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GSE68169
Mus musculus
24 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
A detailed knowledge of the mechanisms underlying brain aging is fundamental to understand its functional decline and the baseline upon which brain pathologies superimpose. Endogenous protective mechanisms must contribute to the adaptability and plasticity still present in the healthy aged brain. Apolipoprotein D (ApoD) is one of the few genes with a consistent and evolutionarily conserved up-regulation in the aged brain. ApoD protecting roles upon stress or injury are well known, but a study of the effects of ApoD expression in the normal aging process is still missing. Using an ApoD-knockout mouse we analyze the effects of ApoD on factors contributing to the functional maintenance of the aged brain. We focused our cellular and molecular analyses in cortex and hippocampus at an age representing the onset of senescence where mortality risks are below 25%, avoiding bias towards long-lived animals. Lack of ApoD causes a prematurely aged brain without altering lifespan. Age-dependent hyperkinesia and memory deficits are accompanied by differential molecular effects in cortex and hippocampus. Transcriptome analyses reveal distinct effects of ApoD loss on the molecular age-dependent patterns of cortex and hippocampus, with different cell-type contributions to age-regulated gene expression. Markers of glial reactivity, proteostasis, and oxidative and inflammatory damage reveal early signs of aging and enhanced brain deterioration in the ApoD-knockout brain. The lack of ApoD results in an age-enhanced significant reduction in neuronal calcium-dependent functionality markers and signs of early reduction of neuronal numbers in the cortex, thus impinging upon parameters clearly differentiating neurodegenerative conditions from healthy brain aging. Our data support the hypothesis that the physiological increased brain expression of ApoD represents a homeostatic anti-aging mechanism.
Publication Title
Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 17 Downloadable Samples
Illumina HiSeq 2500
Description
Recent pre-clinical and clinical evidences indicate that hematopoietic stem and progenitor cells (HSPCs) and/or their progeny can serve as vehicles for therapeutic molecule delivery across the blood brain barrier by contributing to the turnover of myeloid cell populations in the brain. However, the differentiation and functional characteristics of the cells reconstituted after transplantation are still to be determined, and in particular whether bona fide microglia could be reconstituted by the donor cell progeny post-transplant to be assessed. We here firstly demonstrate that HSPC transplantation can generate transcriptionally-dependable new microglia through a stepwise process reminiscent of physiological post-natal microglia maturation. Hematopoietic cells able to generate new microglia upon transplantation into myeloablated recipients are retained within human and murine long-term hematopoietic stem cells (HSCs). Similar transcriptionally dependable new microglia cells can also be generated by intra-cerebral ventricular delivery of HSPCs. Importantly, this novel route is associated to a clinically relevant faster and more widespread microglia replacement compared to systemic HSPC injection. Overall, this work supports the relevance and feasibility of employing HSPCs for renewing brain myeloid and microglia cells with new populations endowed with the ability to exert therapeutic effects in the central nervous system, and identifies novel modalities, such as transplantation of enriched stem cell fractions and direct brain delivery of HSPCs, for increasing the actual contribution of the transplanted cells to microgliosis and their therapeutic activity. Overall design: mRNA profiles of µ and TAµ myeloid brain populations were obtained in triplicate mice of Adult control, P10 control and Adult BU-treated mice after GFP Lin-transplantation (both µ and TAµ populations)
Publication Title
Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
CNS-delivery of Interleukin 4 (IL-4) - via a lentiviral-mediated gene therapy strategy - skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Overall design: RNAseq analysis of sorted microglia from mice receiving IL-4 gene therapy
Publication Title
Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system.
Publication Title
Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 43 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these sub-haploinsufficient cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases.
Publication Title
MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these sub-haploinsufficient cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases.
Publication Title
MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 53 Downloadable Samples
- Illumina HiSeq 2500
Description
Comprehensive knowledge of the dynamic changes in the cardiac transciptome can inform disease mechanism. Previous transcriptome profiling studies on heart failure rely on either microarray or RNA-Seq with low coverage, leaving a large portion of the transcriptome unexplored. Additionally, previous studies only examined two end stages of the disease, onset and late-stage heart failure. Profile of the transcriptome in the middle stage of disease progression can reveal critical molecular events underlying disease transition. Towards these goals, we conducted a multi-factorial RNA-Seq experiment, comparing the dynamic changes in the transcriptome of two murine models of heart failure, pressure overload and loss of mitochondrial complex I. Our data represents the deepest transcriptome coverage to date, covering onset, progression, and late stage of the disease. We found extensive differences in the expression magnitude and dynamics of the transciptomes in different heart failure models. In addition, such differences are associated with progressive worsening of cardiac physiology. Our analysis revealed that mitochondrial dysfunction combined with stress leads to increased number of differentially expressed long intergenic noncoding RNAs, including a recently identified lincRNA that is a master regulator of the cardiac lineage during development. Overall design: Cardiac tissues were cleaned with PBS and harvested at 1, 2, 4, and 8 weeks after surgeries by freezing in liquid nitrogen. Cardiac RNA profiles of wild type (WT) and ndufs4H-/- mice after surgeries were generated by deep sequencing at 4 time points, in quadruplicate, using Illumina HiSeq2000. The three factors of the data are genetic (WT vs. ndufs4H-/-), environmental stress (trans-aortic constriction vs. Sham controls), and time (Week 1, Week 2, Week 4 and Week 8). Thus, there are 16 samples in total and each sample has 4 replicates.
Publication Title
Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
The aim of the project was to characterize the transcriptional landscape of human HUVEC cells exposed to oxidative stress (oxstress). In order to do so cell cultures have been exposed to 200uM H2O2 for either 16 hours or 36 hours to induce oxstress. Total ribodepleted RNA obtained from both time points have been sequenced and small RNA for the 16 hours time point have been sequenced as well. Datasets have been characterized and overlapped. This entry contains the dataset of small RNA. Overall design: Two conditions are available: control untreated HUVEC cells and HUVEC cells exposed to 200uM H2O2 for 16 hours. Each condition is available in triplicate. All samples underwent two unpooled rounds of sequencing, for a total of 24 samples.
Publication Title
Central role of the p53 pathway in the noncoding-RNA response to oxidative stress.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Mus musculus
- 35 Downloadable Samples
- Illumina HiSeq 2500
Description
The rising prevalence of obesity and its associated metabolic abnormalities have become global diseases that carry considerable morbidity and mortality. While there is certainly an important genetic component, extensive human epidemiologic and animal model data suggest an epigenetic component to obesity. Nevertheless, the cellular and molecular underpinnings of these pathways and how they contribute to the development of obesity remain to be elucidated. Suv420h1 and h2 are histone methyltransferases responsible for chromatin compaction and gene repression. Through in vivo, ex-vivo and in vitro studies, we found that Suv420h1 and h2 respond to environmental stimuli and regulate metabolism by downregulating PPAR-?, a master transcriptional regulator of lipid storage and glucose metabolism. Accordingly, mice lacking Suv420h proteins activate PPAR-? target genes in brown adipose tissue to increase mitochondria respiration, improve glucose tolerance and reduce adipose tissue to fight obesity. We conclude that Suv420h proteins are key epigenetic regulator of PPAR-? and the pathways controlling metabolism and weight balance in response to environmental stimuli. Overall design: For experiment 1, total RNA was isolated from males and females control- and Suv420h dKO-derived BAT. For experiment 2, total RNA was isolated from BAT collected from females control and Suv420h dKO mice after both diet regimes (nd = normal diet, hfd = high fat diet).
Publication Title
The Suv420h histone methyltransferases regulate PPAR-γ and energy expenditure in response to environmental stimuli.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples