Details of the Researcher

PHOTO

Kyoko Ochiai
Section
Graduate School of Medicine
Job title
Associate Professor
Degree

  • Ph.D (Hiroshima University)

e-Rad No.
10455785

Research History 5

  • 2025/08 - Present
    東北大学大学院医学系研究科 生物化学分野　准教授

  • 2011/08 - 2025/07
    東北大学大学院　医学系研究科生物化学分野　助教

  • 2021/07 - 2024/06
    東北大学プロミネントリサーチフェロー

  • 2007 - 2011
    University of Chicago　Molecular Genetics and Cell Biology　Research associate

  • 2007 -
    東北大学大学院　医学系研究科生物化学分野　研究支援者

Education 2

  • Hiroshima University

    2002/04 - 2007/01

  • Hiroshima University　Faculty of Dentistry

    1996/04 - 2002/03

Research Interests 7

  • Chromatin regulation

  • B細胞分化制御

  • Signaling pathway

  • Gene regulatory network

  • Epigenetics

  • Transcription factor

  • Differentiation

Research Areas 2

  • Life sciences / Immunology /

  • Life sciences / Medical biochemistry /

Awards 2

  1. 2024年度 医学部奨学賞 金賞

    2025/01　東北大学大学院医学系研究科・医学部　B細胞クロマチン制御による抗原特異的抗体産生機構の解明

  2. 東北大学プロミネントリサーチフェロー

    2021/07　東北大学

Papers 33

  1. Protocol for in vitro BCR-mediated plasma cell differentiation and purification of chromatin-associated proteins. International-journal Invited Peer-reviewed

    Kyoko Ochiai, Hiroki Shima, Tsuyoshi Ikura, Marissa C Franke, Evelyn P Sievert, Roger Sciammas, Kazuhiko Igarashi

    STAR protocols　2　(3)　100633-100633　2021/09/17

    DOI： 10.1016/j.xpro.2021.100633 　

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    Molecular-level understanding of plasma cell (PC) differentiation has been modeled using lipopolysaccharide (LPS) stimulation in vitro. However, this system does not involve the B-cell receptor (BCR)-a critical component of B cell biology. Here, we present a protocol for in vitro PC differentiation system dependent on BCR signaling that easily scales up for cell number-demanding applications, including protein complex purification. We describe how to set up this system and detail applications for endogenous complex purification of chromatin-associated proteins. For further details on the use and execution of this protocol, please refer to Sciammas et al. (2011) and Ochiai et al. (2018, 2020).

  2. Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4. International-journal Peer-reviewed

    Kyoko Ochiai, Mari Yamaoka, Amrutha Swaminathan, Hiroki Shima, Hitoshi Hiura, Mitsuyo Matsumoto, Daisuke Kurotaki, Jun Nakabayashi, Ryo Funayama, Keiko Nakayama, Takahiro Arima, Tomokatsu Ikawa, Tomohiko Tamura, Roger Sciammas, Philippe Bouvet, Tapas K Kundu, Kazuhiko Igarashi

    Cell reports　33　(12)　108517-108517　2020/12/22

    DOI： 10.1016/j.celrep.2020.108517 　

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    The chromatin protein positive coactivator 4 (PC4) has multiple functions, including chromatin compaction. However, its role in immune cells is largely unknown. We show that PC4 orchestrates chromatin structure and gene expression in mature B cells. B-cell-specific PC4-deficient mice show impaired production of antibody upon antigen stimulation. The PC4 complex purified from B cells contains the transcription factors (TFs) IKAROS and IRF4. IKAROS protein is reduced in PC4-deficient mature B cells, resulting in de-repression of their target genes in part by diminished interactions with gene-silencing components. Upon activation, the amount of IRF4 protein is not increased in PC4-deficient B cells, resulting in reduction of plasma cells. Importantly, IRF4 reciprocally induces PC4 expression via a super-enhancer. PC4 knockdown in human B cell lymphoma and myeloma cells reduces IKAROS protein as an anticancer drug, lenalidomide. Our findings establish PC4 as a chromatin regulator of B cells and a possible therapeutic target adjoining IKAROS in B cell malignancies.

