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

2019 ◽  
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.

scholarly journals Genome-wide identification of directed gene networks using large-scale population genomics data

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
René Luijk ◽  
◽  
Koen F. Dekkers ◽  
Maarten van Iterson ◽  
Wibowo Arindrarto ◽  
...  
Keyword(s):  
Gene Networks ◽  
Large Scale ◽  
Population Genomics ◽  
Genome Wide ◽  
Scale Population

scholarly journals Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma

2020 ◽  
Author(s):  
Lauren J. Mills ◽  
Milcah C. Scott ◽  
Pankti Shah ◽  
Anne R. Cunanan ◽  
Archana Deshpande ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Immune Cell ◽  
Cell Types ◽  
Structural Variations ◽  
Canine Osteosarcoma ◽  
Genome Wide ◽  
Highly Correlated ◽  
Murine Osteosarcoma ◽  
Methylation Patterns

AbstractOsteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor suppressor p53 TP53 is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples.SignificanceThis is the first large scale study of DNA methylation in osteosarcoma and lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of different genomic landscapes.

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

2021 ◽  
Vol 9 ◽  
Author(s):  
Jasmin Gegner ◽  
Heiko Vogel ◽  
André Billion ◽  
Frank Förster ◽  
Andreas Vilcinskas
Keyword(s):  
Dna Methylation ◽  
Manduca Sexta ◽  
Histone Deacetylases ◽  
Transcriptional Reprogramming ◽  
Evolution And Development ◽  
Genome Wide ◽  
A Genome ◽  
Genes Encoding ◽  
Methylation Patterns ◽  
Complete Metamorphosis

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.

scholarly journals DNA methylation reprogramming in medaka fish, a promising animal model for environmental epigenetics research

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Xuegeng Wang ◽  
Ramji K Bhandari
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Primordial Germ Cell ◽  
Preimplantation Embryos ◽  
Phenotypic Traits ◽  
Developmental Potential ◽  
Genome Wide ◽  
Genome Methylation ◽  
Methylation Patterns ◽  
Human And Mouse

Abstract DNA methylation is a major epigenetic modification that undergoes dramatic changes in two epigenetic reprogramming windows during development: first in preimplantation embryos and second in primordial germ cell (PGC) specification. In both windows, DNA methylation patterns are reprogrammed genome-wide, and the majority of inherited methylation marks are erased, generating cells with broad developmental potential. Recent studies reported that the reprogramming of genome methylation in medaka is similar to human and mouse, suggesting that medaka may serve as a suitable biomedical model for comparative studies focused on the epigenetic and transgenerational inheritance of phenotypic traits. In this mini review, we will discuss how somatic and germ cells in post-fertilization stage embryos are epigenetically reprogrammed in mammals and fishes with a particular focus on DNA methylation dynamics.

scholarly journals Regulation of DNA methylation on key parasitism genes of Cysticercus cellulosae revealed by integrative epigenomic-transcriptomic analyses

2018 ◽  
Author(s):  
Shumin Sun ◽  
Xiaolei Liu ◽  
Guanyu Ji ◽  
Xuelin Wang ◽  
Junwen Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Developmental Regulation ◽  
Taenia Solium ◽  
Host Interactions ◽  
Genome Wide ◽  
Cysticercus Cellulosae ◽  
Genes Encoding ◽  
Genome Bisulfite Sequencing ◽  
Parasitism Genes

