Abstract:SummaryDown syndrome (DS) is the leading genetic cause of mental retardation and is caused by a third copy of human chromosome 21. The different pathologies of DS involve many tissues with a distinct array of neural phenotypes. Here we characterize embryonic stem cell lines with DS (DS-ESCs), and focus on the neural aspects of the disease. Our results show that neural progenitor cells (NPCs) differentiated from five independent DS-ESC lines display increased apoptosis and downregulation of forehead development… Show more
“…Furthermore, we observed that our DEGs are enriched for targets of RUNX1 (Enrichr: ENCODE and ChEA Consensus TFs from ChIP-X; adjusted p value 0.042) such as TGFB2 and EMP1 at both differentiation stages in line with previous reports (Supplementary Fig. 2) [38, 48].…”
Section: Resultssupporting
confidence: 91%
“…3d). The strongest and most consistent upregulation at both differentiation stages was identified for RUNX1 encoding the transcription factor AML1 (average log2 fold change = 4.4), supporting its recently reported role in DS neurogenesis [38]. Together, these observations indicate that several DEGs on HSA21 implicated in neuronal functions strongly deviate from the predicted 3:2 levels in our trisomic model.Fig.…”
Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene
APP
, supporting its role for disturbed neurogenesis, and the transcription factors
OLIG1
,
OLIG2
and
RUNX1
, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.
Electronic supplementary material
The online version of this article (10.1007/s12035-019-1585-3) contains supplementary material, which is available to authorized users.
“…Furthermore, we observed that our DEGs are enriched for targets of RUNX1 (Enrichr: ENCODE and ChEA Consensus TFs from ChIP-X; adjusted p value 0.042) such as TGFB2 and EMP1 at both differentiation stages in line with previous reports (Supplementary Fig. 2) [38, 48].…”
Section: Resultssupporting
confidence: 91%
“…3d). The strongest and most consistent upregulation at both differentiation stages was identified for RUNX1 encoding the transcription factor AML1 (average log2 fold change = 4.4), supporting its recently reported role in DS neurogenesis [38]. Together, these observations indicate that several DEGs on HSA21 implicated in neuronal functions strongly deviate from the predicted 3:2 levels in our trisomic model.Fig.…”
Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene
APP
, supporting its role for disturbed neurogenesis, and the transcription factors
OLIG1
,
OLIG2
and
RUNX1
, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.
Electronic supplementary material
The online version of this article (10.1007/s12035-019-1585-3) contains supplementary material, which is available to authorized users.
“…RSUME down-regulation in spinal tissues of SOD1 G86R mice could negative impact motor units through these biological processes. Runx1 is a transcription factor stimulating neuronal differentiation and axonal plasticity and reduces BMP signaling and expression of Calca (Yoshikawa et al, 2015 , 2016 ; Halevy et al, 2016 ). Runx1 is a positive regulator of the expression of genes related to sphingolipid metabolism (Kilbey et al, 2010 ).…”
Lipid metabolism is drastically dysregulated in amyotrophic lateral sclerosis and impacts prognosis of patients. Animal models recapitulate alterations in the energy metabolism, including hypermetabolism and severe loss of adipose tissue. To gain insight into the molecular mechanisms underlying disease progression in amyotrophic lateral sclerosis, we have performed RNA-sequencing and lipidomic profiling in spinal cord of symptomatic SOD1G86R mice. Spinal transcriptome of SOD1G86R mice was characterized by differential expression of genes related to immune system, extracellular exosome, and lysosome. Hypothesis-driven identification of metabolites showed that lipids, including sphingomyelin(d18:0/26:1), ceramide(d18:1/22:0), and phosphatidylcholine(o-22:1/20:4) showed profound altered levels. A correlation between disease severity and gene expression or metabolite levels was found for sphingosine, ceramide(d18:1/26:0), Sgpp2, Sphk1, and Ugt8a. Joint-analysis revealed a significant enrichment of glycosphingolipid metabolism in SOD1G86R mice, due to the down-regulation of ceramide, glucosylceramide, and lactosylceramide and the overexpression of genes involved in their recycling in the lysosome. A drug-gene interaction database was interrogated to identify potential drugs able to modulate the dysregulated genes from the signaling pathway. Our results suggest that complex lipids are pivotally changed during the first phase of motor symptoms in an animal model of amyotrophic lateral sclerosis.
“…Although the cellular and molecular mechanisms driving these different phenotypes are incompletely understood, altered stem cell function is a potential common link. For example, expansion and differentiation defects in neuronal stem cells impair neurogenesis in the developing brain and adult brain of individuals with Down syndrome 6 – 8 . Hematopoietic stem cells accumulate DNA damage, prematurely senesce and fail to expand in mouse models of Down syndrome 9 , 10 .…”
Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