  3. Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell. Peer-reviewed

    Ochiai K, Kondo H, Okamura Y, Shima H, Kurokochi Y, Kimura K, Funayama R, Nagashima T, Nakayama K, Yui K, Kinoshita K, Igarashi K

    Blood Advances　2　(8)　883-894　2018/04

    DOI： 10.1182/bloodadvances.2017010413 　

    ISSN： 2473-9529

  4. The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation Peer-reviewed

    Toru Tamahara, Kyoko Ochiai, Akihiko Muto, Yukinari Kato, Nicolas Sax, Mitsuyo Matsumoto, Takeyoshi Koseki, Kazuhiko Igarashi

    MOLECULAR AND CELLULAR BIOLOGY　37　(24)　2017/12

    DOI： 10.1128/MCB.00418-17 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  5. Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network Peer-reviewed

    Kazuhiko Igarashi, Kyoko Ochiai, Ari Itoh-Nakadai, Akihiko Muto

    IMMUNOLOGICAL REVIEWS　261　(1)　116-125　2014/09

    DOI： 10.1111/imr.12201 　

    ISSN： 0105-2896

    eISSN： 1600-065X

  6. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling Peer-reviewed

    Marcus R. Clark, Malay Mandal, Kyoko Ochiai, Harinder Singh

    NATURE REVIEWS IMMUNOLOGY　14　(2)　69-80　2014/02

    DOI： 10.1038/nri3570 　

    ISSN： 1474-1733

    eISSN： 1474-1741

  7. Transcriptional Regulation of Germinal Center B and Plasma Cell Fates by Dynamical Control of IRF4 Peer-reviewed

    Kyoko Ochiai, Mark Maienschein-Cline, Giorgia Simonetti, Jianjun Chen, Rebecca Rosenthal, Robert Brink, AnitaS. Chong, Ulf Klein, AaronR. Dinner, Harinder Singh, Roger Sciammas

    Immunity　38　(5)　918-929　2013/05/23

    DOI： 10.1016/j.immuni.2013.04.009 　

    ISSN： 1074-7613 1097-4180

  8. A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation Peer-reviewed

    Kyoko Ochiai, Mark Maienschein-Cline, Malay Mandal, Joseph R. Triggs, Eric Bertolino, Roger Sciammas, Aaron R. Dinner, Marcus R. Clark, Harinder Singh

    NATURE IMMUNOLOGY　13　(3)　300-U124　2012/03

    DOI： 10.1038/ni.2210 　

    ISSN： 1529-2908

    eISSN： 1529-2916

  9. Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch Peer-reviewed

    Akihiko Muto, Kyoko Ochiai, Yoshitaka Kimura, Ari Itoh-Nakadai, Kathryn L. Calame, Dai Ikebe, Satoshi Tashiro, Kazuhiko Igarashi

    EMBO JOURNAL　29　(23)　4048-4061　2010/12

    DOI： 10.1038/emboj.2010.257 　

    ISSN： 0261-4189

  10. Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6 Peer-reviewed

    Kyoko Ochiai, Akihiko Muto, Hiromu Tanaka, Shinichiro Takahashi, Kazuhiko Igarashi

    INTERNATIONAL IMMUNOLOGY　20　(3)　453-460　2008/03

    DOI： 10.1093/intimm/dxn005 　

    ISSN： 0953-8178

  11. Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells Peer-reviewed

    Kyoko Ochiai, Yasutake Katoh, Tsuyoshi Ikura, Yutaka Hoshikawa, Tetsuo Noda, Hajime Karasuyama, Satoshi Tashiro, Akihiko Muto, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(50)　38226-38234　2006/12

    DOI： 10.1074/jbc.M607592200 　

    ISSN： 0021-9258

  12. Feedback loops in B-cell chromatin regulation as a therapeutic target for modulating antibody production and malignancies: insights from BACH2 Invited Peer-reviewed

    Kyoko Ochiai, Kazuhiko Igarashi

    Experimental Hematology　2026/01

    DOI： 10.1016/j.exphem.2025.105284 　

  13. Positive coactivator PC4 shows dynamic nucleolar distribution required for rDNA transcription and protein synthesis. International-journal

    Stephanie Kaypee, Kyoko Ochiai, Hiroki Shima, Mitsuyo Matsumoto, Mahabub Alam, Tsuyoshi Ikura, Tapas K Kundu, Kazuhiko Igarashi

