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Transcriptome profiling of normal and DNMT3L-overexpressing human neurons [RNA-seq]

ABSTRACT: The objective of this study is to test the gene expression changes caused by DNMT3L overexpression in human neurons. The total RNA of each sample was extracted from the lentivirus infected, early differentiated human neuroprogenitors with ZsGreen (n=3) or DNMT3L (n=3) overexpression by using TRIzol reagent. Then the RNA samples were processed for high throughput transcriptome sequencing on Illumina HiSeq 3000 platform. Results: among 57 905 cleaned RNAs, 7983 RNAs were differentially expressed in DNMT3L overexpressing neurons compared with control neurons, with q-value ≤ 0.05. After limited the cut-off by adding |fold change| ≥ 1.5, the numbers of differential expressed RNAs lowered to 1073, with more down-regulation (590) than up-regulation (483). The differential expressed genes distributed in all chromosomes, also showing the pattern of more down-regulation than up-regulation in every chromosome except chromosome 21. Functional annotation with DAVID revealed the top functional groups including type I interferon signaling pathway and RNA and protein processing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157080 | GEO | 2020/08/29

REPOSITORIES: GEO

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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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Transcriptome profiling of normal and DNMT3L-overexpressing human neurons [RNA-seq]

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