Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

Mao, Rong; Wang, Xiaowen; Spitznagel, Edward L.; Frelin, Laurence P.; Ting, Jason C.; Ding, Huashi; Kim, Jung-whan; Ruczinski, Ingo; Downey, Thomas J.; Pevsner, Jonathan

doi:10.1186/gb-2005-6-13-r107

Cited by 142 publications

(99 citation statements)

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“…We compared the amniocyte dataset with our previously published data from the second trimester AF supernatant (NCBI GEO ID: GSE16176), and datasets generated by other groups using iPSCs and iPSC-derived neurons (NCBI GEO IDs: GSE48611, GSE42956) as well as human post-mortem fetal cerebrum and cerebellum data (NCBI GEO ID: GSE1397) from fetuses with T21 and age and sex-matched euploid fetuses47917. Because of the limited number of differentially-regulated genes detected at FDRs off 5% and 20%, we used the top 1% up- and down-regulated genes in all of these datasets for a more comprehensive functional pathway analysis.…”

Section: Methodsmentioning

confidence: 99%

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome

Guedj

Pennings

Massingham

et al. 2016

Sci Rep

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Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn, and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice.

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Section: Methodsmentioning

confidence: 99%

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome

Guedj

Pennings

Massingham

et al. 2016

Sci Rep

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“…While several reports have investigated gene expression in postmortem human DS brains or derived pluripotent stem cells (Letourneau et al, 2014; Lockstone et al, 2007; Mao et al, 2003, 2005), these studies are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation. We therefore set out to characterize the spatiotemporal dynamics of gene expression in the DS and matched euploid brain and to subsequently decipher the biological processes affected over the course of prenatal and postnatal development.…”

Section: Introductionmentioning

confidence: 99%

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Olmos-Serrano

Kang

Tyler

et al. 2016

Neuron

211

259

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SUMMARY Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS and provide a transcriptional framework for further investigating DS neuropathogenesis.

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“…We conducted expression profile analysis using Affymetrix U133 Plus 2.0 GeneChip® with standard protocols (Affimetrix), as published (Mao et al, 2005). These transcripts corresponded to 22,500 human transcript sets.…”

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confidence: 99%

“…PCA allows visualization of highly dimensional data along principal component axes. These axes reflect the degree of variance in the data allowing the identification of groups of data having possible biological relevance (Kondo et al, 2013; Mao et al, 2005). To test which biological functions contribute these distributions, we applied Gene Ontology Consortium functional analysis (www.geneontology.org) on the TIBCO Spotfire DecisionSite analytic platform, according to the established protocol (Tavazoie et al, 1999).…”

mentioning

confidence: 99%

Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: Utility and limitation of the surrogate tissues in research for brain disorders

Horiuchi

Kano

Ishizuka

et al. 2013

Neuroscience Research

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Human olfactory cells obtained by rapid nasal biopsy have been suggested to be a good surrogate system to address brain disease-associated molecular changes. Nonetheless, whether use of this experimental strategy is justified remains unclear. Here we compared expression profiles of olfactory cells systematically with those from the brain tissues and other cells. Principal component analysis indicated that the expression profiles of olfactory cells are very different from those of blood cells, but are closer to those of stem cells, in particular mesenchymal stem cells, that can be differentiated into the cells of the central nervous system.

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Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

Abstract: Microarray analysis of transcript levels in fetal cerebellum and heart tissues of Down syndrome patients showed a disruption only of chromosome 21 gene expression.

Cited by 142 publications

References 50 publications

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: Utility and limitation of the surrogate tissues in research for brain disorders

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