Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo.
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ABSTRACT:
SUBMITTER: Legault LM
PROVIDER: S-EPMC7518706 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In early embryos, DNA methylation is remodelled to initiate the developmental program. For mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution maps of DNA methylation in mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryo and placenta. We show that the asymmetry between embryonic and placental DNA methylation patterns occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, the de novo methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially palliate for the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal de novo methyltransferase, the compensatory DNA methylation mechanism on DMRs becomes less effective.
2020-02-18 | GSE95610 | GEO
Project description:cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.
| S-EPMC16833 | biostudies-literature
Project description:Mouse embryos acquire global DNA methylation of their genome during implantation. However the exact roles of DNA methyltransferases (DNMTs) in embryos have not been studied comprehensively. Here we systematically analyze the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos. We find a strict division of function between DNMT1, responsible for maintenance methylation, and DNMT3A/B, solely responsible for methylation acquisition in development. By analyzing severely hypomethylated embryos, we uncover multiple functions of DNA methylation that is used as a mechanism of repression for a panel of genes including not only imprinted and germline genes, but also lineage-committed genes and 2-cell genes. DNA methylation also suppresses multiple retrotransposons and illegitimate transcripts from cryptic promoters in transposons and gene bodies. Our work provides a thorough analysis of the roles of DNA methyltransferases and the importance of DNA methylation for transcriptome integrity in mammalian embryos.
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Project description:Mounting evidence points to critical roles for DNA modifications, including 5-methylcytosine (5mC) and its oxidized forms, in the development, plasticity and disorders of the mammalian nervous system. The novel DNA base 5-hydroxymethylcytosine (5hmC) is known to be capable of initiating passive or active DNA demethylation, but whether and how extensively 5hmC functions in shaping the post-mitotic neuronal DNA methylome is unclear. Here we report the genome-wide distribution of 5hmC in dentate granule neurons from adult mouse hippocampus in vivo. 5hmC in the neuronal genome is highly enriched in gene bodies, especially in exons, and correlates with gene expression. Direct genome-wide comparison of 5hmC distribution between embryonic stem cells and neurons reveals extensive differences, reflecting the functional disparity between these two cell types. Importantly, integrative analysis of 5hmC, overall DNA methylation and gene expression profiles of dentate granule neurons in vivo reveals the genome-wide antagonism between these two states of cytosine modifications, supporting a role for 5hmC in shaping the neuronal DNA methylome by promoting active DNA demethylation.
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Project description:BackgroundPreterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The "fetal origins" hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs).ResultsEnrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth.ConclusionThese studies form the basis for future studies on the epigenetics of preterm birth, "fetal programming" and the impact of environment exposures on this important clinical challenge.
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Project description:Use of cannabidiol (CBD), the most abundant non-psychoactive compound found in cannabis (Cannabis sativa), has recently increased as a result of widespread availability of CBD-containing products. CBD is FDA-approved for the treatment of epilepsy and exhibits anxiolytic, antipsychotic, prosocial, and other behavioral effects in animal studies and clinical trials, however, the underlying mechanisms governing these phenotypes are still being elucidated. The epigenome, particularly DNA methylation, is responsive to environmental input and can govern persistent patterns of gene regulation affecting phenotype across the life course. In order to understand the epigenomic activity of cannabidiol exposure in the adult brain, 12-week-old male wild-type a/a Agouti viable yellow (Avy ) mice were exposed to either 20 mg/kg CBD or vehicle daily by oral administration for 14 days. Hippocampal tissue was collected and reduced-representation bisulfite sequencing (RRBS) was performed. Analyses revealed 3,323 differentially methylated loci (DMLs) in CBD-exposed animals with a small skew toward global hypomethylation. Genes for cell adhesion and migration, dendritic spine development, and excitatory postsynaptic potential were found to be enriched in a gene ontology term analysis of DML-containing genes, and disease ontology enrichment revealed an overrepresentation of DMLs in gene sets associated with autism spectrum disorder, schizophrenia, and other phenotypes. These results suggest that the epigenome may be a key substrate for CBD's behavioral effects and provides a wealth of gene regulatory information for further study.
