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WGBS of medial frontal cortices of P28 offspring from breeding of Dnmt3l conditional knockin and Emx1-cre mice

ABSTRACT: The objective of the study was to examine the genomic DNA methylation changes in the medial frontal cortices of P28 offspring from the breeding of Dnmt3l conditional knockin and Emx1-cre mice, the strain of C57BL/6J. There were 12 samples in total- CC1rest, CC3rest, CF2rest, B-3, B-4, and B-5 were medial frontal cortices from the male and female Emx1-cre mice, respectively, which were used as the control groups (CON). CC2rest, CD5rest, CF1rest, D-1, CD6rest, and CD16rest were medial frontal cortices from the male and female Dnmt3l overexpression mice, respectively, which were used as the experimental groups (OE). The genomic DNA of each sample was extracted from the medial frontal cortices. We analyzed methylation level changes across the genome using methylation-capture followed by bisulfite sequencing. Overall, among the more than 1.7 million captured CpG sites, 16.38% had significant differences in methylation levels; the overall methylation rate of the genome was slightly increased (~5%); the methylation level distribution of all CpG sites did not change significantly. In different functional regions of the genome, most of the differentially methylated CpG sites were mildly increased (β value difference <0.2), and most of the methylation difference sites were concentrated in the intergenic and intron regions.

ORGANISM(S): Mus musculus

PROVIDER: GSE271949 | GEO | 2024/08/31

REPOSITORIES: GEO

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Project description:The objective of the study was to examine the gene expression changes in the medial frontal cortices of P28 offspring from the breeding of Dnmt3l conditional knockin and Emx1-cre mice, strain of C57BL/6J. There were 12 samples in total- A-1, A-2, A-3, B-1, B-2, B-3, C-1, C-2, C-3, D-1, D-2, and D-3. A-1 to A-3 and B-1 to B-3 were medial frontal cortices from the male and female Emx1-cre mice respectively, which were used as the control groups (CON). C-1 to C-3 and D-1 to D-3 were medial frontal cortices from the male and female Dnmt3l overexpression mice respectively, which were used as the experimental groups (OE). The total RNA of each sample was extracted from the medial frontal cortices by using TRIzol reagent. Then the RNA samples were processed for high throughput transcriptome sequencing on Illumina HiSeq 3000 platform. There were two types of libraries: the circRNA, mRNA, and lncRNA were all constructed by removing rRNA (one library, three types of RNA were analyzed together), and the insert fragment was about 300bp; the small RNA was constructed and analyzed separately, mainly microRNA of about 22bp. Results: among 119414 cleaned mRNAs, 3015 were differentially expressed in OE group compared with CON group (p value ≤ 0.05 and expression change ≥2 fold). The differential expressed genes distributed in all chromosomes. Functional annotation with GO and KEGG enrichment revealed the top functional groups including ATP binding, zinc ion binding, glutamatergic synapse, dopaminergic synapse, MAPK signaling pathway, and PI3K-Akt signaling pathway. Among 23698 lncRNAs, 658 were differentially expressed in OE group compared with CON group (p value ≤ 0.05 and expression change ≥2 fold). Among 10673 circRNAs, 49 were differentially expressed in OE group compared with CON group (p value ≤ 0.05 and expression change ≥2 fold). Among 1821 microRNAs, 101 were differentially expressed in OE group compared with CON group (p value ≤ 0.05 and expression change ≥2 fold).

Project description:Background: Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results: DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions: Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

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WGBS of medial frontal cortices of P28 offspring from breeding of Dnmt3l conditional knockin and Emx1-cre mice

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