Project name: HTA2.0 (human transcriptome array) analysis of control iPSC-derived motor neurons (MN), FUS-H517D-hetero-iPSC-MN, and FUS-H517D-homo-iPSC-MNs

Description: To assess RNA regulation in the MN possessing mutated FUS-H517D gene.Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of familial amyotrophic lateral sclerosis (fALS). Mutated FUS causes accumulation of DNA damage stress and stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular etiology of mutated FUS-dependent fALS (fALS-FUS) remains unclear. Here, Bayesian gene regulatory networks (GRN) calculated by Super-Computer with transcriptome data sets of induced pluripotent stem cell (iPSC)-derived MNs possessing mutated FUSH517D (FUSH517D MNs) and FUSWT identified TIMELESS, PRKDC and miR-125b-5p as "hub genes" which influence fALS-FUS GRNs. miR-125b-5p expression up-regulated in FUSH517D MNs, showed opposite correlations against FUS and TIMELESS mRNA levels as well as reported targets of miR-125b-5p. In addition, ectopic introduction of miR-125b-5p could suppress mRNA expression levels of FUS and TIMELESS in the cells. Furthermore, we found TIMELESS and PRKDC among key players of DNA damage stress response (DDR) were down-regulated in FUSH517D MNs and cellular model analysis validated DDR under impaired DNA-PK activity promoted cytosolic FUS mis-localization to SGs. Our GRNs based on iPSC models would reflect fALS-FUS molecular etiology.Overall design: RNA from each control MN, FALS-derived MN possessing H517D mutation in hetero and isogenic MN possessing H517D mutation in homo. One array per biological replicate.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Last updated: 2018-08-09