Multi-influential interactions alters behaviour and cognition through six main biological cascades in Down syndrome mouse models

AbstractDown syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21. To provide novel insights into genotype–phenotype correlations, we screened the in vivo DS mouse library with standardized behavioural tests, magnetic resonance imaging (MRI) and hippocampal gene expression. Altogether this approach brings novel insights into the field. First, we unravelled several genetic interactions between different regions of the chromosome 21 and how they importantly contribute in altering the outcome of the phenotypes in brain function and structure. Then, in depth analysis of misregulated expressed genes involved in synaptic dysfunction highlitghed 6 biological cascades centered around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to advance in our understanding of DS and therapies development.HighlightsBrain function and morphology changes in DS mouse models result from multiple genetic lociEach combination of loci induces specific alteration of gene expression profile in mouse modelsAltered gene expression converges to a few functional pathwys in DS mouse hippocampiThe synaptic pathway analysis leads to six connected biological cascades and defines a specific DS disease network

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A unique downregulation of h2-calponin gene expression in Down syndrome: a possible attenuation mechanism for fetal survival by methylation at the CpG island in the trisomic chromosome 21.

Molecular and Cellular Biology ◽

10.1128/mcb.17.2.707 ◽

1997 ◽

Vol 17 (2) ◽

pp. 707-712 ◽

Cited By ~ 11

Author(s):

J Kuromitsu ◽

H Yamashita ◽

H Kataoka ◽

T Takahara ◽

M Muramatsu ◽

...

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Normal Level ◽

Cpg Island ◽

Chromosome 21 ◽

Miscarriage Rate ◽

Fetal Survival ◽

Attenuation Mechanism ◽

Downstream Gene Expression

To understand the effect of trisomic chromosome 21 on the cause of Down syndrome (DS), DNA methylation in the CpG island, which regulates the expression of adjacent genes, was investigated with the DNAs of chromosome 21 isolated from DS patients and their parents. A methylation-sensitive enzyme, BssHII, was used to digest DNAs of chromosome 21, and the resulting DNA fragments were subjected to RLGS (restriction landmark genomic scanning). Surprisingly, the CpG island of the h2-calponin gene was shown to be specifically methylated by comparative studies with RLGS and Southern blot analysis. In association with this methylation, h2-calponin gene expression was attenuated to the normal level, although other genes in the DS region of chromosome 21 were expressed dose dependently at 1.5 times the normal level. These results and the high miscarriage rate associated with trisomy 21 embryos imply that the altered in vivo methylation that attenuates downstream gene expression, which is otherwise lethal, permits the generation of DS neonates. The h2-calponin gene detected by the RLGS procedure may be one such gene that is attenuated.

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Identification of dysregulated genes in lymphocytes from children with Down syndrome

Genome ◽

10.1139/g07-100 ◽

2008 ◽

Vol 51 (1) ◽

pp. 19-29 ◽

Cited By ~ 28

Author(s):

Cesar A. Sommer ◽

Erika C. Pavarino-Bertelli ◽

Eny M. Goloni-Bertollo ◽

Flavio Henrique-Silva

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Trisomy 21 ◽

Molecular Mechanisms ◽

Cell Types ◽

Cell Receptor ◽

Chromosome 21 ◽

Global Changes ◽

Real Time Quantitative Pcr ◽

Functional Classes

The molecular mechanisms by which trisomy of human chromosome 21 disrupts normal development are not well understood. Global transcriptome studies attempting to analyze the consequences of trisomy in Down syndrome (DS) tissues have reported conflicting results, which have led to the suggestion that the analysis of specific tissues or cell types may be more productive. In the present study, we set out to analyze global changes of gene expression in lymphocytes from children with trisomy 21 by means of the serial analysis of gene expression (SAGE) methodology. Two SAGE libraries were constructed using pooled RNA of normal and Down syndrome children. Comparison between DS and normal profiles revealed that most of the transcripts were expressed at similar levels and functional classes of abundant genes were equally represented. Among the 242 significantly differentially expressed SAGE tags, several transcripts downregulated in DS code for proteins involved in T-cell and B-cell receptor signaling (e.g., PI3Kδ, RGS2, LY6E, FOS, TAGAP, CD46). The SAGE data and interindividual variability were validated by real-time quantitative PCR. Our results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS.

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Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

10.1101/2020.10.20.347013 ◽

2020 ◽

Author(s):

Matias Fuentealba ◽

Daniel K. Fabian ◽

Handan Melike Dönertaş ◽

Janet M. Thornton ◽

Linda Partridge

Keyword(s):

Gene Expression ◽

Mouse Models ◽

Molecular Mechanisms ◽

Mitochondrial Metabolism ◽

Mutant Mice ◽

Functional Enrichment ◽

List Type ◽

Gene Sets ◽

Normal Ageing ◽

Transcriptomic Changes

AbstractGenetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.HighlightsTranscriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespanThe major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolismGene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing

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Blood and Brain Gene Expression Trajectories Underlying Neuropathology and Cognitive Impairment in Neurodegeneration

10.1101/548974 ◽

2019 ◽

Author(s):

Yasser Iturria-Medina ◽

Ahmed F. Khan ◽

Quadri Adewale ◽

Keyword(s):

