Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression

Lu, Jie; Mccarter, Monika; Lian, Gewei; Esposito, Giuseppe; Capoccia, Elena; Delli-Bovi, Laurent C.; Hecht, Jonathan L.; Sheen, Volney L.

doi:10.1093/hmg/ddw043

Cited by 54 publications

(58 citation statements)

References 52 publications

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“…ARHGAP18 in Cluster 18, CDC42BPA in Cluster 3, CXCL12 in Cluster 8, and HS3ST2 in Cluster 5 previously reported with schizophrenia (45)(46)(47)(48); KCTD12 in Cluster 9 and PSAT1 in Cluster 8 previously reported with depressive disorder (49,50); ADAMTS1 in Cluster 10, DOCK2 in Cluster 10, HS3ST2 in Cluster 5, NAMPT in Cluster 5, and NAV in Cluster 5 previously reported with Alzheimer's disease (51)(52)(53)(54)(55); and PEX10 in Cluster 11 previously reported with Down syndrome (56).…”

Section: Gene Interpretationmentioning

confidence: 88%

Clustering by phenotype and genome-wide association study in autism

Narita

Nagai

Mizuno

et al. 2019

Preprint

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Background: Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. Methods:We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage. Results:In the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P<5.0×10 −8 . Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 gene had a significantly different distribution in the cases vs. controls in the replication cohort. Conclusions:These findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

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Section: Gene Interpretationmentioning

confidence: 88%

Clustering by phenotype and genome-wide association study in autism

Narita

Nagai

Mizuno

et al. 2019

Preprint

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“…In humans, trisomy of chromosome 21 causes Down’s syndrome. DNMT3L is encoded at the locus associated with the Down’s syndrome and is ectopically expressed in the brains of neonatal patients with Down’s syndrome, resulting in global hypermethylation at many genomic loci (Aapola et al, ; Lu et al, ). In our present study, DNMTs‐Tg mice also exhibited hypermethylation of several genomic loci in the brain.…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice

Sasaki

Hara

Yamakami

et al. 2019

Molecular Reproduction Devel

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DNA methylation is generally known to inactivate gene expression. The DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, catalyze somatic cell lineage‐specific DNA methylation, while DNMT3A and DNMT3L catalyze germ cell lineage‐specific DNA methylation. How such lineage‐ and gene‐specific DNA methylation patterns are created remains to be elucidated. To better understand the regulatory mechanisms underlying DNA methylation, we generated transgenic mice that constitutively expressed DNMT3A and DNMT3L, and analyzed DNA methylation, gene expression, and their subsequent impact on ontogeny. All transgenic mice were born normally but died within 20 weeks accompanied with cardiac hypertrophy. Several genes were repressed in the hearts of transgenic mice compared with those in wild‐type mice. CpG islands of these downregulated genes were highly methylated in the transgenic mice. This abnormal methylation occurred in the perinatal stage. Conversely, monoallelic DNA methylation at imprinted loci was faithfully maintained in all transgenic mice, except H19 . Thus, the loci preferred by DNMT3A and DNMT3L differ between somatic and germ cell lineages.

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“…21 Interestingly, two separate studies of DS fetal frontal cortex have found that while significant DS-differential CpGs located on HSA21 displayed a balance of hypermethylation and hypomethylation, the significant CpGs across all other chromosomes were predominantly hypermethylated. 21,22 The DS differentially methylated CpGs belonged to genes involved in ubiquitin mediated proteolysis and Alzheimer's disease pathways. 22 Taken together, the differences in CpG methylation observed across a variety of DS cells/tissues are not only relevant to early developmental events but also appear to be maintained into adulthood.…”

Section: Introductionmentioning

confidence: 99%

“…21,22 The DS differentially methylated CpGs belonged to genes involved in ubiquitin mediated proteolysis and Alzheimer's disease pathways. 22 Taken together, the differences in CpG methylation observed across a variety of DS cells/tissues are not only relevant to early developmental events but also appear to be maintained into adulthood.…”

Section: Introductionmentioning

confidence: 99%

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights

Laufer¹,

Hwang²,

Ciernia³

et al. 2018

Preprint

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Down Syndrome (DS) is the most common genetic cause of intellectual disability, in which an extra copy of human chromosome 21 (HSA21) affects regional DNA methylation profiles across the genome. Although DNA methylation has been previously examined at select regulatory regions across the genome in a variety of DS tissues and cells, differentially methylated regions (DMRs) have yet to be examined in an unbiased sequencing-based approach. Here, we present the first analysis of DMRs from whole genome bisulfite sequencing (WGBS) data of human DS and matched control brain, specifically frontal cortex. While no global differences in DNA methylation were observed, we identified 3,152 DS-DMRs across the entire genome, the majority of which were hypermethylated in DS. DS-DMRs were significantly enriched at CpG islands and de-enriched at specific gene body and regulatory regions. Functionally, the hypermethylated DS-DMRs were enriched for one-carbon metabolism, membrane transport, and glutamatergic synaptic signaling, while the hypomethylated DMRs were enriched for proline isomerization, glial immune response, and apoptosis. Furthermore, in a cross-tissue comparison to previous studies of DNA methylation from diverse DS tissues and reference epigenomes, hypermethylated DS-DMRs showed a strong cross-tissue concordance, while a more tissuespecific pattern was observed for the hypomethylated DS-DMRs. Overall, this approach highlights that low-coverage WGBS of clinical samples can identify epigenetic alterations to known biological pathways, which are potentially relevant to therapeutic treatments and include metabolic pathways. These results also provide new insights into the genome-wide effects of genetic alterations on DNA methylation profiles indicative of altered neurodevelopment and brain function.

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Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression

Cited by 54 publications

References 52 publications

Clustering by phenotype and genome-wide association study in autism

Clustering by phenotype and genome-wide association study in autism

Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights

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