Complete Metamorphosis in Manduca sexta Involves Specific Changes in DNA Methylation Patterns

The transition between morphologically distinct phenotypes during complete metamorphosis in holometabolous insects is accompanied by fundamental transcriptional reprogramming. Using the tobacco hornworm (Manduca sexta), a powerful model for the analysis of insect evolution and development, we conducted a genome-wide comparative analysis of gene expression and DNA methylation in caterpillars and adults to determine whether complete metamorphosis has an epigenetic basis in this species. Bisulfite sequencing indicated a generally low level of DNA methylation with a unimodal CpGO/E distribution. Expression analysis revealed that 24 % of all known M. sexta genes (3.729) were upregulated in last-instar larvae relative to the adult moth, whereas 26 % (4.077) were downregulated. We also identified 4.946 loci and 4.960 regions showing stage-specific differential methylation. Interestingly, genes encoding histone acetyltransferases and histone deacetylases were differentially methylated in the larvae and adults, indicating there is crosstalk between different epigenetic mechanisms. The distinct sets of methylated genes in M. sexta larvae and adults suggest that complete metamorphosis involves epigenetic modifications associated with profound transcriptional reprogramming, involving approximately half of all the genes in this species.

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A Genome-Wide Study of DNA Methylation Patterns and Gene Expression Levels in Multiple Human and Chimpanzee Tissues

PLoS Genetics ◽

10.1371/journal.pgen.1001316 ◽

2011 ◽

Vol 7 (2) ◽

pp. e1001316 ◽

Cited By ~ 142

Author(s):

Athma A. Pai ◽

Jordana T. Bell ◽

John C. Marioni ◽

Jonathan K. Pritchard ◽

Yoav Gilad

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Expression Levels ◽

Genome Wide ◽

A Genome ◽

Methylation Patterns ◽

Genome Wide Study ◽

Gene Expression Levels

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Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

10.1101/823807 ◽

2019 ◽

Cited By ~ 1

Author(s):

Paul J. Hop ◽

René Luijk ◽

Lucia Daxinger ◽

Maarten van Iterson ◽

Koen F. Dekkers ◽

...

Keyword(s):

Dna Methylation ◽

Large Scale ◽

Population Genomics ◽

Epigenetic Modification ◽

Binding Activity ◽

Dna Binding Activity ◽

Genome Wide ◽

Scale Population ◽

Genes Encoding ◽

Methylation Patterns

SUMMARYDNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identified 818 genes that influence DNA methylation patterns in blood using large-scale population genomics data. By employing genetic instruments as causal anchors, we identified directed associations between gene expression and distant DNA methylation levels, whilst ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. We found that DNA methylation patterns are commonly shaped by transcription factors that consistently increase or decrease DNA methylation levels. However, we also observed genes encoding proteins without DNA binding activity with widespread effects on DNA methylation (e.g. NFKBIE, CDCA7(L) and NLRC5) and we suggest plausible mechanisms underlying these findings. Many of the reported genes were unknown to influence DNA methylation, resulting in a comprehensive resource providing insights in the principles underlying epigenetic regulation.

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Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

European Respiratory Review ◽

10.1183/16000617.0036-2016 ◽

2016 ◽

Vol 25 (140) ◽

pp. 135-140 ◽

Cited By ~ 17

Author(s):

Prakash Chelladurai ◽

Werner Seeger ◽

Soni Savai Pullamsetti

Keyword(s):

Dna Methylation ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Epigenetic Mechanisms ◽

Aberrant Expression ◽

Genome Wide ◽

A Genome ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date.

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Abstract MP31: DNA Methylation Patterns are Associated with Genetic Variation and Systemic Inflammation

Circulation ◽

10.1161/circ.127.suppl_12.amp31 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Stella Aslibekyan ◽

Alexis C Frazier-Wood ◽

Devin M Absher ◽

Jin Sha ◽

Degui Zhi ◽

...

Keyword(s):

