Hatano, Hiroaki

写真a

Affiliation

School of Medicine, Department of Microbiology and Immunology ( Shinanomachi )

Position

Instructor

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Papers 【 Display / hide 】

  • T cell plasticity in systemic lupus erythematosus revealed by large-scale T cell receptor repertoire and transcriptome studies

    Yasuo Nagafuchi, Masahiro Nakano, Kaitlyn A. Lagattuta, Mineto Ota, Hiroaki Hatano, Haruka Takahashi, Takahiro Itamiya, Hajime Inokuchi, Soumya Raychaudhuri, Tomohisa Okamura, Keishi Fujio, Kazuyoshi Ishigaki

    (Cold Spring Harbor Laboratory)   2025.01

    　View Summary

    Abstract

    CD4+ T cell plasticity plays a pivotal role in immune homeostasis. However, evidence of T cell plasticity and its pathological role in human systemic lupus erythematosus (SLE) is missing due to the lack of a reporter system. Here we utilized T cell receptor (TCR) repertoire data as a molecular signatures alongside transcriptomic dataset. Using a large-scale ImmuNexUT database of autoimmune disease patients including 117 SLE cases, we quantified T cell plasticity across 13 fine-grained T cell-types. We analyzed 6,392 samples in total and identified two orthogonal signatures of repertoire and transcriptome, the cell-type and disease signatures, allowing us to investigate CD4+ T cell plasticity comprehensively. Among all possible patterns, the plasticity level was the highest in effector regulatory T cells (eTreg) to Th1 plasticity, which was replicated in an independent cohort. Moreover, eTreg-to-Th1 plasticity positively correlated with SLE disease activity. Our study provides novel evidence that Treg plasticity is involved in SLE pathology.

  • Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

    Chi Tian, Yuntian Zhang, Yihan Tong, Kian Hong Kock, Donald Yuhui Sim, Fei Liu, Jiaqi Dong, Zhixuan Jing, Wenjing Wang, Junbin Gao, Le Min Tan, Kyung Yeon Han, Yoshihiko Tomofuji, Masahiro Nakano, Eliora Violain Buyamin, Radhika Sonthalia, Yoshinari Ando, Hiroaki Hatano, Kyuto Sonehara, Xin Jin, Marie Loh, John Chambers, Chung-Chau Hon, Murim Choi, Jong-Eun Park, Kazuyoshi Ishigaki, Tomohisa Okamura, Keishi Fujio, Yukinori Okada, Woong-Yang Park, Jay W Shin, Xavier Roca, Shyam Prabhakar, Boxiang Liu

    Nature genetics 56 ( 12 ) 2739 - 2752 2024.12

    ISSN  1061-4036

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    Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5' splice site of TCHP exon 4 that putatively modulates the risk of Graves' disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

  • An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases

    Akiko Oguchi, Akari Suzuki, Shuichiro Komatsu, Hiroyuki Yoshitomi, Shruti Bhagat, Raku Son, Raoul Jean Pierre Bonnal, Shohei Kojima, Masaru Koido, Kazuhiro Takeuchi, Keiko Myouzen, Gyo Inoue, Tomoya Hirai, Hiromi Sano, Yujiro Takegami, Ai Kanemaru, Itaru Yamaguchi, Yuki Ishikawa, Nao Tanaka, Shigeki Hirabayashi, Riyo Konishi, Sho Sekito, Takahiro Inoue, Juha Kere, Shunichi Takeda, Akifumi Takaori-Kondo, Itaru Endo, Shinpei Kawaoka, Hideya Kawaji, Kazuyoshi Ishigaki, Hideki Ueno, Yoshihide Hayashizaki, Massimiliano Pagani, Piero Carninci, Motoko Yanagita, Nicholas Parrish, Chikashi Terao, Kazuhiko Yamamoto, Yasuhiro Murakawa, Matteo Guerrini, Hiroaki Hatano, Michihiro Kono, Masahiro Nakano, Kohei Tomizuka, Soichiro Yoshino

    Science (American Association for the Advancement of Science (AAAS))  385 ( 6704 )  2024.07

    ISSN  00368075

    　View Summary

    <jats:p>
    Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5′ single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4
    <jats:sup>+</jats:sup>
    T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type–specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type–resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.
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  • Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis.

    Haruka Tsuchiya, Mineto Ota, Haruka Takahashi, Hiroaki Hatano, Megumi Ogawa, Sotaro Nakajima, Risa Yoshihara, Tomohisa Okamura, Shuji Sumitomo, Keishi Fujio

    Inflammation and regeneration 44 ( 1 ) 29 - 29 2024.06

    ISSN  1880-9693

    　View Summary

    BACKGROUND: Current strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA). METHODS: SFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. RESULTS: We found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1. CONCLUSIONS: JAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.

  • Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms

    Inamo Jun, Suzuki Akari, Ueda Mahoko Takahashi, Yamaguchi Kensuke, Nishida Hiroshi, Suzuki Katsuya, Kaneko Yuko, Takeuchi Tsutomu, Hatano Hiroaki, Ishigaki Kazuyoshi, Ishihama Yasushi, Yamamoto Kazuhiko, Kochi Yuta

    Nature Communications (Springer Nature)  15 ( 1 ) 4285 - 4285 2024.05

    　View Summary

    Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

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Reviews, Commentaries, etc. 【 Display / hide 】

  • ゲノム編集技術を用いた遺伝子多型機能解明のピットフォールと対策

    河野 通大, 波多野 裕明, 浅原 健一郎, 高橋 悠, バゲルザデレザ , 川島 麗, 荒川 貴博, 中野 正博, 石垣 和慶

    日本臨床免疫学会総会プログラム・抄録集 ((一社)日本臨床免疫学会)  53回   117 - 117 2025.08

  • 全身性免疫疾患　獲得免疫　独自のシークエンス技術を用いた関節リウマチリスク多型機能の解明

    河野 通大, 波多野 裕明, 浅原 健一郎, バゲルザデレザ , 川島 麗, 荒川 貴博, 中野 正博, 石垣 和慶

    日本臨床免疫学会総会プログラム・抄録集 ((一社)日本臨床免疫学会)  53回   73 - 73 2025.08

  • 健康長寿者の末梢血における細胞障害性CD4+T細胞の異質性探索研究

    井口 創, 中野 正博, 浅原 健一郎, 西野 貴大, 高橋 悠, 波多野 裕明, 河野 通大, 夏本 文輝, 佐々木 貴史, 新井 康通, 橋本 浩介, 金子 祐子, 石垣 和慶

    日本臨床免疫学会総会プログラム・抄録集 ((一社)日本臨床免疫学会)  53回   132 - 132 2025.08

  • 疾患病態に寄与するtranscription factor-gene regulatory networkの解明

    高橋 悠, 波多野 裕明, 中野 正博, 土田 優美, 住友 秀次, 鈴木 亜香里, 高地 雄太, 藤尾 圭志, 山本 一彦, 石垣 和慶

    日本臨床免疫学会総会プログラム・抄録集 ((一社)日本臨床免疫学会)  53回   133 - 133 2025.08

  • IKBKE遺伝子の新規バリアントが同定された多関節炎・不明熱の一例

    山田 紗依子, 永渕 泰雄, 夏本 文輝, 河野 正憲, 波多野 裕明, 太田 峰人, 原田 広顕, 庄田 宏文, 岡村 僚久, 小崎 健次郎, 藤尾 圭志

    日本臨床免疫学会総会プログラム・抄録集 ((一社)日本臨床免疫学会)  50回   104 - 104 2022.10

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Courses Taught 【 Display / hide 】

  • IMMUNOLOGY

    2026

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