Assessment and site-specific manipulation of DNA (hydroxy-)methylation during mouse corticogenesis
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ABSTRACT:
PROVIDER: PRJNA413136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6130250.fastq.gz | Fastqsanger.gz | |||
| SRR6130260.fastq.gz | Fastqsanger.gz | |||
| SRR6130270.fastq.gz | Fastqsanger.gz | |||
| SRR6130280.fastq.gz | Fastqsanger.gz | |||
| SRR6130251.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: In this study we investigated the molecular role of cytosine modification in the developing cortex of mice. To this aim we isolated thee linage related cell populations of the developing cortex and mapped both, 5mC as well as 5hmC on a genome-wide scale. Furthermore we established a system to site-specifcally demethylate DNA by using a dCas9-Tet1 fusion protein. Methods: Neuronal stem cells (Btg2-/Tubb3-), neurogenic progenitors (Btg2+/Tubb3-) and neurons (Tubb3+) were isolated from E14.5 Btg2-RFP/Tubb3-GFP double heterozygous mouse embryos (Aprea et al. 2013) and were used for a comparative immunoprecipitation of 5mC and 5hmC (Tan et al. 2013). Results: We were able to identify several genomic regions that change dynamically (hydroxy-)methylation patterns in specific cell type. Specifically for regions losing 5mC and gaining 5hmC we found a consistent enrichment in neurogenesis related GOterms, genomic features, transcription factor binding motifs and different histone marks. Furthermore we found that loss in 5mC and gain in 5hmC correlate with each other and lead to the upregulation of nearby genes. Site-specific demethylation of the identified differentially (hydroxy-)methylated regions in vivo, led to a premature upregulation of the nearby genes which resulted in an altered development of the brain.
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Project description:Dynamic changes in DNA (hydroxy-)methylation are fundamental for stem cell differentiation. However, the signature of these epigenetic marks in specific cell types during corticogenesis is unknown. Moreover, site-specific manipulation of cytosine modifications is needed to reveal the significance and function of these changes. Here, we report the first assessment of (hydroxy-)methylation in neural stem cells, neurogenic progenitors, and newborn neurons during mammalian corticogenesis. We found that gain in hydroxymethylation and loss in methylation occur sequentially at specific cellular transitions during neurogenic commitment. We also found that these changes predominantly occur within enhancers of neurogenic genes up-regulated during neurogenesis and target of pioneer transcription factors. We further optimized the use of dCas9-Tet1 manipulation of (hydroxy-)methylation, locus-specifically, in vivo, showing the biological relevance of our observations for Dchs1, a regulator of corticogenesis involved in developmental malformations and cognitive impairment. Together, our data reveal the dynamics of cytosine modifications in lineage-related cell types, whereby methylation is reduced and hydroxymethylation gained during the neurogenic lineage concurrently with up-regulation of pioneer transcription factors and activation of enhancers for neurogenic genes.
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Project description:Understanding genomic functions requires site-specific manipulation of loci via efficient protein effector targeting systems. However, few approaches for targeted manipulation of the epigenome are available in plants. Here, we adapt the dCas9-SunTag system to engineer targeted gene activation and DNA methylation in Arabidopsis. We demonstrate that a dCas9-SunTag system utilizing the transcriptional activator VP64 drives robust and specific activation of several loci, including protein coding genes and transposable elements, in diverse chromatin contexts. In addition, we present a CRISPR-based methylation targeting system for plants, utilizing a SunTag system with the catalytic domain of the Nicotiana tabacum DRM methyltransferase, which efficiently targets DNA methylation to specific loci, including the FWA promoter, triggering a developmental phenotype, and the SUPERMAN promoter. These SunTag systems represent valuable tools for the site-specific manipulation of plant epigenomes.
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