AbstractBackgroundThe life cycle of Taenia solium is characterized by different stages of development, requiring various kinds of hosts that can appropriately harbor the eggs (proglottids), the oncospheres, the larvae and the adults. Similar to other metazoan pathogens, T. solium undergoes transcriptional and developmental regulation via epigenetics during its complex lifecycle and host interactions.ResultIn the present study, we integrated whole-genome bisulfite sequencing and RNA-seq technologies to characterize the genome-wide DNA methylation and its effect on transcription of Cysticercus cellulosae of T. solium. We confirm that the T. solium genome in the cysticercus stage is epigenetically modified by DNA methylation in a pattern similar to that of other invertebrate genomes, i.e., sparsely or moderately methylated. We also observed an enrichment of non-CpG methylation in defined genetic elements of the T. solium genome. Furthermore, an integrative analysis of both the transcriptome and the DNA methylome indicated a strong correlation between these two datasets, suggesting that gene expression might be tightly regulated by DNA methylation. Importantly, our data suggested that DNA methylation might play an important role in repressing key parasitism-related genes, including genes encoding excretion-secretion proteins, thereby raising the possibility of targeting DNA methylation processes as a useful strategy in therapeutics of cysticercosis.ConclusionOur study will provide a foundation for future studies to explore this key epigenetic modification in development of Cysticercus cellulosae and in human cysticercus disease.

Examination of the dynamics of global DNA methylation pattern establishment during spermatogenesiss

2007 ◽  
Vol 30 (4) ◽  
pp. 90
Author(s):  
Kirsten Niles ◽  
Sophie La Salle ◽  
Christopher Oakes ◽  
Jacquetta Trasler
Keyword(s):  
Dna Methylation ◽  
Germ Cell ◽  
Germ Cells ◽  
Epigenetic Modification ◽  
Methylation Pattern ◽  
Chromosome 9 ◽  
Specific Gene ◽  
Global Methylation ◽  
Dna Methylation Pattern ◽  
Methylation Patterns

Background: DNA methylation is an epigenetic modification involved in gene expression, genome stability, and genomic imprinting. In the male, methylation patterns are initially erased in primordial germ cells (PGCs) as they enter the gonadal ridge; methylation patterns are then acquired on CpG dinucleotides during gametogenesis. Correct pattern establishment is essential for normal spermatogenesis. To date, the characterization and timing of methylation pattern acquisition in PGCs has been described using a limited number of specific gene loci. This study aimed to describe DNA methylation pattern establishment dynamics during male gametogenesis through global methylation profiling techniques in a mouse model. Methods: Using a chromosome based approach, primers were designed for 24 regions spanning chromosome 9; intergenic, non-repeat, non-CpG island sequences were chosen for study based on previous evidence that these types of sequences are targets for testis-specific methylation events. The percent methylation was determined in each region by quantitative analysis of DNA methylation using real-time PCR (qAMP). The germ cell-specific pattern was determined by comparing methylation between spermatozoa and liver. To examine methylation in developing germ cells, spermatogonia from 2 day- and 6 day-old Oct4-GFP (green fluorescent protein) mice were isolated using fluorescence activated cell sorting. Results: As compared to liver, four loci were hypomethylated and five loci were hypermethylated in spermatozoa, supporting previous results indicating a unique methylation pattern in male germ cells. Only one region was hypomethylated and no regions were hypermethylated in day 6 spermatogonia as compared to mature spermatozoa, signifying that the bulk of DNA methylation is established prior to type A spermatogonia. The methylation in day 2 spermatogonia, germ cells that are just commencing mitosis, revealed differences of 15-20% compared to day 6 spermatogonia at five regions indicating that the most crucial phase of DNA methylation acquisition occurs prenatally. Conclusion: Together, these studies provide further evidence that germ cell methylation patterns differ from those in somatic tissues and suggest that much of methylation at intergenic sites is acquired during prenatal germ cell development. (Supported by CIHR)

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

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.

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

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.

Genome-Wide DNA Methylation Patterns Analysis of Noncoding RNAs in Temporal Lobe Epilepsy Patients

2017 ◽  
Vol 55 (1) ◽  
pp. 793-803 ◽  
Author(s):  
Wenbiao Xiao ◽  
Yuze Cao ◽  
Hongyu Long ◽  
Zhaohui Luo ◽  
Shuyu Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Noncoding Rnas ◽  
Genome Wide ◽  
Methylation Patterns

Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessilyn Dunn ◽  
Haiwei Qiu ◽  
Soyeon Kim ◽  
Daudi Jjingo ◽  
Ryan Hoffman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Western Diet ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

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