Identification of Hub Molecules of FUS-ALA by Bayesian Gene Regulatory Network Analysis of iPSC Model: iBRN

Abstract

Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, etc., thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, non-biased Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, termed iBRN were applied to transcriptome of iPSC-derived MNs possessing wild-type form of FUS and FUSH517D (FUSH517D MNs). iBRN revealed “hub molecules”, which strongly influenced network, predicting miR-125b-5p-TIMELESS axis and PRKDC as key candidates for the molecular aetiology. Indeed, this axis was augmented in FUSH517D MNs and miR-125b-5p down-regulated DNA repair-related genes including TIMELESS. Importantly, both introduction of miR-125b-5p and knocking down Timeless caused DNA damage. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, iBRN provides the first compelling evidence to elucidate molecular aetiology.