Gene Expression ◽

Cognitive Impairment ◽

Molecular Mechanisms ◽

Learning Algorithm ◽

Late Onset ◽

Molecular Pathways ◽

List Type ◽

Disease Evolution ◽

The Brain

SUMMARYNeurodegenerative disorders take decades to develop and their early detection is challenged by confounding non-pathological aging processes. For all neurodegenerative conditions, we lack longitudinal gene expression (GE) data covering their large temporal evolution, which hinders the fully understanding of the underlying dynamic molecular mechanisms. Here, we aimed to overcome this limitation by introducing a novel GE contrastive trajectory inference (GE-cTI) method that reveals enriched temporal patterns in a diseased population. Evaluated on 1969 subjects in the spectrum of late-onset Alzheimer’s and Huntington’s diseases (from ROSMAP, HBTRC and ADNI studies), this unsupervised machine learning algorithm strongly predicts neuropathological severity (e.g. Braak, Amyloid and Vonsattel stages). Furthermore, when applied to in-vivo blood samples (ADNI), it predicts 97% of the variance in memory deterioration and its future declining rate, supporting the identification of a powerful and minimally invasive (blood-based) tool for early clinical screening and disease prevention. This technique also allows the discovery of genes and molecular pathways, in both peripheral and brain tissues, that are highly predictive of disease evolution. Eighty percent of the most predictive molecular pathways identified in the brain were also top predictors in the blood. The GE-cTI is a promising tool for revealing complex neuropathological mechanisms, with direct implications for implementing personalized dynamic treatments in neurology.HIGHLIGHTS- Unsupervised learning detects enriched gene expression (GE) trajectories in disease- These plasma and brain GE trajectories predict neuropathology and future cognitive impairment- Most predictive molecular functions/pathways in the brain are also top predictors in the plasma- By identifying plasma GE trajectories, patients can be easily screened and follow dynamic treatments

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Faculty Opinions recommendation of Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090195.543413 ◽

2007 ◽

Author(s):

Giovanni Neri

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Human Chromosome ◽

Chromosome 21 ◽

Disease Phenotypes ◽

Human Chromosome 21

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The Mechanisms Behind the Biological Activity of Flavonoids

Current Medicinal Chemistry ◽

10.2174/0929867325666180706104829 ◽

2019 ◽

Vol 26 (39) ◽

pp. 6976-6990 ◽

Cited By ~ 12

Author(s):

Ana María González-Paramás ◽

Begoña Ayuda-Durán ◽

Sofía Martínez ◽

Susana González-Manzano ◽

Celestino Santos-Buelga

Keyword(s):

Gene Expression ◽

Biological Activity ◽

Phenolic Compounds ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Radical Scavenging ◽

Model Organism ◽

Stress Theory ◽

Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

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Decrease in the T-box1 gene expression in embryonic brain and adult hippocampus of down syndrome mouse models

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.12.026 ◽

2021 ◽

Vol 535 ◽

pp. 87-92

Author(s):

Ryohei Shimizu ◽

Keiichi Ishihara ◽

Eri Kawashita ◽

Haruhiko Sago ◽

Kazuhiro Yamakawa ◽

...

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Mouse Models ◽

Embryonic Brain ◽

Adult Hippocampus

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Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

Epigenetics & Chromatin ◽

10.1186/s13072-021-00387-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Benjamin I. Laufer ◽

J. Antonio Gomez ◽

Julia M. Jianu ◽

Janine M. LaSalle

Keyword(s):

Dna Methylation ◽

Down Syndrome ◽

Neuronal Differentiation ◽

Molecular Mechanisms ◽

Cpg Island ◽

Differential Methylation ◽

Chromosome 21 ◽

Pairwise Comparisons ◽

Genome Wide ◽

A Genome

Abstract 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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Serial analysis of gene expression (SAGE) during porcine embryo development

Reproduction Fertility and Development ◽

10.1071/rd03081 ◽

2004 ◽

Vol 16 (2) ◽

pp. 87 ◽

Cited By ~ 12

Author(s):

Le Ann Blomberg ◽

Kurt A. Zuelke

Keyword(s):

Gene Expression ◽

Functional Genomics ◽

Embryo Development ◽

Molecular Mechanisms ◽

Physiological Role ◽

Transgenic Animals ◽

Specific Gene ◽

Research Strategies

Functional genomics provides a powerful means for delving into the molecular mechanisms involved in pre-implantation development of porcine embryos. High rates of embryonic mortality (30%), following either natural mating or artificial insemination, emphasise the need to improve the efficiency of reproduction in the pig. The poor success rate of live offspring from in vitro-manipulated pig embryos also hampers efforts to generate transgenic animals for biotechnology applications. Previous analysis of differential gene expression has demonstrated stage-specific gene expression for in vivo-derived embryos and altered gene expression for in vitro-derived embryos. However, the methods used to date examine relatively few genes simultaneously and, thus, provide an incomplete glimpse of the physiological role of these genes during embryogenesis. The present review will focus on two aspects of applying functional genomics research strategies for analysing the expression of genes during elongation of pig embryos between gestational day (D) 11 and D12. First, we compare and contrast current methodologies that are being used for gene discovery and expression analysis during pig embryo development. Second, we establish a paradigm for applying serial analysis of gene expression as a functional genomics tool to obtain preliminary information essential for discovering the physiological mechanisms by which distinct embryonic phenotypes are derived.

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