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Project description:Methylation of CpG dinucleotides is a fundamental mechanism of epigenetic regulation in eukaryotic genomes. Development of methods for rapid genome wide methylation profiling will greatly facilitate both hypothesis and discovery driven research in the field of epigenetics. In this regard, a single molecule approach to methylation profiling offers several unique advantages that include elimination of chemical DNA modification steps and PCR amplification.A single molecule approach is presented for the discernment of methylation profiles, based on optical mapping. We report results from a series of pilot studies demonstrating the capabilities of optical mapping as a platform for methylation profiling of whole genomes. Optical mapping was used to discern the methylation profile from both an engineered and wild type Escherichia coli. Furthermore, the methylation status of selected loci within the genome of human embryonic stem cells was profiled using optical mapping.The optical mapping platform effectively detects DNA methylation patterns. Due to single molecule detection, optical mapping offers significant advantages over other technologies. This advantage stems from obviation of DNA modification steps, such as bisulfite treatment, and the ability of the platform to assay repeat dense regions within mammalian genomes inaccessible to techniques using array-hybridization technologies.
| S-EPMC2516518 | biostudies-other
Project description:Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5-61?years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n?=?12) and HumanMethylationEPIC BeadChip arrays (n?=?21). For the EPIC methylation data averaged for each CpG across subjects, the saliva-brain correlation (r?=?0.90) was higher than that for blood-brain (r?=?0.86) and buccal-brain (r?=?0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.
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Project description:The placental epigenome plays a vital role in regulating mammalian growth and development. Aberrations in placental DNA methylation are linked to several disease states, including intrauterine growth restriction and preeclampsia. Studying the evolution and development of the placental epigenome is critical to understanding the origin and progression of such diseases. Although high-resolution studies have found substantial variation between placental methylomes of different species, the nature of methylome variation has yet to be characterized within any individual species. We conducted a study of placental DNA methylation at high resolution in multiple strains and closely related species of house mice (Mus musculus musculus, Mus m. domesticus, and M. spretus), across developmental timepoints (embryonic days 15-18), and between two distinct layers (labyrinthine transport and junctional endocrine). We observed substantial genome-wide methylation heterogeneity in mouse placenta compared with other differentiated tissues. Species-specific methylation profiles were concentrated in retrotransposon subfamilies, specifically RLTR10 and RLTR20 subfamilies. Regulatory regions such as gene promoters and CpG islands displayed cross-species conservation, but showed strong differences between layers and developmental timepoints. Partially methylated domains exist in the mouse placenta and widen during development. Taken together, our results characterize the mouse placental methylome as a highly heterogeneous and deregulated landscape globally, intermixed with actively regulated promoter and retrotransposon sequences.
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Project description:The objective of this study was to discover DNA methylation biomarkers for detecting non-small lung cancer (NSCLC) in bronchial washings and understanding the association between DNA methylation and smoking cessation.DNA methylation was analyzed in bronchial washing samples from 70 NSCLCs and 53 hospital-based controls using Illumina HumanMethylation450K BeadChip. Methylation levels in these bronchial washings were compared to those in 897 primary lung tissues of The Cancer Genome Atlas (TCGA) data.Twenty-four CpGs (p?<?1.03E-07) were significantly methylated in bronchial washings from 70 NSCLC patients compared to those from 53 controls. The CpGs also had significant methylation in the TCGA cohort. The 123 participants were divided into a training set (N?=?82) and a test set (N?=?41) to build a classification model. Logistic regression model showed the best performance for classification of lung cancer in bronchial washing samples: the sensitivity and specificity of a marker panel consisting of seven CpGs in TFAP2A, TBX15, PHF11, TOX2, PRR15, PDGFRA, and HOXA11 genes were 87.0 and 83.3% in the test set, respectively. The area under the curve (AUC) was equal to 0.87 (95% confidence interval?=?0.73-0.96, p?<?0.001). Methylation levels of two CpGs in RUNX3 and MIR196A1 genes were inversely associated with duration of smoking cessation in the controls, but not in NSCLCs, after adjusting for pack-years of smoking.The present study suggests that NSCLC may be detected by analyzing methylation changes of seven CpGs in bronchial washings. Furthermore, smoking cessation may lead to decreased DNA methylation in nonmalignant bronchial epithelial cells in a gene-specific manner.
| S-EPMC5960087 | biostudies-other