Similar Datasets
Project description:While embryonic brain development and neurodegeneration have been examined extensively, the events that govern postnatal brain maturation are less understood. During this period, widespread changes in synaptic connectivity are evident1,2 and, perturbations of synaptic development or maturation can have severe neurobehavioral consequences as seen in autism spectrum disorders (ASD), epilepsy and schizophrenia3-6. Recent studies have led to the unexpected discovery that marked increases in non-canonical (non-CG) DNA methylation occur during postnatal brain maturation7-14. This de novo CH methylation (where H= A, C, T), which occurs 1-4 weeks postnatally in mice and 1-15 years in humans7, is important for experience-dependent fine tuning of gene expression15 . The critical period of CH methylation appears to be mediated by Dnmt3a, the DNA methyltransferase that catalyzes CH methylation8,9. During brain maturation, Dnmt3a levels are elevated and then sharply decline7,16, and a strict control of CH methylation seems important as mutations or variants of Dnmt3a are associated with ASD, epilepsy and intellectual disability17-19. Here we identify the microRNA miR-29 as an essential regulator of Dnmt3a and CH methylation during brain maturation. Mice deficient in miR-29 or mice in which miR-29 can no longer target Dnmt3a exhibit enhanced levels of Dnmt3a, global CH hypermethylation, and repression of neuronal genes specifically associated with synaptic activity and neurotransmission. Importantly, these mice appear normal at birth, but subsequently exhibit severe neurological deficits including susceptibility to seizures and premature lethality. Together, these results identify an essential function of miR-29 in defining the critical period of DNA methylation during brain maturation, the absence of which results in neurobehavioral deficits.
2021-02-14 | GSE157841 | GEO
Project description:While embryonic brain development and neurodegeneration have been examined extensively, the events that govern postnatal brain maturation are less understood. During this period, widespread changes in synaptic connectivity are evident1,2 and, perturbations of synaptic development or maturation can have severe neurobehavioral consequences as seen in autism spectrum disorders (ASD), epilepsy and schizophrenia3-6. Recent studies have led to the unexpected discovery that marked increases in non-canonical (non-CG) DNA methylation occur during postnatal brain maturation7-14. This de novo CH methylation (where H= A, C, T), which occurs 1-4 weeks postnatally in mice and 1-15 years in humans7, is important for experience-dependent fine tuning of gene expression15 . The critical period of CH methylation appears to be mediated by Dnmt3a, the DNA methyltransferase that catalyzes CH methylation8,9. During brain maturation, Dnmt3a levels are elevated and then sharply decline7,16, and a strict control of CH methylation seems important as mutations or variants of Dnmt3a are associated with ASD, epilepsy and intellectual disability17-19. Here we identify the microRNA miR-29 as an essential regulator of Dnmt3a and CH methylation during brain maturation. Mice deficient in miR-29 or mice in which miR-29 can no longer target Dnmt3a exhibit enhanced levels of Dnmt3a, global CH hypermethylation, and repression of neuronal genes specifically associated with synaptic activity and neurotransmission. Importantly, these mice appear normal at birth, but subsequently exhibit severe neurological deficits including susceptibility to seizures and premature lethality. Together, these results identify an essential function of miR-29 in defining the critical period of DNA methylation during brain maturation, the absence of which results in neurobehavioral deficits.
2021-04-07 | GSE140163 | GEO
Project description:Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.