    Cell communication and signaling : CCS　23　(1)　283-283　2025/06/14

    DOI： 10.1186/s12964-025-02238-4 　

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    The nucleolus is the site of rDNA transcription and ribosome biogenesis. Alterations in nucleolar function and architecture correlate with drastic heterochromatin rearrangement and global changes in gene expression. However, the precise mechanism that connects nucleolar function to heterochromatin organization and transcription is yet unknown. Here, we report that the RNA polymerase II (RNA pol II) transactivator and chromatin condenser, Positive Coactivator 4 (PC4), is a bona fide nucleolar protein. PC4 showed dynamic nucleolar accumulation, which is critical for rDNA transcription. The lysine acetyltransferase, KAT5 (Tip60) acetylates PC4 at K35, which facilitates nucleolar release of PC4 and concomitated inhibition of rDNA transcription. By employing PC4 mutant, which is defective in nucleolar accumulation, we found that nucleolar PC4 is crucial for RNA pol I-mediated rDNA transcription. To validate this significant novel role of PC4, in the context of nucleolus organization and function, at the organismal level, we looked into B cell-specific conditional knockout of Sub1 encoding PC4 in mice, which revealed that indeed the rDNA transcription and protein synthesis in B cells are severely repressed in the absence of PC4. Furthermore, PC4 CKO B cells were associated with the loss of H3K9me3-marked heterochromatin foci but not global H3K9me3 levels. LC-MS/MS analysis of the H3K9me3 chromatin complexes revealed that most non-histone heterochromatin proteins were reduced or absent in the constitutive heterochromatin of PC4 CKO B cells. These findings establish PC4 as a critical functional component of nucleolus for rDNA transcription.

  14. Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response

    Miki Watanabe-Matsui, Shun Kadoya, Kei Segawa, Hiroki Shima, Tadashi Nakagawa, Yuko Nagasawa, Shuichiro Hayashi, Mitsuyo Matsumoto, Mariko Ikeda, Akihiko Muto, Kyoko Ochiai, Long C. Nguyen, Katsumi Doh-Ura, Mikako Shirouzu, Keiko Nakayama, Kazutaka Murayama, Kazuhiko Igarashi

    iScience　28　(1)　111529-111529　2025/01

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2024.111529 　

    ISSN： 2589-0042

  15. Absolute quantification of BACH1 and BACH2 transcription factors in B and plasma cells reveals their dynamic changes and unique roles

    Takeshi Kurasawa, Akihiko Muto, Mitsuyo Matsumoto, Kyoko Ochiai, Kazutaka Murayama, Kazuhiko Igarashi

    The Journal of Biochemistry　176　(6)　449-459　2024/09/25

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/jb/mvae065 　

    ISSN： 0021-924X

    eISSN： 1756-2651

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    Abstract Changes in the absolute protein amounts of transcription factors are important for regulating gene expression during cell differentiation and in responses to changes in the cellular and extracellular environment. However, few studies have focused on the absolute quantification of mammalian transcription factors. In this study, we established an absolute quantification method for the transcription factors BACH1 and BACH2, which are expressed in B cells and regulated by direct heme binding. The method used purified recombinant proteins as controls in western blotting and was applied to mouse naïve B cells in the spleen, as well as activated B cells and plasma cells. BACH1 was present in naïve B cells at approximately half the levels of BACH2. In activated B cells, BACH1 decreased compared to naïve B cells, whilst BACH2 increased. In plasma cells, BACH1 increased back to the same extent as in naïve B cells, whilst BACH2 was not detected. Their target genes, Prdm1 and Hmox1, were highly induced in plasma cells. BACH1 was found to undergo degradation with lower concentrations of heme than BACH2. Therefore, BACH1 and BACH2 are similarly abundant in B cells but differ in heme sensitivity, potentially regulating gene expression differently depending on their heme responsiveness.

