Identification of genes and key molecular pathways determining cluster/hub cells and analysis of their association with human diseases

• Project Area: Morphological features and gene expression patterns underlying hub neurons
• Project/Area Number: 20H05777
• Research Category: Grant-in-Aid for Transformative Research Areas (B)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Takata Atsushi 国立研究開発法人理化学研究所, 脳神経科学研究センター, チームリーダー (90643693)
• Project Period (FY): 2020-10-02 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥43,550,000 (Direct Cost: ¥33,500,000、Indirect Cost: ¥10,050,000); Fiscal Year 2022: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2021: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2020: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000)
• Keywords: マルチモーダル一細胞 / RNAシーケンス / 精神神経疾患 / 遺伝統計 / 機械学習

Outline of Research at the Start

本研究領域は、神経ネットワーク内で機能的クラスタを形成する細胞群（クラスタ細胞）と、クラスタ内ネットワークで中心となる細胞（ハブ細胞）のダイナミズムを決定づける剛軟因子、すなわち神経細胞形態（剛）と遺伝子発現変動（軟）の追究を目標とする。本研究班では、一細胞神経活動記録とRNA-seqデータを突合させたマルチモーダル一細胞解析の手法開発を領域内連携で進め、またそのデータの多角的バイオインフォマティクス解析を行う。これらの解析によって、クラスタ/ハブ細胞を決定づける「軟」因子を遺伝子レベル、分子経路レベルで特定し、また疾患等における役割を明らかにすることを目指す。

Outline of Final Research Achievements

In this project, we developed a prototype of an experimental and analytical pipeline to rapidly identify clusters/hub cells from wide field-of-view neural activity recording data, artificially label these cells, and analyze their transcriptomic profiles using single-cell RNA-seq, by closely collaborating with the Murayama and Takeda groups. Our Planned Research group established an informatics pipeline for single-cell RNA-seq data to quantify expression levels of genes including artificially expressed genes for labeling, identify genes characterizing the cell population of interest, and statistically evaluate the overlap between these genes and disease-associated genes or genomic loci. We also applied this pipeline to single-cell RNA-seq data from the brain of an animal model of neuropsychiatric disorder and identified cell types with prominent disease-associated alterations in the transcriptomic profile.

Academic Significance and Societal Importance of the Research Achievements

本領域では、神経活動データ・一細胞RNA-seqデータ・神経形態データ等を、神経科学者・数理情報学者・バイオインフォマティストの密な連携を通じて統合的に解析し、その対応関係等を明らかにするためのパイプライン開発を進めた。この枠組みは、本領域で主要対象としたハブ/クラスタ細胞のみならず、あらゆるタイプの関心細胞集団を対象としたマルチモーダル研究に応用可能であるため、学術的意義が高いものと考える（ただし、さらなる性能向上の必要性があるとも認識している）。また、こういった解析手法を用いたヒト脳疾患の研究は、病態理解に新たな洞察をもたらし治療・予防法開発にも繋がりうるという点で社会的意義を有する。

