RT Journal Article
SR Electronic
T1 Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.07.425798
DO 10.1101/2021.01.07.425798
A1 Masahiro Nogami
A1 Mitsuru Ishikawa
A1 Atsushi Doi
A1 Osamu Sano
A1 Takefumi Sone
A1 Tetsuya Akiyama
A1 Masashi Aoki
A1 Atsushi Nakanishi
A1 Kazuhiro Ogi
A1 Masato Yano
A1 Hideyuki Okano
YR 2021
UL http://biorxiv.org/content/early/2021/01/08/2021.01.07.425798.abstract
AB 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, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, “Non-biased” Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed “hub molecules”, which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517D MNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.HighlightsA new platform technology, “iBRN”, Bayesian gene regulatory network analysis based on iPSC cellsiBRN identifies hub molecules to strongly influence the gene network in FUS-ALSPRKDC specifically acts as a guardian against FUS mis-localization during DNA damage stressmiR-125b-5p-TIMELESS axis regulates DNA repair-related genes in FUS-ALS.Competing Interest StatementH.O. is a paid member of the Scientific Advisory Board of San Bio Co., Ltd. H.O.. is a paid member of K Pharma, Inc. M.Y is a scientific advisor of K Pharma, Inc.The other authors declare that they have no conflict of interest.