  16. Accelerated plasma-cell differentiation in Bach2-deficient mouse B cells is caused by altered IRF4 functions. International-journal Peer-reviewed

    Kyoko Ochiai, Hiroki Shima, Toru Tamahara, Nao Sugie, Ryo Funayama, Keiko Nakayama, Tomohiro Kurosaki, Kazuhiko Igarashi

    The EMBO journal　2024/04/11

    DOI： 10.1038/s44318-024-00077-6 　

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    Transcription factors BACH2 and IRF4 are both essential for antibody class-switch recombination (CSR) in activated B lymphocytes, while they oppositely regulate the differentiation of plasma cells (PCs). Here, we investigated how BACH2 and IRF4 interact during CSR and plasma-cell differentiation. We found that BACH2 organizes heterochromatin formation of target gene loci in mouse splenic B cells, including targets of IRF4 activation such as Aicda, an inducer of CSR, and Prdm1, a master plasma-cell regulator. Release of these gene loci from heterochromatin in response to B-cell receptor stimulation was coupled to AKT-mTOR pathway activation. In Bach2-deficient B cells, PC genes' activation depended on IRF4 protein accumulation, without an increase in Irf4 mRNA. Mechanistically, a PU.1-IRF4 heterodimer in activated B cells promoted BACH2 function by inducing gene expression of Bach2 and Pten, a negative regulator of AKT signaling. Elevated AKT activity in Bach2-deficient B cells resulted in IRF4 protein accumulation. Thus, BACH2 and IRF4 mutually modulate the activity of each other, and BACH2 inhibits PC differentiation by both the repression of PC genes and the restriction of IRF4 protein accumulation.

  17. TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22. International-journal

    Liang Liu, Mitsuyo Matsumoto, Miki Watanabe-Matsui, Tadashi Nakagawa, Yuko Nagasawa, Jingyao Pang, Bert K K Callens, Akihiko Muto, Kyoko Ochiai, Hirotaka Takekawa, Mahabub Alam, Hironari Nishizawa, Mikako Shirouzu, Hiroki Shima, Keiko Nakayama, Kazuhiko Igarashi

    International journal of molecular sciences　25　(8)　2024/04/09

    DOI： 10.3390/ijms25084141 　

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    BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species. While BACH1 is rapidly degraded when it is bound to heme, it remains unclear how BACH1 degradation is regulated under other conditions. We found that FBXO22, a ubiquitin ligase previously reported to promote BACH1 degradation, polyubiquitinated BACH1 only in the presence of heme in a highly purified reconstitution assay. In parallel to this regulatory mechanism, TANK binding kinase 1 (TBK1), a protein kinase that activates innate immune response and regulates iron metabolism via ferritinophagy, was found to promote BACH1 degradation when overexpressed in 293T cells. While TBK1 phosphorylated BACH1 at multiple serine and threonine residues, BACH1 degradation was observed with not only the wild-type TBK1 but also catalytically impaired TBK1. The BACH1 degradation in response to catalytically impaired TBK1 was not dependent on FBXO22 but involved both autophagy-lysosome and ubiquitin-proteasome pathways judging from its suppression by using inhibitors of lysosome and proteasome. Chemical inhibition of TBK1 in hepatoma Hepa1 cells showed that TBK1 was not required for the heme-induced BACH1 degradation. Its inhibition in Namalwa B lymphoma cells increased endogenous BACH1 protein. These results suggest that TBK1 promotes BACH1 degradation in parallel to the FBXO22- and heme-dependent pathway, placing BACH1 as a downstream effector of TBK1 in iron metabolism or innate immune response.

  18. Exploring novel functions of BACH2 in the acquisition of antigen-specific antibodies. International-journal Peer-reviewed

    Kyoko Ochiai, Kazuhiko Igarashi

    International immunology　35　(6)　257-265　2023/05/19

    DOI： 10.1093/intimm/dxac065 　

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    BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class-switch and affinity-maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively. In addition, our recent observation raises the possibility that BACH2 has diverse functions, such as those in gene activation. Since dysfunction of BACH2 leads to the onset of human immune deficiencies, revealing new functions of BACH2 may give a cue to solve how BACH2 contributes to preventing these diseases.

  19. BACH1 Expression Is Promoted by Tank Binding Kinase 1 (TBK1) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin. International-journal Peer-reviewed

    Liang Liu, Mitsuyo Matsumoto, Miki Matsui-Watanabe, Kyoko Ochiai, Bert K K Callens, Long Chi Nguyen, Yushi Kozuki, Miho Tanaka, Hironari Nishizawa, Kazuhiko Igarashi

    Antioxidants (Basel, Switzerland)　11　(8)　2022/07/27

    DOI： 10.3390/antiox11081460 　

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    BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC-1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC-1 cells. Flow cytometry analysis showed that AsPC-1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells.

  20. 遺伝情報を調節するメチル化連動システム S-アデノシルメチオニン代謝系による遺伝子発現の調節機構

    五十嵐 和彦, Nguyen Long Chi, 石井 悠翔, 加藤 浩貴, 落合 恭子, 松本 光代, 島 弘季

    日本生化学会大会プログラム・講演要旨集　93回　[3S02m-03]　2020/09

    Publisher: (公社)日本生化学会

  21. Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation. International-journal Peer-reviewed

    Katsushi Suzuki, Mitsuyo Matsumoto, Yasutake Katoh, Liang Liu, Kyoko Ochiai, Yuta Aizawa, Ryoichi Nagatomi, Hiroshi Okuno, Eiji Itoi, Kazuhiko Igarashi

    PloS one　15　(8)　e0236781　2020

    DOI： 10.1371/journal.pone.0236781 　

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    It has been reported that Bach1-deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that Bach1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of Bach1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by Bach1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in Bach1-deficient mice and Bach1-silenced C2C12 cells. Therefore, Bach1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.

  22. Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors. International-journal Peer-reviewed

    Daisuke Kurotaki, Jun Nakabayashi, Akira Nishiyama, Haruka Sasaki, Wataru Kawase, Naofumi Kaneko, Kyoko Ochiai, Kazuhiko Igarashi, Keiko Ozato, Yutaka Suzuki, Tomohiko Tamura

    Cell reports　22　(10)　2628-2641　2018/03/06

    DOI： 10.1016/j.celrep.2018.02.048 　

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    Monocytes and dendritic cells (DCs), mononuclear phagocytes essential for immune responses, develop from hematopoietic stem cells via monocyte-DC progenitors (MDPs). The molecular basis of their development remains unclear. Because promoter-distal enhancers are key to cell fate decisions, we analyzed enhancer landscapes during mononuclear phagocyte development in vivo. Monocyte- and DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Although Irf8-/- mononuclear phagocyte progenitors, including MDPs, displayed grossly normal gene expression patterns, their enhancer landscapes resembled that of an upstream progenitor population. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and, therefore, direct future gene expression to achieve mononuclear phagocyte development.

  23. S-Adenosylmethionine Synthesis Is Regulated by Selective N-6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1 Peer-reviewed

    Hiroki Shima, Mitsuyo Matsumoto, Yuma Ishigami, Masayuki Ebina, Akihiko Muto, Yuho Sato, Sayaka Kumagai, Kyoko Ochiai, Tsutomu Suzuki, Kazuhiko Igarashi

    CELL REPORTS　21　(12)　3354-3363　2017/12

    DOI： 10.1016/j.celrep.2017.11.092 　

    ISSN： 2211-1247

  24. A Bach2-Cebp Gene Regulatory Network for the Commitment of Multipotent Hematopoietic Progenitors Peer-reviewed

    Ari Itoh-Nakadai, Mitsuyo Matsumoto, Hiroki Kato, Junichi Sasaki, Yukihiro Uehara, Yuki Sato, Risa Ebina-Shibuya, Mizuho Morooka, Ryo Funayama, Keiko Nakayama, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

    CELL REPORTS　18　(10)　2401-2414　2017/03

    DOI： 10.1016/j.celrep.2017.02.029 　

    ISSN： 2211-1247

  25. Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3 Peer-reviewed

    Hiromu Tanaka, Akihiko Muto, Hiroki Shima, Yasutake Katoh, Nicolas Sax, Shinya Tajima, Andrey Brydun, Tsuyoshi Ikura, Naoko Yoshizawa, Hisao Masai, Yutaka Hoshikawa, Tetsuo Noda, Masaki Nio, Kyoko Ochiai, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(12)　6316-6330　2016/03

    DOI： 10.1074/jbc.M116.713842 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  26. The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization Peer-reviewed

    Ryo Ando, Hiroki Shima, Toru Tamahara, Yoshihiro Sato, Miki Watanabe-Matsui, Hiroki Kato, Nicolas Sax, Hozumi Motohashi, Keiko Taguchi, Masayuki Yamamoto, Masaki Nio, Tatsuya Maeda, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(4)　1826-1840　2016/01

