Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models.

ABSTRACT: An important line of postgenomic research seeks to understand how genetic factors can influence epigenetic patterning. Here we review epigenetic effects of chromosomal aneuploidies, focusing on findings in Down syndrome (DS, trisomy 21). Recent work in human DS and mouse models has shown that the extra chromosome 21 acts in trans to produce epigenetic changes, including differential CpG methylation (DS-DM), in specific sets of downstream target genes, mostly on other chromosomes. Mechanistic hypotheses emerging from these data include roles of chromosome 21-linked methylation pathway genes (DNMT3L and others) and transcription factor genes (RUNX1, OLIG2, GABPA, ERG and ETS2) in shaping the patterns of DS-DM. The findings may have broader implications for trans-acting epigenetic effects of chromosomal and subchromosomal aneuploidies in other human developmental and neuropsychiatric disorders, and in cancers.

SUBMITTER: Do C

PROVIDER: S-EPMC5549717 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models.

Do Catherine C Xing Zhuo Z Yu Y Eugene YE Tycko Benjamin B

Epigenomics 20161202 2

An important line of postgenomic research seeks to understand how genetic factors can influence epigenetic patterning. Here we review epigenetic effects of chromosomal aneuploidies, focusing on findings in Down syndrome (DS, trisomy 21). Recent work in human DS and mouse models has shown that the extra chromosome 21 acts in trans to produce epigenetic changes, including differential CpG methylation (DS-DM), in specific sets of downstream target genes, mostly on other chromosomes. Mechanistic hyp ...[more]

PMID: 27911079

Similar Datasets

Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models.

Project description:BackgroundTrisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood.ResultsHere, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects.ConclusionsThese data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning.

| S-EPMC4659173 | biostudies-literature

Trans-effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-10-30 | GSE74519 | GEO

Trans-effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-10-30 | E-GEOD-74519 | biostudies-arrayexpress

Trans-effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models

Project description:Trans-effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models

| PRJNA300631 | ENA

Correction of Down syndrome and Edwards syndrome aneuploidies in human cell cultures.

Project description:Aneuploidy, an abnormal number of chromosomes, has previously been considered irremediable. Here, we report findings that euploid cells increased among cultured aneuploid cells after exposure to the protein ZSCAN4, encoded by a mammalian-specific gene that is ordinarily expressed in preimplantation embryos and occasionally in stem cells. For footprint-free delivery of ZSCAN4 to cells, we developed ZSCAN4 synthetic mRNAs and Sendai virus vectors that encode human ZSCAN4. Applying the ZSCAN4 biologics to established cultures of mouse embryonic stem cells, most of which had become aneuploid and polyploid, dramatically increased the number of euploid cells within a few days. We then tested the biologics on non-immortalized primary human fibroblast cells derived from four individuals with Down syndrome—the most frequent autosomal trisomy of chromosome 21. Within weeks after ZSCAN4 application to the cells in culture, fluorescent in situ hybridization with a chromosome 21-specific probe detected the emergence of up to 24% of cells with only two rather than three copies. High-resolution G-banded chromosomes further showed up to 40% of cells with a normal karyotype. These findings were confirmed by whole-exome sequencing. Similar results were obtained for cells with the trisomy 18 of Edwards syndrome. Thus a direct, efficient correction of aneuploidy in human fibroblast cells seems possible in vitro using human ZSCAN4.

| S-EPMC4596399 | biostudies-literature

Mouse models of Down syndrome: gene content and consequences.

Project description:Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is trisomic for 125 human protein-coding orthologs, but only 90 of these are Hsa21 orthologs and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret the results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review the functional information on Hsa21 protein-coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.

| S-EPMC5471624 | biostudies-literature

Down syndrome mouse models have an abnormal enteric nervous system.

