This study aimed to clarify the role of PRMT5 in the hematopoietic stem cell (HSC) compartment, and elucidate the functional relevance of PRMT5-mediated splicing in HSCs. We confirm the cell intrinsic requirement for PRMT5 in HSC maintenance, and present evidence suggesting that PRMT5 deficiency perturbs HSC proteostasis. Notably, we also uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair; loss of which leads to unresolved DNA damage, p53 activation and rapid HSC exhaustion. Overall, these findings establish PRMT5-mediated splicing as a major determinant of HSC fate, and highlight the need to maintain an adequate level of PRMT5 activity in HSCs. Overall design: Hematopoietic stem cells (HSCs; Lineage-Sca-1+CD48-CD150+), isolated from Prmt5fl/fl or Prmt5?/? littermate- and gender-matched mice 7 days post-induction, were subjected to RNA-seq. HSCs for each independent sample were obtained from bone marrow cells pooled from two mice. Three independent samples were obtained for each group.
PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells.
Specimen part, Cell line, Subject
View SamplesPompe disease is caused by autosomal recessive mutations in the GAA gene, which encodes acid alpha-glucosidase. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease induced pluripotent stem cells (PomD-iPSCs) and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features, and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen, abundant intracellular LAMP-1- or LC3-positive granules, and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to rhGAA reversed the major pathologic phenotypes. Further, L-carnitine and 3- methyladenine treatment reduced defective cellular respiration and buildup of phagolysosomes, respectively, in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for development of novel therapeutic strategies for Pompe disease.
Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification.
Specimen part
View SamplesStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.
No sample metadata fields
View SamplesStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.
No sample metadata fields
View SamplesThe arabidopsis L-type lectin receptor kinase-VI.2 positively regulates bacterial PAMP-triggered immunity.
The lectin receptor kinase-VI.2 is required for priming and positively regulates Arabidopsis pattern-triggered immunity.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Dynamics of oscillatory phenotypes in Saccharomyces cerevisiae reveal a network of genome-wide transcriptional oscillators.
No sample metadata fields
View SamplesGenetic and environmental factors influence the phenotype of an organism. Time is rarely considered when studying changes in cellular phenotype. Time-resolved microarray data revealed genome-wide transcriptional changes in cells oscillating with ~2 and ~4 h periods. We mapped the global patterns of transcriptional oscillations into a 3-dimensional map to represent different cellular phenotypes of oscillation period. This map shows the dynamic nature of transcripts through time and concentration space, and that they are ordered and coupled to each other. Although cells differed in oscillation periods, transcripts involved in certain processes were conserved in a deterministic way. This ordered timing of biological process may allow cells to grow energetically efficient. Decreased glucose levels in the media were found to increase the redox cycles of yeast strain CEN.PK113-7D. Glucose may have acted as signaling molecules for timing longer catabolic processes in the cell population. As oscillation period lengthened, the peak to trough ratio of transcripts increased and the percent of cells in the unbudded (G0/G1) phase of the cell cycle increased. Gene transcripts appear to be coordinated with metabolic functions and the cell cycle.
Dynamics of oscillatory phenotypes in Saccharomyces cerevisiae reveal a network of genome-wide transcriptional oscillators.
No sample metadata fields
View SamplesGenetic and environmental factors influence the phenotype of an organism. Time is rarely considered when studying changes in cellular phenotype. Time-resolved microarray data revealed genome-wide transcriptional changes in cells oscillating with ~2 and ~4 h periods. We mapped the global patterns of transcriptional oscillations into a 3-dimensional map to represent different cellular phenotypes of oscillation period. This map shows the dynamic nature of transcripts through time and concentration space, and that they are ordered and coupled to each other. Although cells differed in oscillation periods, transcripts involved in certain processes were conserved in a deterministic way. This ordered timing of biological process may allow cells to grow energetically efficient. Decreased glucose levels in the media were found to increase the redox cycles of yeast strain CEN.PK113-7D. Glucose may have acted as signaling molecules for timing longer catabolic processes in the cell population. As oscillation period lengthened, the peak to trough ratio of transcripts increased and the percent of cells in the unbudded (G0/G1) phase of the cell cycle increased. Gene transcripts appear to be coordinated with metabolic functions and the cell cycle.
Dynamics of oscillatory phenotypes in Saccharomyces cerevisiae reveal a network of genome-wide transcriptional oscillators.
No sample metadata fields
View SamplesIdentification of downstream genes of onecut transcriptions factors in the developing retina
Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development.
No sample metadata fields
View SamplesNext Generation Sequencing technologies have enabled de novo gene fusion discovery that could reveal candidates with therapeutic significance in cancer. Here we present an open-source software package, ChimeraScan, for the discovery of chimeric transcription between two independent transcripts. Overall design: Three cancer cell lines with known gene fusions
ChimeraScan: a tool for identifying chimeric transcription in sequencing data.
No sample metadata fields
View Samples