| S-EPMC8103628 | biostudies-literature
Project description:MicroRNA-29 is an essential regulator of non-CG methylation during brain maturation
| PRJNA662952 | ENA
Project description:MicroRNA-29 is an essential regulator of non-CG methylation during brain maturation [RNA-seq]
| PRJNA588453 | ENA
Project description:MicroRNA-29 is an essential regulator of non-CG methylation during brain maturation [Bisulfite-seq]
| PRJNA662955 | ENA
Project description:Silencing of transposable elements (TEs) is established by small RNA-directed DNA methylation (RdDM). Maintenance of silencing is then based on a combination of RdDM and RNA-independent mechanisms involving DNA methyltransferase MET1 and chromodomain DNA methyltransferases (CMTs). Involvement of RdDM, according to this model should decrease with TE age but here we show a different pattern in tomato and Arabidopsis. In these species the CMTs silence long terminal repeat (LTR) transposons in the distal chromatin that are younger than those affected by RdDM. To account for these findings we propose that, after establishment of primary RdDM as in the original model, there is an RNA-independent maintenance phase involving CMTs followed by secondary RdDM. This progression of epigenetic silencing in the gene-rich distal chromatin is likely to influence the transcriptome either in cis or in trans depending on whether the mechanisms are RNA-dependent or -independent.
| S-EPMC7060349 | biostudies-literature
Project description:Brain aging is marked by cognitive decline and susceptibility to neurodegeneration. Calorie restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal central nervous system cellular and memory functions and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life long CR prevents age-related hippocampal DNA methylation changes. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24-month-old mice fed a 40% calorie-restricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ∼40,000 differentially methylated CG and ∼80,000 CH sites with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR-specific DNA methyltransferase 1 and Tet methylcytosine dioxygenase 3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the prolongevity effects of CR working through an epigenetic mechanism.
| S-EPMC5955819 | biostudies-literature
Project description:DNA methylation at gene promoters in a CG context is associated with transcriptional repression, including at genes silenced on the inactive X chromosome in females. Non-CG methylation (mCH) is a distinct feature of the neuronal epigenome that is differentially distributed between males and females on the X chromosome. However, little is known about differences in mCH on the active (Xa) and inactive (Xi) X chromosomes because stochastic X-chromosome inactivation (XCI) confounds allele-specific epigenomic profiling. We used whole-genome bisulfite sequencing in a mouse model with nonrandom XCI to examine allele-specific DNA methylation in frontal cortex. Xi was largely devoid of mCH, whereas Xa contained abundant mCH similar to the male X chromosome and the autosomes. In contrast to the repressive association of DNA methylation at CG dinucleotides (mCG), mCH accumulates on Xi in domains with transcriptional activity, including the bodies of most genes that escape XCI and at the X-inactivation center, validating this epigenetic mark as a signature of transcriptional activity. Escape genes showing CH hypermethylation were the only genes with CG-hypomethylated promoters on Xi, a well-known mark of active transcription. Finally, we found extensive allele-specific mCH and mCG at autosomal imprinted regions, some with a negative correlation between methylation in the two contexts, further supporting their distinct functions. Our findings show that neuronal mCH functions independently of mCG and is a highly dynamic epigenomic correlate of allele-specific gene regulation.
| S-EPMC5389278 | biostudies-literature
Project description:Cytosine (DNA) methylation in plants regulates the expression of genes and transposons. While methylation in plant genomes occurs at CG, CHG, and CHH sequence contexts, the comparative roles of the individual methylation contexts remain elusive. Here, we present Physcomitrella patens as the second plant system, besides Arabidopsis thaliana, with viable mutants with an essentially complete loss of methylation in the CG and non-CG contexts. In contrast to A. thaliana, P. patens has more robust CHH methylation, similar CG and CHG methylation levels, and minimal cross-talk between CG and non-CG methylation, making it possible to study context-specific effects independently. Our data found CHH methylation to act in redundancy with symmetric methylation in silencing transposons and to regulate the expression of CG/CHG-depleted transposons. Specific elimination of CG methylation did not dysregulate transposons or genes. In contrast, exclusive removal of non-CG methylation massively up-regulated transposons and genes. In addition, comparing two exclusively but equally CG- or CHG-methylated genomes, we show that CHG methylation acts as a greater transcriptional regulator than CG methylation. These results disentangle the transcriptional roles of CG and non-CG, as well as symmetric and asymmetric methylation in a plant genome, and point to the crucial role of non-CG methylation in genome regulation.
| S-EPMC7777129 | biostudies-literature