species. In insects, DNA methylation systems are reduced, and methylation rates are often low. Low methylation levels probed by whole genome bisulfite sequencing require great care with respect to data quality control and intepretation. Here we introduce BWASP/R, a reproducible, scalable workflow, that allows efficient, scalable, and entirely reproducible analyses of raw DNA methylation sequencing data. Consistent application of quality control filters and analysis parameters provides fair comparisons among different studies and an integrated view of all experiments on one species. We describe the capabilities of the BWASP/R workflow by re-analyzing several publicly available social insect WGBS datasets, comprising 70 samples and cumulatively 147 replicates from four different species. We show that the CpG methylome comprises only about 1.5% of CpG sites in the honeybee genome and that the cumulative data are consistent with genetic signatures of site accessibility and physiological control of methylation levels.Significance StatementDNA methylation in the honeybee genome occurs almost entirely at CpG sites. Methylation rates are small compared to rates in mammalian or plant genomes. De novo analysis of all published honeybee methylation studies and statistical modeling suggests that the CpG methylome consists of about only 300,000 sites. The development of a fully reproducible, scalable, portable workflow allows for easy accessible updates of integrative views of all current experiments. The integrated results for the honeybee are consistent with genetic determination of methylation site accessibility by yet uncharacterized sequence features and physiological control of methylation levels at those sites.

scholarly journals Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B

2020 ◽  
Vol 48 (7) ◽  
pp. 3949-3961 ◽  
Author(s):  
Chien-Chu Lin ◽  
Yi-Ping Chen ◽  
Wei-Zen Yang ◽  
James C K Shen ◽  
Hanna S Yuan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
De Novo ◽  
Water Channel ◽  
Dna Methyltransferases ◽  
Structural Basis ◽  
Cpg Sites ◽  
Methylation Patterns

Abstract DNA methyltransferases are primary enzymes for cytosine methylation at CpG sites of epigenetic gene regulation in mammals. De novo methyltransferases DNMT3A and DNMT3B create DNA methylation patterns during development, but how they differentially implement genomic DNA methylation patterns is poorly understood. Here, we report crystal structures of the catalytic domain of human DNMT3B–3L complex, noncovalently bound with and without DNA of different sequences. Human DNMT3B uses two flexible loops to enclose DNA and employs its catalytic loop to flip out the cytosine base. As opposed to DNMT3A, DNMT3B specifically recognizes DNA with CpGpG sites via residues Asn779 and Lys777 in its more stable and well-ordered target recognition domain loop to facilitate processive methylation of tandemly repeated CpG sites. We also identify a proton wire water channel for the final deprotonation step, revealing the complete working mechanism for cytosine methylation by DNMT3B and providing the structural basis for DNMT3B mutation-induced hypomethylation in immunodeficiency, centromere instability and facial anomalies syndrome.

scholarly journals Transposable element expression in tumors is associated with immune infiltration and increased antigenicity

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu Kong ◽  
Christopher M. Rose ◽  
Ashley A. Cass ◽  
Alexander G. Williams ◽  
Martine Darwish ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Potential Consequence ◽  
Sequencing Data ◽  
Antiviral Responses ◽  
Genome Wide ◽  
Cancer Genome Atlas ◽  
Demethylation Agent

AbstractProfound global loss of DNA methylation is a hallmark of many cancers. One potential consequence of this is the reactivation of transposable elements (TEs) which could stimulate the immune system via cell-intrinsic antiviral responses. Here, we develop REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observe increased expression of over 400 TE subfamilies, of which 262 appear to result from a proximal loss of DNA methylation. The most recurrent TEs are among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent results in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing inflammation and the display of potentially immunogenic neoantigens.

Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2498-2498
Author(s):  
Claudia Gebhard ◽  
Mohammed Sadeh ◽  
Dagmar Glatz ◽  
Lucia Schwarzfischer ◽  
Rainer Spang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Cpg Island ◽  
Cpg Islands ◽  
Sequencing Data ◽  
Cpg Island Methylator Phenotype ◽  
Chip Sequencing ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns

Abstract Abstract 2498 CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome. DNA methylation profiles across 23.000 CpG islands revealed highly heterogeneous methylation patterns in AML with over 6000 CpG islands showing aberrant de novo methylation in AML. Based on these profiles we selected a subset of 380 CpG islands (covering 15.000 individual CpGs) for detailed fine-mapping analyses of aberrant DNA methylation in 185 patients with AML (50% normal karyotype). We found that a proportion of patients (5/185) displayed a concerted hypermethylation at almost all studied loci, representing the rare CpG island methylator phenotype (CIMP) in AML. Meta analysis of methylation profiling and published ChIP sequencing data separated CpG islands in two groups. A highly correlated subgroup of CpG island regions was strongly associated with histone H3 lysine 27 trimethylation in human hematopoietic progenitor cells, suggesting that disease-related de novo DNA methylation at these CpG islands is linked with polycomb group protein (PcG)-mediated repression. The group of mainly non-PcG target CpG islands showed heterogeneous methylation patterns across patients and unsupervised hierarchical clustering revealed a correlation of methylation profiles with genetic disease markers, including oncofusion proteins as well as CEBPA- and NPM1-mutations. Our study suggests that both epigenetic as well as genetic aberrations may underlay AML-related changes in CpG island DNA methylation states. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Ines Verlinden ◽  
Fabian Güiza ◽  
Inge Derese ◽  
Pieter J. Wouters ◽  
Koen Joosten ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Illness ◽  
Parenteral Nutrition ◽  
Time Course ◽  
De Novo ◽  
Healthy Children ◽  
Cpg Sites ◽  
A Genome ◽  
Early Parenteral Nutrition ◽  
The Impact

Abstract Background A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

scholarly journals Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

2014 ◽  
Vol 5 (4) ◽  
pp. 288-298 ◽  
Author(s):  
K. Broberg ◽  
S. Ahmed ◽  
K. Engström ◽  
M. B. Hossain ◽  
S. Jurkovic Mlakar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
De Novo ◽  
Arsenic Exposure ◽  
Later Life ◽  
Linear Regression Models ◽  
Early Gestation ◽  
Cpg Sites ◽  
Genome Wide

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (rS-values>−0.62), but in girls only 207 (41%) showed inverse correlation (rS-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

scholarly journals Genome wide efficiency profiling reveals modulation of maintenance and de novo methylation by Tets

2020 ◽  
Author(s):  
Pascal Giehr ◽  
Charalampos Kyriakopoulos ◽  
Karl Nordström ◽  
Abduhlrahman Salhab ◽  
Fabian Müller ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Epigenetic Modification ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Sequencing Data ◽  
Reduced Representation ◽  
Genome Wide ◽  
Global And Local

AbstractBackgroundDNA methylation is an essential epigenetic modification which is set and maintained by DNA methyl transferases (Dnmts) and removed via active and passive mechanisms involving Tet mediated oxidation. While the molecular mechanisms of these enzymes are well studied, their interplay on shaping cell specific methylomes remains less well understood. In our work we model the activities of Tets and Dnmts at single CpGs across the genome using a novel type of high resolution sequencing data.ResultsTo accurately measure 5mC and 5hmC levels at single CpGs we developed RRHPoxBS, a reduced representation hairpin oxidative bisulfite sequencing approach. Using this method we mapped the methylomes and hydroxymethylomes of wild type and Tet triple knockout mouse embryonic stem cells. These comprehensive datasets were then used to develop an extended Hidden Markov model allowing us i) to determine the symmetrical methylation and hydroxymethylation state at millions of individual CpGs, ii) infer the maintenance and de novo methylation efficiencies of Dnmts and the hydroxylation efficiencies of Tets at individual CpG positions. We find that Tets exhibit their highest activity around unmethylated regulatory elements, i.e. active promoters and enhancers. Furthermore, we find that Tets’ presence has a profound effect on the global and local maintenance and de novo methylation activities by the Dnmts, not only substantially contributing to a universal demethylation of the genome but also shaping the overall methylation landscape.ConclusionsOur analysis demonstrates that a fine tuned and locally controlled interplay between Tets and Dnmts is important to modulate de novo and maintenance activities of Dnmts across the genome. Tet activities contribute to DNA methylation patterning in the following ways: They oxidize 5mC, they locally shield DNA from accidental de novo methylation and at the same time modulate maintenance and de novo methylation efficiencies of Dnmts across the genome.

scholarly journals Mammalian DNA methyltransferases: new discoveries and open questions

2018 ◽  
Vol 46 (5) ◽  
pp. 1191-1202 ◽  
Author(s):  
Humaira Gowher ◽  
Albert Jeltsch
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferases ◽  
Structure And Function ◽  
Future Research ◽  
Ongoing Research ◽  
Cpg Sites ◽  
Open Questions ◽  
High Preference ◽  
And Function ◽  
Methylation Patterns