Research Products

• [Journal Article] Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder (2021)
  • Author(s): Nishioka Masaki、Kazuno An-a、Nakamura Takumi、Sakai Naomi…Oka Takashi、Matoba Nana、Kataoka Muneko、Alkanaq Ahmed N.、Hamanaka Kohei、Tsuboi Takashi、Sengoku Toru、Ogata Kazuhiro、Iwata Nakao、Ikeda Masashi、Matsumoto Naomichi、Kato Tadafumi、Takata Atsushi
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3750-3750
  • DOI: 10.1038/s41467-021-23453-w
  • Peer Reviewed / Open Access
• [Journal Article] Complete sequencing of expanded SAMD12 repeats by long-read sequencing with Cas9-mediated enrichment. (2021)
  • Author(s): Mizuguchi T, Toyota T, Miyatake S, Mitsuhashi S, Doi H, Kudo Y, Kishida H, Hayashi N, Tusburaya RS, Kinoshita M, Fukuyama T, Fukuda H, Koshimizu E, Tsuchida N, Uchiyama Y, Fujita A, Takata A, Miyake N, Kato M, Tanaka F, Adachi H, Matsumoto N.
  • Journal Title: Brain Volume: 144 Issue: 4 Pages: 1103-1117
  • DOI: 10.1093/brain/awab021
  • Peer Reviewed / Open Access
• [Journal Article] ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice (2021)
  • Author(s): Aoto K, Kato M, Akita T, Nakashima M, Mutoh H, Akasaka N, Tohyama J, Nomura Y, Hoshino K, Ago Y, Tanaka R, Epstein O, Ben-Haim R, Heyman E, Miyazaki T, Belal H, Takabayashi S, Ohba C, Takata A, Mizuguchi T, Miyatake S, Miyake N, Fukuda A, Matsumoto N and Saitsu H
  • Journal Title: Nat Commun Volume: 12 Issue: 1 Pages: 2107-2107
  • DOI: 10.1038/s41467-021-22389-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Refinement of the clinical variant interpretation framework by statistical evidence and machine learning (2021)
  • Author(s): Takata Atsushi、Hamanaka Kohei、Matsumoto Naomichi
  • Journal Title: Med Volume: - Issue: 5 Pages: 611-632.e9
  • DOI: 10.1016/j.medj.2021.02.003
  • Peer Reviewed
• [Journal Article] De novo ATP1A3 variants cause polymicrogyria (2021)
  • Author(s): Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
  • Journal Title: Science Advances Volume: 7 Issue: 13 Pages: 2368-2368
  • DOI: 10.1126/sciadv.abd2368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy (2021)
  • Author(s): Itai T, Hamanaka K, Sasaki K, Saitsu H, Miyatake S, Matsumoto N et al.
  • Journal Title: Hum Mutat Volume: 42 Issue: 1 Pages: 66-76
  • DOI: 10.1002/humu.24130
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia (2020)
  • Author(s): Hiromoto Y, Azuma Y, Suzuki Y, Hoshina M, Uchiyama Y, Mitsuhashi S, Miyatake S, Mizuguchi T, Takata A, Miyake N, Kato M, Matsumoto N.
  • Journal Title: Hum Genome Var Volume: 7 Issue: 1 Pages: 43-43
  • DOI: 10.1038/s41439-020-00131-9
  • Peer Reviewed / Open Access
• [Journal Article] Whole exome sequencing of fetal structural anomalies detected by ultrasonography (2020)
  • Author(s): Aoi Hiromi、Mizuguchi Takeshi、Suzuki Toshifumi、Makino Shintaro、Yamamoto Yuka...Takata Atsushi、Miyake Noriko、Takeda Satoru、Itakura Atsuo、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 5 Pages: 499-507
  • DOI: 10.1038/s10038-020-00869-8
  • Peer Reviewed
• [Journal Article] Efficient detection of copy‐number variations using exome data: Batch‐ and sex‐based analyses (2020)
  • Author(s): Uchiyama Yuri、Yamaguchi Daisuke、Iwama Kazuhiro, et al.
  • Journal Title: Human Mutation Volume: 42 Issue: 1 Pages: 50-65
  • DOI: 10.1002/humu.24129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy (2020)
  • Author(s): Sakamoto Masamune、Iwama Kazuhiro、Sekiguchi Futoshi、Mashimo Hideaki、Kumada Satoko、Ishigaki Keiko、Okamoto Nobuhiko、Behnam Mahdiyeh、Ghadami Mohsen、Koshimizu Eriko、Miyatake Satoko、Mitsuhashi Satomi、Mizuguchi Takeshi、Takata Atsushi、Saitsu Hirotomo、Miyake Noriko、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 4 Pages: 401-407
  • DOI: 10.1038/s10038-020-00853-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The identification of two pathogenic variants in a family with mild and severe forms of developmental delay (2020)
  • Author(s): Miyake Noriko、Heydari Shermineh、Garshasbi Masoud、Saitoh Shinji、Nasiri Jafar、Hamanaka Kohei、Takata Atsushi、Matsumoto Naomichi、Beheshti Farnaz Hosseini、Chaleshtori Ahmad Reza Salehi
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 4 Pages: 445-448
  • DOI: 10.1038/s10038-020-0809-8
  • Peer Reviewed / Int'l Joint Research
• [Presentation] クラスタ/ハブ細胞を決定する 遺伝子・鍵分子経路の 特定およびヒト疾患 との関連解析 (2022)
  • Author(s): 高田 篤
  • Organizer: 学術変革B領域 ハブ決定剛軟因子 領域シンポジウム
• [Presentation] Investigation of newly arising mutations in psychiatric disorders and their implication in abnormal aging (2022)
  • Author(s): 高田 篤
  • Organizer: RIKEN Aging Project Annual Meeting
• [Presentation] The rare variant genetics of neuropsychiatric disorders; exome sequencing and beyond (2021)
  • Author(s): 高田 篤
  • Organizer: The 1st CJK (China-Japan-Korea) International Meeting on Neuroscience
  • Int'l Joint Research
• [Presentation] 統計学と人工知能で世界標準の遺伝子診断ガイドラインをカイゼンする (2021)
  • Author(s): 高田 篤
  • Organizer: AMEDゲノム医療基盤研究開発課・令和2年度成果報告会
• [Presentation] クラスタ/ハブ細胞を決定する 遺伝子・鍵分子経路の 特定およびヒト疾患 との関連解析 (2021)
  • Author(s): 高田 篤
  • Organizer: クラスタ／ハブダイナミズムの決定剛軟因子キックオフシンポジウム
• [Presentation] 自閉スペクトラム症のゲノム解析 (2020)
  • Author(s): 高田 篤
  • Organizer: 日本人類遺伝学会第65回大会
• [Remarks] プレスリリース「双極性障害に先天的・後天的デノボ変異がともに関連―双極性障害の病態理解が一歩前進―」
  • URL: https://www.riken.jp/press/2021/20210622_3/index.html
• [Remarks] 統計学と人工知能で世界標準の遺伝子診断ガイドラインをカイゼンする
  • URL: https://www.yokohama-cu.ac.jp/amedrc/news/202103takata.html