    DOI： 10.1074/jbc.M115.661702 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  27. 転写因子による細胞分化・増殖抑制 転写因子IRF4が支配する胚中心B細胞および形質細胞分化誘導の遺伝子発現ネットワーク

    落合 恭子, 近藤 晴香, 岡村 容伸, 木下 賢吾, 五十嵐 和彦

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2W9-6]　2015/12

    Publisher: (公社)日本生化学会

  28. The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program Peer-reviewed

    Ari Itoh-Nakadai, Reina Hikota, Akihiko Muto, Kohei Kometani, Miki Watanabe-Matsui, Yuki Sato, Masahiro Kobayashi, Atsushi Nakamura, Yuichi Miura, Yoko Yano, Satoshi Tashiro, Jiying Sun, Tomokatsu Ikawa, Kyoko Ochiai, Tomohiro Kurosaki, Kazuhiko Igarashi

    NATURE IMMUNOLOGY　15　(12)　1171-1180　2014/12

    DOI： 10.1038/ni.3024 　

    ISSN： 1529-2908

    eISSN： 1529-2916

  29. The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program. Peer-reviewed

    Itoh-Nakadai Ari, Hikota Reina, Muto Akihiko, Kometani Kohei, Watanabe-Matsui Miki, Sato Yuki, Kobayashi Masahiro, Nakamura Atsushi, Miura Yuichi, Yano Yoko, Tashiro Satoshi, Sun Jiying, Ikawa Tomokatsu, Ochiai Kyoko, Kurosaki Tomohiro, Igarashi Kazuhiko

    Nature immunology　15　(12)　2014

    DOI： 10.1038/ni.3024 　

    ISSN： 1529-2916

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    :Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.

  30. PO-123 B細胞終末分化におけるエピジェネティック制御の解明(小児外科基礎研究,ポスターセッション,病気の子供達に笑顔 小児外科に夢そして革新を,第47回 日本小児外科学会学術集会)

    田中 拡, 武藤 哲彦, 落合 恭子, 和田 基, 佐々木 英之, 風間 理郎, 西 功太郎, 工藤 博典, 安藤 亮, 五十嵐 和彦, 仁尾 正記

    日本小児外科学会雑誌　46　(3)　660-660　2010

    Publisher: 特定非営利活動法人 日本小児外科学会

    DOI： 10.11164/jjsps.46.3_660_1 　

  31. Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development Peer-reviewed

    Malay Mandal, Sarah E. Powers, Kyoko Ochiai, Katia Georgopoulos, Barbara L. Kee, Harinder Singh, Marcus R. Clark

    NATURE IMMUNOLOGY　10　(10)　1110-U91　2009/10

    DOI： 10.1038/ni.1785 　

    ISSN： 1529-2908

  32. Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation

    Kazuhiko Igarashi, Kyoko Ochiai, Akihiko Muto

    JOURNAL OF BIOCHEMISTRY　141　(6)　783-789　2007/06

    DOI： 10.1093/jb/mvm106 　

    ISSN： 0021-924X

  33. Identification of six major outer membrane proteins from Actinobacillus actinomycetemcomitans Peer-reviewed

    H Komatsuzawa, R Asakawa, T Kawai, K Ochiai, T Fujiwara, MA Taubman, M Ohara, H Kurihara, M Sugai

