Explore the vast range of titles available.

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. DNA methyltrasferases play important role during mouse embryo development. Here the authors reveal the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos genome-wide.

In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development. DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.

Background Cytosine DNA methylation is a heritable epigenetic mark present in most eukaryotic groups. While the patterns and functions of DNA methylation have been extensively studied in mouse and human, their conservation in other vertebrates remains poorly explored. In this study, we interrogated the distribution and function of DNA methylation in primary fibroblasts of seven vertebrate species including bio-medical models and livestock species (human, mouse, rabbit, dog, cow, pig, and chicken). Results Our data highlight both divergence and conservation of DNA methylation patterns and functions. We show that the chicken genome is hypomethylated compared to other vertebrates. Furthermore, compared to mouse, other species show a higher frequency of methylation of CpG-rich DNA. We reveal the conservation of large unmethylated valleys and patterns of DNA methylation associated with X-chromosome inactivation through vertebrate evolution and make predictions of conserved sets of imprinted genes across mammals. Finally, using chemical inhibition of DNA methylation, we show that the silencing of germline genes and endogenous retroviruses (ERVs) are conserved functions of DNA methylation in vertebrates. Conclusions Our data highlight conserved properties of DNA methylation in vertebrate genomes but at the same time point to differences between mouse and other vertebrate species.

Background Spermatozoa have a remarkable epigenome in line with their degree of specialization, their unique nature and different requirements for successful fertilization. Accordingly, perturbations in the establishment of DNA methylation patterns during male germ cell differentiation have been associated with infertility in several species. While bull semen is widely used in artificial insemination, the literature describing DNA methylation in bull spermatozoa is still scarce. The purpose of this study was therefore to characterize the bull sperm methylome relative to both bovine somatic cells and the sperm of other mammals through a multiscale analysis. Results The quantification of DNA methylation at CCGG sites using luminometric methylation assay (LUMA) highlighted the undermethylation of bull sperm compared to the sperm of rams, stallions, mice, goats and men. Total blood cells displayed a similarly high level of methylation in bulls and rams, suggesting that undermethylation of the bovine genome was specific to sperm. Annotation of CCGG sites in different species revealed no striking bias in the distribution of genome features targeted by LUMA that could explain undermethylation of bull sperm. To map DNA methylation at a genome-wide scale, bull sperm was compared with bovine liver, fibroblasts and monocytes using reduced representation bisulfite sequencing (RRBS) and immunoprecipitation of methylated DNA followed by microarray hybridization (MeDIP-chip). These two methods exhibited differences in terms of genome coverage, and consistently, two independent sets of sequences differentially methylated in sperm and somatic cells were identified for RRBS and MeDIP-chip. Remarkably, in the two sets most of the differentially methylated sequences were hypomethylated in sperm. In agreement with previous studies in other species, the sequences that were specifically hypomethylated in bull sperm targeted processes relevant to the germline differentiation program (piRNA metabolism, meiosis, spermatogenesis) and sperm functions (cell adhesion, fertilization), as well as satellites and rDNA repeats. Conclusions These results highlight the undermethylation of bull spermatozoa when compared with both bovine somatic cells and the sperm of other mammals, and raise questions regarding the dynamics of DNA methylation in bovine male germline. Whether sperm undermethylation has potential interactions with structural variation in the cattle genome may deserve further attention.

Airborne pollution is a rising concern in urban areas. Epidemiological studies in humans and animal experiments using rodent models indicate that gestational exposure to airborne pollution, in particular diesel engine exhaust (DE), reduces birth weight, but effects depend on exposure duration, gestational window and nanoparticle (NP) concentration. Our aim was to evaluate the effects of gestational exposure to diluted DE on feto-placental development in a rabbit model. Pregnant females were exposed to diluted (1 mg/m(3)), filtered DE (NP diameter ≈ 69 nm) or clean air (controls) for 2 h/day, 5 days/week by nose-only exposure (total exposure: 20 days in a 31-day gestation). DE exposure induced early signs of growth retardation at mid gestation with decreased head length (p = 0.04) and umbilical pulse (p = 0.018). Near term, fetal head length (p = 0.029) and plasma insulin and IGF1 concentrations (p = 0.05 and p = 0.019) were reduced. Placental function was also affected, with reduced placental efficiency (fetal/placental weight) (p = 0.049), decreased placental blood flow (p = 0.009) and fetal vessel volume (p = 0.002). Non-aggregated and \"fingerprint\" NP were observed at various locations, in maternal blood space, in trophoblastic cells and in the fetal blood, demonstrating transplacental transfer. Adult female offspring were bred with control males. Although fetoplacental biometry was not affected near term, second generation fetal metabolism was modified by grand-dam exposure with decreased plasma cholesterol (p = 0.008) and increased triglyceride concentrations (p = 0.015). Repeated daily gestational exposure to DE at levels close to urban pollution can affect feto-placental development in the first and second generation.

Background: Cytosine DNA methylation is a heritable epigenetic mark present in most eukaryotic groups. While the patterns and functions of DNA methylation have been extensively studied in mouse and human, their conservation in other vertebrates remains poorly explored. In this study, we interrogated the distribution and function of DNA methylation in primary fibroblasts of seven vertebrate species including bio-medical models and livestock species (human, mouse, rabbit, dog, cow, pig, and chicken). Results: Our data highlight both divergence and conservation of DNA methylation patterns and functions. We show that the chicken genome is hypomethylated compared to other vertebrates. Furthermore, compared to mouse, other species show a higher frequency of methylation of CpG-rich DNA. We reveal the conservation of large unmethylated valleys and patterns of DNA methylation associated with X-chromosome inactivation through vertebrate evolution and make predictions of conserved sets of imprinted genes across mammals. Finally, using chemical inhibition of DNA methylation, we show that the silencing of germline genes and endogenous retroviruses (ERVs) are conserved functions of DNA methylation in vertebrates. Conclusions: Our data highlight conserved properties of DNA methylation in vertebrate genomes but at the same time point to differences between mouse and other vertebrate species.