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SRP165983
Homo sapiens
15 Downloadable Samples
Illumina HiSeq 1500
Description
Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasia and Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect in patients. Because ATR governs DNA repair response, the mutation has been considered the cause of an impaired response to DNA replication stress in neuronal progenitor cells (NPCs), which is associated with the pathogenesis of microcephaly. However, the precise mechanism through which the mutation causes SS remains unclear. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone by genome editing. Interestingly, SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs. In SS-NPCs, abnormal mitotic spindles were observed more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that a CLK1 inhibitor, TG003, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Furthermore, treatment with TG003 restored the function of ATR in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model of SS revealed a novel function of the ATR mutation in NPCs and NPC-specific missplicing, proving its usefulness for dissecting the pathophysiology of ATR-SS. Overall design: RNA-sequencing was conducted to identify the transcriptomic profiling of iPSC-derived cells
Publication Title
Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Interleukin 9 (IL-9) producing helper T (Th9) cells play a crucial role in allergic inflammation, autoimmunity, immunity to extracellular pathogens and anti-tumor immune response. In addition to Th9, Th2, Th17 and Foxp3+ Treg cells produce IL-9. Transcription factor that is critical for IL-9 induction in Th2, Th9 and Th17 cells has not been identified. Here we show that Foxo1, a forkhead family transcription factor, requires for IL-9 induction in Th9 and Th17 cells. We further show that inhibition of AKT enhances IL-9 induction in Th9 cells while it reciprocally regulates IL-9 and IL-17 in Th17 cells via Foxo1. Mechanistically, Foxo1 binds and transactivates IL-9 and IRF4 promoters in Th9, Th17 and iTregs. Furthermore, loss of Foxo1 attenuates IL-9 in mouse and human Th9 and Th17 cells, and ameliorates allergic inflammation in asthma. Our findings thus identify that Foxo1 is essential for IL-9 induction in Th9 and Th17 cells. Overall design: Transcriptional analysis of Th0 and TGF-beta 1 + IL-4 induced Th9 cells
Publication Title
Transcription factor Foxo1 is essential for IL-9 induction in T helper cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 22 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
TGF-beta3 produced by developing Th17 cells induces highly pathogenic T cells that are functionally and molecularly distinct from TGF-beta1-induced Th17 cells. The microarray data represent a distinct molecular signature for pathogenic versus non-pathogenic Th17 cells.
Publication Title
Induction and molecular signature of pathogenic TH17 cells.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix HT Mouse Genome 430A Array (htmg430a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Type 1 regulatory T (Tr1) cells are induced by interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. Here, we show that the transcription factors IRF1 and BATF are induced early during treatment with IL-27 and are required for the differentiation and function of Tr1 cells in vitro and in vivo. Epigenetic and transcriptional analyses reveal that both transcription factors influence chromatin accessibility and expression of genes required for Tr1 cell function. IRF1 and BATF deficiencies uniquely alter the chromatin landscape, suggesting that these factors serve a pioneering function during Tr1 cell differentiation. Overall design: Transcriptinal analysis of IL27-induced of WT, Irf1 KO, and Batf KO cells
Publication Title
Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix HT Mouse Genome 430A Array (htmg430a)
Description
Type 1 regulatory T (Tr1) cells are induced by the interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. Here, we show that the transcription factors IRF1 and BATF are induced early during treatment with IL-27 and are required for the differentiation and function of Tr1 cells in vitro and in vivo . Epigenetic and transcriptional analyses reveal that both transcription factors influence chromatin accessibility and expression of genes required for Tr1 cell function. IRF1 and BATF deficiencies uniquely alter the chromatin landscape, suggesting that these factors serve a pioneering function during Tr1 cell differentiation.
Publication Title
Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
To normalize transcriptome data we combined total RNA isolated from 10^6 resting or activated B cells with 1 µl of 1/10 dilution of Ambion’s ERCC RNA Spike-in Mix (92 mRNA standards). mRNA was then isolated and processed following Illumina’s RNA-seq protocol v2.
Publication Title
Global regulation of promoter melting in naive lymphocytes.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 69 Downloadable Samples
- Illumina HiSeq 2000
Description
Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer''s Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD. Overall design: mRNA profile from aged (CA1 and liver) and APP/PS1 (CA1) animals treated with oral vehicle or SAHA for 4 weeks
Publication Title
HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 86 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dynamic regulatory network controlling TH17 cell differentiation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 61 Downloadable Samples
- Illumina Genome Analyzer
Description
Despite their enormous importance, the molecular circuits that control the differentiation of Th17 cells remain largely unknown. Recent studies have reconstructed regulatory networks in mammalian cells, but have focused on short-term responses and relied on perturbation approaches that cannot be applied to primary T cells. Here, we develop a systematic strategy – combining transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based tools for performing gene perturbations in primary T cells – to derive and experimentally validate a temporal model of the dynamic regulatory network that controls Th17 differentiation. The network is arranged into two self-reinforcing and mutually antagonistic modules that either suppress or promote Th17 differentiation. The two modules contain 12 novel regulators with no previous implication in Th17 differentiation, which may be essential to maintain the appropriate balance of Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors that are embedded within a comprehensive temporal network and identifies novel drug targets and organizational principles for the differentiation of Th17 cells. Overall design: RNA-seq of knockdown of 12 genes in Th17 cell differentiation
Publication Title
Dynamic regulatory network controlling TH17 cell differentiation.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples