Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN
Summary: 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121001133 |
| _version_ | 1819105137976672256 |
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| author | Masahiro Nogami Mitsuru Ishikawa Atsushi Doi Osamu Sano Takefumi Sone Tetsuya Akiyama Masashi Aoki Atsushi Nakanishi Kazuhiro Ogi Masato Yano Hideyuki Okano |
| author_facet | Masahiro Nogami Mitsuru Ishikawa Atsushi Doi Osamu Sano Takefumi Sone Tetsuya Akiyama Masashi Aoki Atsushi Nakanishi Kazuhiro Ogi Masato Yano Hideyuki Okano |
| author_sort | Masahiro Nogami |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-22T02:17:28Z |
| format | Article |
| id | doaj.art-1410dd69c2fd495e97b6d914072ba267 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T02:17:28Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1410dd69c2fd495e97b6d914072ba2672022-12-21T18:42:14ZengElsevierNeurobiology of Disease1095-953X2021-07-01155105364Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRNMasahiro Nogami0Mitsuru Ishikawa1Atsushi Doi2Osamu Sano3Takefumi Sone4Tetsuya Akiyama5Masashi Aoki6Atsushi Nakanishi7Kazuhiro Ogi8Masato Yano9Hideyuki Okano10Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, Japan; Shonan Incubation Laboratories, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, Japan; Corresponding author at: Asia New Chemical Entity Production Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, Japan.Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, JapanCell Innovator, Fukuoka 812-8582, JapanInnovative Biology Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, JapanDepartment of Physiology, Keio University School of Medicine, Tokyo 160-8582, JapanDepartment of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDepartment of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanShonan Incubation Laboratories, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, Japan; T-CiRA Discovery, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, JapanInnovative Biology Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, Japan; Shonan Incubation Laboratories, Research, Takeda Pharmaceutical Company Limited, Fujisawa 251-8555, JapanDepartment of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Corresponding author.Summary: 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.http://www.sciencedirect.com/science/article/pii/S0969996121001133Induced pluripotent stem cellBayesian gene regulatory network analysis based on iPSC-derived cell model (iBRN)Amyotrophic lateral sclerosis (ALS)Fused in sarcoma/translated in liposarcoma (FUS)DNA damage response (DDR) |
| spellingShingle | Masahiro Nogami Mitsuru Ishikawa Atsushi Doi Osamu Sano Takefumi Sone Tetsuya Akiyama Masashi Aoki Atsushi Nakanishi Kazuhiro Ogi Masato Yano Hideyuki Okano Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN Neurobiology of Disease Induced pluripotent stem cell Bayesian gene regulatory network analysis based on iPSC-derived cell model (iBRN) Amyotrophic lateral sclerosis (ALS) Fused in sarcoma/translated in liposarcoma (FUS) DNA damage response (DDR) |
| title | Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN |
| title_full | Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN |
| title_fullStr | Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN |
| title_full_unstemmed | Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN |
| title_short | Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN |
| title_sort | identification of hub molecules of fus als by bayesian gene regulatory network analysis of ipsc model ibrn |
| topic | Induced pluripotent stem cell Bayesian gene regulatory network analysis based on iPSC-derived cell model (iBRN) Amyotrophic lateral sclerosis (ALS) Fused in sarcoma/translated in liposarcoma (FUS) DNA damage response (DDR) |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121001133 |
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