Project description:Children with trisomy 21 (Down syndrome [DS]) have a 130-fold increased incidence of Hirschsprung Disease (HSCR), a developmental defect where the enteric nervous system (ENS) is missing from distal bowel (i.e., distal bowel is aganglionic). Treatment for HSCR is surgical resection of aganglionic bowel, but many children have bowel problems after surgery. Post-surgical problems like enterocolitis and soiling are especially common in children with DS. To determine how trisomy 21 affects ENS development, we evaluated the ENS in two DS mouse models, Ts65Dn and Tc1. These mice are trisomic for many chromosome 21 homologous genes, including Dscam and Dyrk1a, which are hypothesized to contribute to HSCR risk. Ts65Dn and Tc1 mice have normal ENS precursor migration at E12.5 and almost normal myenteric plexus structure as adults. However, Ts65Dn and Tc1 mice have markedly reduced submucosal plexus neuron density throughout the bowel. Surprisingly, the submucosal neuron defect in Ts65Dn mice is not due to excess Dscam or Dyrk1a, since normalizing copy number for these genes does not rescue the defect. These findings suggest the possibility that the high frequency of bowel problems in children with DS and HSCR may occur because of additional unrecognized problems with ENS structure.

| S-EPMC6629165 | biostudies-literature

Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome.

Project description:Down Syndrome (DS) is the most common genetic disorder associated with intellectual disability (ID). Excitatory neurons of DS patients and mouse models show decreased size of dendritic field and reduction of spine density. Whether these defects are caused by cell autonomous alterations or by abnormal multicellular circuitry is still unknown. In this work, we explored this issue by culturing cortical neurons obtained from two mouse models of DS: the widely used Ts65Dn and the less characterized Ts2Cje. We observed that, in the in vitro conditions, axon specification and elongation, as well as dendritogenesis, take place without evident abnormalities, indicating that the initial phases of neuronal differentiation do not suffer from the presence of an imbalanced genetic dosage. Conversely, our analysis highlighted differences between trisomic and euploid neurons in terms of reduction of spine density, in accordance with in vivo data obtained by other groups, proposing the presence of a cell-intrinsic malfunction. This work suggests that the characteristic morphological defects of DS neurons are likely to be caused by the possible combination of cell-intrinsic defects together with cell-extrinsic cues. Additionally, our data support the possibility of using the more sustainable line Ts2Cje as a standard model for the study of DS.

| S-EPMC6795679 | biostudies-literature

Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome.

Project description:Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

| S-EPMC6996020 | biostudies-literature

Meiotic behavior of aneuploid chromatin in mouse models of Down syndrome.

Project description:Aneuploidy, which leads to unpaired chromosomal axes during meiosis, is frequently accompanied by infertility. We previously showed, using three mouse models of Down syndrome, that it is an extra chromosome, but not extra gene dose, that is associated with male infertility and virtual absence of post-meiotic gem cells. Here, we test the hypothesis that aneuploid segments are differentially modified and expressed during meiosis, depending on whether they are present as an extra chromosome or not. In all three models examined, the trisomic region lacks a pairing partner, but in one case, spermatocytes have an extra (and unpaired) chromosome, while the two other models involve translocation of the trisomic region rather than an extra chromosome. An extra unpaired chromosome was always modified by phosphorylation of histone H2AX and lacked RNA PolII. But in the case of trisomic regions attached to a paired chromosome, assembly of these protein modifications was affected by the position of a trisomic region relative to a centromere and the physical extent of the unpaired chromatin. Analysis of gene expression in testes revealed that extra copy number alone was not sufficient for meiotic upregulation of genes in the trisomic interval. Additionally and unexpectedly, presence of meiotic gene silencing chromatin modifications was not sufficient for downregulation of genes in unpaired trisomic chromatin. Thus, the meiotic chromatin modifications that are cytologically visible are unlikely to be directly involved in sterility versus fertility of DS models. Finally, the presence of an extra unpaired chromosome, but not the presence of extra (trisomic) genes, caused global deregulation of transcription in spermatocytes. These results reveal mechanisms by which an extra chromosome, but not trisomic gene dose, impact on meiotic progress and infertility.

| S-EPMC2848991 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data