Grabole et al. 2016 (PRJNA314507)

General Details

Title Modeling the Neuropathology of Tuberous Sclerosis with Human Stem Cells Reveals a Role for Inflammation and Angiogenic Growth Factors [Treatment]
Organism
Number of Samples 24
Release Date 2016/03/07 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP071235
ENA SRP071235
GEO
BioProject PRJNA314507

Publication

Title
Authors Grabole N,Zhang JD,Aigner S,Ruderisch N,Costa V,Weber FC,Theron M,Berntenis N,Spleiss O,Ebeling M,Yeo GW,Jagasia R,Kiialainen A
Journal Genome medicine
Publication Date 2016 Sep 21
Abstract Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumor growths in multiple organs and neurological symptoms induced by mTOR hyperfunction. Because the molecular pathology is highly complex and the etiology poorly understood, we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology and suggest new targets for treatment. We investigate the disease phenotype of TSC by neural differentiation of a human stem cell model that had been deleted for TSC2 by genome editing. Comprehensive genomic analysis was performed by RNA sequencing and ribosome profiling to obtain a detailed genome-wide description of alterations on both the transcriptional and translational level. The molecular effect of mTOR inhibitors used in the clinic was monitored and comparison to published data from patient biopsies and mouse models highlights key pathogenic processes. TSC2-deficient neural stem cells showed severely reduced neuronal maturation and characteristics of astrogliosis instead. Transcriptome analysis indicated an active inflammatory response and increased metabolic activity, whereas at the level of translation ribosomal transcripts showed a 5'UTR motif-mediated increase in ribosome occupancy. Further, we observed enhanced protein synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but transcriptional dysfunction persisted. Our results extend the understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies.
PMC PMC5031259
PMID 27655340
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR3208881 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208882 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208885 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208886 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208889 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208890 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208893 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208894 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208897 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208898 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208901 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208902 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208905 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208906 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208909 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208910 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208913 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208914 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208917 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208918 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208921 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208922 PRJNA314507 Homo sapiens Ribo-Seq
SRR3208925 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
SRR3208926 PRJNA314507 Homo sapiens Ribo-Seq rapamycin
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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