Project description:Background: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Results: Here, 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 brain cells. 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, implicating a mechanism involving altered transcription factor binding. 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. Conclusions: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. Examination of methylation changes in two mouse models of Down syndrome with sub-chromosomal duplications, Dp(10)1Yey and Dp(16)1Yey, compared to one littermate wild type mouse using whole genome bisulfite sequencing.
Project description:Down Syndrome (DS) is a relatively severe chromosomal disorder associated with many significant clinical anomalies. Nowadays, it is still challenging to collect DS samples for studies in clinical settings. In addition, there are no perfect animal models for DS. Therefore, we constructed disease-specific induced pluripotent stem cells（iPSCs）to explore a new modality for non-invasive prenatal diagnosis of DS.
Project description:This case-control study utilized mass spectrometry-based proteomics to compare exosomes from non-diabetic stroke (nDS=14), diabetic stroke (DS=13), and healthy control (HC=12) subjects. Among 1288 identified proteins, 387 were statistically compared. Statistical comparisons using a general linear model (log2 foldchange 0.58 and FDR-p0.05) were performed for nDS vs. HC, DS vs. HC, and DS vs. nDS. DS vs. HC and DS vs. nDS comparisons produced 155 and 159 differentially expressed proteins, respectively.
Project description:In this study we performed a systematic analysis of the non-coding RNA (ncRNA) transcriptomes of the Down Syndrome (DS) developing hippocampus using the DS mouse model Dp16(1)Yey. DS, caused by the trisomy of chromosome 21 (HSA21) is the most frequent human chromosomal disorder. Hippocampal-dependent learning and memory impairment is one of the most significant deficits of DS. ncRNAs: microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) have been increasingly revealed to be participating in various biological activities, especially in the brain development and neuronal functions. This study provides a map of the dysregulated lncRNAs and circRNAs in the DS developing hippocampus for the first time.
Project description:Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer’s disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.