As part of the epigenetic network, DNA methylation is a major regulator of chromatin structure and function. In mammals, it mainly occurs at palindromic CpG sites, but asymmetric methylation at non-CpG sites is also observed. Three enzymes are involved in the generation and maintenance of DNA methylation patterns. DNMT1 has high preference for hemimethylated CpG sites, and DNMT3A and DNMT3B equally methylate unmethylated and hemimethylated DNA, and also introduce non-CpG methylation. Here, we review recent observations and novel insights into the structure and function of mammalian DNMTs (DNA methyltransferases), including new structures of DNMT1 and DNMT3A, data on their mechanism, regulation by post-translational modifications and on the function of DNMTs in cells. In addition, we present news findings regarding the allosteric regulation and targeting of DNMTs by chromatin modifications and chromatin proteins. In combination, the recent publications summarized here impressively illustrate the intensity of ongoing research in this field. They provide a deeper understanding of key mechanistic properties of DNMTs, but they also document still unsolved issues, which need to be addressed in future research.

scholarly journals From asymmetrical to balanced genomic diversification during rediploidization: Subgenomic evolution in allotetraploid fish

2020 ◽  
Vol 6 (22) ◽  
pp. eaaz7677 ◽  
Author(s):  
Jing Luo ◽  
Jing Chai ◽  
Yanling Wen ◽  
Min Tao ◽  
Guoliang Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genome Evolution ◽  
Common Carp ◽  
De Novo ◽  
Reference Quality ◽  
And Function ◽  
Allotetraploid Fish

A persistent enigma is the rarity of polyploidy in animals, compared to its prevalence in plants. Although animal polyploids are thought to experience deleterious genomic chaos during initial polyploidization and subsequent rediploidization processes, this hypothesis has not been tested. We provide an improved reference-quality de novo genome for allotetraploid goldfish whose origin dates to ~15 million years ago. Comprehensive analyses identify changes in subgenomic evolution from asymmetrical oscillation in goldfish and common carp to diverse stabilization and balanced gene expression during continuous rediploidization. The homoeologs are coexpressed in most pathways, and their expression dominance shifts temporally during embryogenesis. Homoeolog expression correlates negatively with alternation of DNA methylation. The results show that allotetraploid cyprinids have a unique strategy for balancing subgenomic stabilization and diversification. Rediploidization process in these fishes provides intriguing insights into genome evolution and function in allopolyploid vertebrates.

scholarly journals Species-Specific Quality Control, Assembly and Contamination Detection in Microbial Isolate Sequences with AQUAMIS

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 644
Author(s):  
Carlus Deneke ◽  
Holger Brendebach ◽  
Laura Uelze ◽  
Maria Borowiak ◽  
Burkhard Malorny ◽  
...  
Keyword(s):  
Quality Control ◽  
Data Exchange ◽  
De Novo ◽  
Standard Procedure ◽  
Source Tracking ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Control Assembly ◽  
Species Specific

Sequencing of whole microbial genomes has become a standard procedure for cluster detection, source tracking, outbreak investigation and surveillance of many microorganisms. An increasing number of laboratories are currently in a transition phase from classical methods towards next generation sequencing, generating unprecedented amounts of data. Since the precision of downstream analyses depends significantly on the quality of raw data generated on the sequencing instrument, a comprehensive, meaningful primary quality control is indispensable. Here, we present AQUAMIS, a Snakemake workflow for an extensive quality control and assembly of raw Illumina sequencing data, allowing laboratories to automatize the initial analysis of their microbial whole-genome sequencing data. AQUAMIS performs all steps of primary sequence analysis, consisting of read trimming, read quality control (QC), taxonomic classification, de-novo assembly, reference identification, assembly QC and contamination detection, both on the read and assembly level. The results are visualized in an interactive HTML report including species-specific QC thresholds, allowing non-bioinformaticians to assess the quality of sequencing experiments at a glance. All results are also available as a standard-compliant JSON file, facilitating easy downstream analyses and data exchange. We have applied AQUAMIS to analyze ~13,000 microbial isolates as well as ~1000 in-silico contaminated datasets, proving the workflow’s ability to perform in high throughput routine sequencing environments and reliably predict contaminations. We found that intergenus and intragenus contaminations can be detected most accurately using a combination of different QC metrics available within AQUAMIS.

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