Dna Methylation ◽

Systemic Inflammation ◽

Quantitative Trait ◽

Inflammatory Marker ◽

Lipid Lowering ◽

Chromosome 11 ◽

Chromosome 20 ◽

Genome Wide ◽

A Genome ◽

Methylation Patterns

Introduction: Chronic systemic inflammation is a complex trait characterized by moderate to high heritability and important implications for cardiovascular health. Previously identified genetic polymorphisms explain only a modest fraction of variability in circulating inflammatory marker concentrations. Hypothesis: We hypothesized that variation in DNA methylation patterns contributes to the missing heritability of inflammatory traits, and that such associations may in turn be influenced by environmental factors (smoking, alcohol, and obesity) as well as common genetic variants. Methods: Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 593), we assayed the methylation status of approximately 450,000 sites across the genome and measured serum concentrations of high-sensitivity C-reactive protein (hsCRP), soluble interleukin-2 receptor alpha (sIL2Ra), interleukin-6 (IL6), tumor necrosis factor alpha (TNFa), and monocyte chemoattractant protein 1 (MCP1). To investigate and validate the associations between DNA methylation patterns and systemic inflammation, we split the GOLDN data set into discovery (n= 451) and replication (n= 142) data sets. During the discovery stage, we modeled continuous methylation scores at each site on inflammatory markers, adjusted for age, sex, study site, and T-cell purity as fixed effects and family structure as a random effect. Results: After correcting for multiple comparisons, the strongest signal was obtained from an intergenic CpG island on chromosome 20 and levels of hsCRP (P=5×10-10) and sILR2a (P=6×10-6). Our findings are consistent with previous linkage studies that have identified a quantitative trait locus for inflammation in an adjacent region of chromosome 20. Moreover, the association with sIL2Ra but not hsCRP was observed in replication analyses (P=0.008). Models adjusting for current smoking status, alcohol consumption, or body mass index did not appreciably change the estimates of association. Finally, we performed a genome-wide analysis to identify quantitative trait loci for methylation of the CpG site on chromosome 20. We found a genome-wide significant (P=3×10×-8) association with rs11223480 on chromosome 11 in OPCML, which encodes a tumor suppressor, and suggestive (P<4×10-6) associations with a cluster of 9 variants located on chromosome 20 in MACROD2, a gene previously reported to be associated with systemic inflammation. Conclusions: We have conducted the first integrated study of epigenetic variation, genotype, and circulating inflammatory marker concentrations. In conclusion, our findings suggest that differential methylation of an intergenic region on chromosome 20, likely in conjunction with the underlying genotype, is associated with systemic inflammation and merits further evaluation as a cardiovascular risk factor.

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DNA methylation marks inter-nucleosome linker regions throughout the human genome

10.7287/peerj.preprints.27v1 ◽

2013 ◽

Author(s):

Benjamin P. Berman ◽

Yaping Liu ◽

Theresa K. Kelly

Keyword(s):

Dna Methylation ◽

Binding Sites ◽

Ctcf Binding ◽

Cpg Dinucleotides ◽

Nucleosome Organization ◽

Genome Wide ◽

A Genome ◽

Sequencing Studies ◽

Methylation Patterns

Nucleosome organization and DNA methylation are two epigenetic mechanisms that are important for proper control of mammalian transcription. Numerous lines of evidence suggest an interaction between these two mechanisms, but the nature of this interaction in vivo remains elusive. Whole-genome DNA methylation sequencing studies have shown that human methylation levels are periodic at intervals of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we propose an alternate explanation for these nucleosomal periodicities. By examining methylation patterns in published datasets, we find that genome-wide methylation levels are highest within the linker regions that occur between nucleosomes in multi-nucleosome arrays. This effect is most prominent within long-range Partially Methylated Domains (PMDs) and the strongly positioned nucleosomes that flank CTCF binding sites. The CTCF-flanking nucleosomes retain positioning even in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper positioning. We propose that DNA methylation is inhibited by histone proteins at CTCF and other unknown classes of nucleosomes within PMDs.

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Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Communications Biology ◽

10.1038/s42003-021-02179-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Todd R. Robeck ◽

Zhe Fei ◽

Ake T. Lu ◽

Amin Haghani ◽

Eve Jourdain ◽

...

Keyword(s):

Dna Methylation ◽

Age Estimation ◽

Species Conservation ◽

Genome Wide ◽

Epigenetic Aging ◽

Highly Correlated ◽

Methylation Patterns ◽

Cg Dinucleotides ◽

Free Ranging ◽

Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

Scientific Reports ◽

10.1038/s41598-020-79126-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Wardah Mahmood ◽

Lars Erichsen ◽

Pauline Ott ◽

Wolfgang A. Schulz ◽

Johannes C. Fischer ◽

...

Keyword(s):

Dna Methylation ◽

Cell Free Dna ◽

The Past ◽

Free Dna ◽

Genome Wide ◽

Cancerous Cell ◽

Pure Cell ◽

Epigenetic Biomarker ◽

Methylation Patterns ◽

Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

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DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽

10.3390/genes12030441 ◽

2021 ◽

Vol 12 (3) ◽

pp. 441

Author(s):

Fanny Pineau ◽

Davide Caimmi ◽

Sylvie Taviaux ◽

Maurane Reveil ◽

Laura Brosseau ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dna Methylation ◽

Clinical Trials ◽

Lung Disease ◽

Disease Severity ◽

Genome Wide ◽

A Genome ◽

Lung Disease Severity ◽

Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

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