TY - JOUR
T1 - Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model
T2 - iBRN
AU - Nogami, Masahiro
AU - Ishikawa, Mitsuru
AU - Doi, Atsushi
AU - Sano, Osamu
AU - Sone, Takefumi
AU - Akiyama, Tetsuya
AU - Aoki, Masashi
AU - Nakanishi, Atsushi
AU - Ogi, Kazuhiro
AU - Yano, Masato
AU - Okano, Hideyuki
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/7
Y1 - 2021/7
N2 - 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.
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 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.
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U2 - 10.1016/j.nbd.2021.105364
DO - 10.1016/j.nbd.2021.105364
M3 - Article
C2 - 33857636
AN - SCOPUS:85105552966
SN - 0969-9961
VL - 155
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 105364
ER -