scholarly journals Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics

2020 ◽  
Vol 29 (5) ◽  
pp. 785-802 ◽  
Author(s):  
Blandine Ponroy Bally ◽  
W Todd Farmer ◽  
Emma V Jones ◽  
Selin Jessa ◽  
J Benjamin Kacerovsky ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Down Syndrome ◽  
Cell Adhesion ◽  
Brain Development ◽  
Trisomy 21 ◽  
Chromatin Accessibility ◽  
Chromosome 21 ◽  
Genome Wide ◽  
And Function ◽  
The Impact

Abstract Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.

scholarly journals Astrocytes in Down Syndrome Across the Lifespan

2021 ◽  
Vol 15 ◽  
Author(s):  
Blandine Ponroy Bally ◽  
Keith K. Murai
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Chromosome 21 ◽  
Early Brain Development ◽  
The Central Nervous System ◽  
Circuit Development ◽  
And Function ◽  
The Impact ◽  
The Brain

Down Syndrome (DS) is the most common genetic cause of intellectual disability in which delays and impairments in brain development and function lead to neurological and cognitive phenotypes. Traditionally, a neurocentric approach, focusing on neurons and their connectivity, has been applied to understanding the mechanisms involved in DS brain pathophysiology with an emphasis on how triplication of chromosome 21 leads to alterations in neuronal survival and homeostasis, synaptogenesis, brain circuit development, and neurodegeneration. However, recent studies have drawn attention to the role of non-neuronal cells, especially astrocytes, in DS. Astrocytes comprise a large proportion of cells in the central nervous system (CNS) and are critical for brain development, homeostasis, and function. As triplication of chromosome 21 occurs in all cells in DS (with the exception of mosaic DS), a deeper understanding of the impact of trisomy 21 on astrocytes in DS pathophysiology is warranted and will likely be necessary for determining how specific brain alterations and neurological phenotypes emerge and progress in DS. Here, we review the current understanding of the role of astrocytes in DS, and discuss how specific perturbations in this cell type can impact the brain across the lifespan from early brain development to adult stages. Finally, we highlight how targeting, modifying, and/or correcting specific molecular pathways and properties of astrocytes in DS may provide an effective therapeutic direction given the important role of astrocytes in regulating brain development and function.

scholarly journals Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome

2021 ◽  
Vol 17 (9) ◽  
pp. e1009317
Author(s):  
Ilario De Toma ◽  
Cesar Sierra ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Differential Expression ◽  
Web Application ◽  
Meta Analysis ◽  
Chromosome 21 ◽  
Complex Disorders ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a “DS network”. We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in “clusters”, so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of “co-deregulation” involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created “metaDEA” an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.

scholarly journals Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

2021 ◽  
Author(s):  
Mengmeng Jin ◽  
Ranji Xu ◽  
Mahabub Maraj Alam ◽  
Ziyuan Ma ◽  
Sining Zhu ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Type I Interferon ◽  
Chromosome 21 ◽  
Type I ◽  
Chimeric Mouse ◽  
Interferon Signaling ◽  
Alzheimers Disease ◽  
Human Microglia ◽  
The Impact

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic neurotransmission, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA-sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

scholarly journals Comparative Genome-Wide Dna Methylation Analysis In Myocardial Tissue From Donors With And Without Down Syndrome

2020 ◽  
Author(s):  
Romina B. Cejas ◽  
Jie Wang ◽  
Rachael Hageman-Blair ◽  
Song Liu ◽  
Javier G. Blanco
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Chromosome 21 ◽  
Myocardial Tissue ◽  
Differentially Methylated Regions ◽  
Cpg Sites ◽  
Genome Wide ◽  
Non Coding Rnas ◽  
Dna Methylation Analysis

AbstractDown syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. More than 480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors’ age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.

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

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.

Molecular Cytogenetic Classification of Down Syndrome and Screening of Somatic Aneuploidy in Mothers

2021 ◽  
pp. 1-9
Author(s):  
Sushil Kumar Jaiswal ◽  
Ashok Kumar ◽  
Amit Kumar Rai
Keyword(s):  
Down Syndrome ◽  
Peripheral Blood ◽  
Trisomy 21 ◽  
Health Management ◽  
Chromosome 21 ◽  
Robertsonian Translocations ◽  
Significant Difference ◽  
And Control

Down Syndrome (DS) caused by trisomy 21 results in various congenital and developmental complications in children. It is crucial to cytogenetically diagnose the DS cases early for their proper health management and to reduce the risk of further DS childbirths in mothers. In this study, we performed a cytogenetic analysis of 436 suspected DS cases using karyotyping and fluorescent in situ hybridization. We detected free trisomies (95.3%), robertsonian translocations (2.4%), isochromosomes (0.6%), and mosaics (1.2%). We observed a slightly higher incidence of DS childbirth in younger mothers compared to mothers with advanced age. We compared the somatic aneuploidy in peripheral blood of mothers having DS children (MDS) and control mothers (CM) to identify biomarkers for predicting the risk for DS childbirths. No significant difference was observed. After induced demethylation in peripheral blood cells, we did not observe a significant difference in the frequency of aneuploidy between MDS and CM. In conclusion, free trisomy 21 is the most common type of chromosomal abnormality in DS. A small number of DS cases have translocations and mosaicism of chromosome 21. Additionally, somatic aneuploidy in the peripheral blood from the mother is not an effective marker to predict DS childbirths.

scholarly journals Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles

2020 ◽  
Author(s):  
Benjamin I Laufer ◽  
Hyeyeon Hwang ◽  
Julia M Jianu ◽  
Charles E Mordaunt ◽  
Ian F Korf ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Early Life ◽  
Trisomy 21 ◽  
Bisulfite Sequencing ◽  
Dried Blood Spots ◽  
Whole Genome ◽  
Genome Wide ◽  
Low Pass ◽  
Genome Bisulfite Sequencing

Abstract Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q < 0.05) differentially methylated regions (DMRs) that distinguished DS from typical development and idiopathic developmental delay were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons with previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q < 0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q < 0.05) enriched for blood-specific chromatin states. A ~28 kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q < 0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early life mechanisms of epigenomic dysregulation resulting from trisomy 21.

scholarly journals Normative range parenting and the developing brain: a scoping review of the literature

2019 ◽  
Author(s):  
Madeline Farber ◽  
Dylan Gee ◽  
Ahmad R. Hariri
Keyword(s):  
Mental Health ◽  
Brain Development ◽  
Scoping Review ◽  
Developmental Trajectories ◽  
Future Research ◽  
Risk And Resilience ◽  
Abuse And Neglect ◽  
Brain Structure And Function ◽  
And Function ◽  
The Impact

Studies of early adversity such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in brain development and mental health. However, the impact of normative range variability in caregiving on such biobehavioral processes remains poorly understood. Thus, we lack an essential foundation for understanding broader, population-representative developmental mechanisms of risk and resilience. Here, we conduct a scoping review of the extant literature centered on the question, “Is variability in normative range parenting associated with variability in brain structure and function?” After removing duplicates and screening by title, abstract, and full-text, 23 records were included in a qualitative review. The most striking outcome of this review was not only how few studies have explored associations between brain development and normative range parenting, but also how little methodological consistency exists across published studies. In light of these limitations, we propose recommendations for future research on normative range parenting and brain development. In doing so, we hope to facilitate evidence-based research that will help inform policies and practices that yield optimal developmental trajectories and mental health.

scholarly journals Genome-wide effects of chromatin on vitamin D signaling

2020 ◽  
Vol 64 (4) ◽  
pp. R45-R56 ◽  
Author(s):  
Andrea Hanel ◽  
Henna-Riikka Malmberg ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Binding Sites ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Transcription Start Sites ◽  
Dihydroxyvitamin D ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Vitamin D Signaling ◽  
The Impact

Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.

scholarly journals Gambaran Erupsi Gigi Permanen pada Anak Sindrom Down Usia 10-16 Tahun di Sekolah Luar Biasa Kabupaten Jember

2018 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Loly Anastasya Sinaga ◽  
Dwi Kartika Apriyono ◽  
Masniari Novita
Keyword(s):  
Down Syndrome ◽  
Special Needs ◽  
Physical Characteristic ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Extra Chromosome ◽  
Descriptive Study ◽  
Chromosome 21 ◽  
Permanent Teeth ◽  
Intellectual Abilities

Background: Down Syndrome is a genetic disorder that occurs because of chromosome 21 has three chromosome (trisomy 21). The extra chromosome changes the genetic balance, physical characteristic, intellectual abilities, and physiological body function. Tooth eruption in Down Syndrome children typically delayed in both the timing and sequence of eruption up to two or three years. Objective: To observe the permanent teeth eruption in Down syndrome children at age 10-16 years old, boys and girls in Special Needs School in Jember. Materials and Methods: This research was a descriptive study with 7 subjects. Each subject was examined then calculated teeth that had emerged or functionally eruption with articualting paper. Result and Conclusion:  Both permanent teeth that is still partially erupted tooth (emerged/ EM) and had erupted perfectly (functionally eruption/ FE) delayed in eruption in Down Syndrome boys and girls at age 10-16 years old.

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