Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN

Masahiro Nogami, Mitsuru Ishikawa, Atsushi Doi, Osamu Sano, Takefumi Sone, Tetsuya Akiyama, Masashi Aoki, Atsushi Nakanishi, Kazuhiro Ogi, Masato Yano, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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, 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 FUS H517D 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.

Original languageEnglish
Article number105364
JournalNeurobiology of Disease
Volume155
DOIs
Publication statusPublished - 2021 Jul

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Bayesian gene regulatory network analysis based on iPSC-derived cell model (iBRN)
  • DNA damage response (DDR)
  • Fused in sarcoma/translated in liposarcoma (FUS)
  • Induced pluripotent stem cell

ASJC Scopus subject areas

  • Neurology

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