    GENE　288　(1-2)　195-201　2002/04

    DOI： 10.1016/S0378-1119(02)00500-0 　

    ISSN： 0378-1119

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Misc. 17

  1. B細胞におけるBACH転写因子のタンパク質量比による転写調節機構の解明

    倉澤岳志, 武藤哲彦, 松本光代, 落合恭子, 村山和隆, 五十嵐和彦, 五十嵐和彦

    日本生化学会大会(Web)　96th　2023

  2. The avoidance of cell death by BACH1 in head and neck cancer cells

    遠藤緋理, 松本光代, 松本光代, 六郷正博, 六郷正博, 落合恭子, 西澤弘成, 五十嵐和彦, 五十嵐和彦

    日本分子生物学会年会プログラム・要旨集(Web)　45th　2022

  3. Regulatory mechanisms of iron metabolism in B cell immune responses by the transcription factor BACH2

    倉澤岳志, 武藤哲彦, 松本光代, 松本光代, 落合恭子, 五十嵐和彦, 五十嵐和彦

    日本分子生物学会年会プログラム・要旨集(Web)　45th　2022

  4. IRF4によって統御されるB細胞—形質細胞分化の遺伝子発現ネットワーク

    落合恭子

    臨床免疫・アレルギー科　71　(3)　1-7　2019

  5. B細胞内のシグナル伝達機構(第7回) IRF4によるB細胞分化制御

    落合 恭子

    炎症と免疫　24　(3)　249-252　2016/04

    Publisher: (株)先端医学社

    ISSN： 0918-8371

  6. 転写因子のBifunctional機能決定の分子機構解明

    落合 恭子

    上原記念生命科学財団研究報告集　29　1-3　2015/12

    Publisher: (公財)上原記念生命科学財団

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    転写因子は、細胞特異的または分化段階特異的に標的遺伝子発現を制御することで細胞分化の方向性を決定する。これまでに、転写因子クロマチン免疫沈降シークエンス法と遺伝子発現解析の双方を実施し、細胞分化誘導時における転写因子直接標的遺伝子を同定した。そして、転写因子と標的遺伝子が構築するGRN(Gene regulatory network)が細胞分化制御に機能することを明らかにした。GRNは、転写因子機能による細胞分化制御の本質であり、ときに自己が制御する遺伝子群によって自己機能増強または減弱を誘導するフィードバックグループを形成する。このとき、多くの転写因子は標的遺伝子活性化と抑制という二極性機能、すなわちBifunctional機能を保持するが、その詳細な分子機構については明らかにされていない。今回、一転写因子がどのようにBifunctional機能を発揮するのか検討した。対象は、形質細胞分化に必須の転写因子IRF4(Interferon regulatory factor 4)とした。IRF4のBifunctional機能に協調的に機能する因子群のスクリーニングを行った結果、標的遺伝子活性化因子としてヒストンアセチル化酵素p300が抽出され、標的遺伝子抑制因子としてヒストン脱アセチル化酵素Hdacが抽出された。

  7. B細胞における転写因子IRF4の濃度依存的な細胞成熟と分化の分子メカニズム

    落合 恭子

    血液内科　68　(5)　712-718　2014/05

    Publisher: (有)科学評論社

    ISSN： 2185-582X

  8. 転写因子Bach2はmTORによって制御される

    玉原亨, 佐藤好宏, 落合恭子, 五十嵐和彦

    日本分子生物学会年会プログラム・要旨集(Web)　37th　2P-0731 (WEB ONLY)　2014

  9. 遺伝子発現制御から解明する細胞分化分岐のメカニズム

    落合 恭子

    東北医学雑誌　125　(2)　269-271　2013/12

    Publisher: 東北医学会

    ISSN： 0040-8700

  10. 最新の医学論文を読みこなそう!(第11回) 遺伝情報発現制御機構とその病態(その2)

    五十嵐 和彦, 落合 恭子

    THE LUNG-perspectives　20　(3)　318-322　2012/08

    Publisher: (株)メディカルレビュー社

    ISSN： 0919-5742

  11. 最新の医学論文を読みこなそう!(第10回) 遺伝情報発現制御機構とその病態(その1)

    五十嵐 和彦, 落合 恭子, Brydun Andrey

    THE LUNG-perspectives　20　(2)　192-197　2012/05

    Publisher: (株)メディカルレビュー社

    ISSN： 0919-5742

  12. B細胞終末分化におけるエピジェネティック制御の解明

    田中 拡, 武藤 哲彦, 落合 恭子, 和田 基, 佐々木 英之, 風間 理郎, 西 功太郎, 工藤 博典, 安藤 亮, 五十嵐 和彦, 仁尾 正記

    日本小児外科学会雑誌　46　(3)　660-660　2010/05

    Publisher: (NPO)日本小児外科学会

    ISSN： 0288-609X

    eISSN： 2187-4247

  13. 【転写因子による生命現象解明の最前線 クロマチン制御機構・エピジェネティクスと転写因子複合体ネットワークの包括的解明】 転写因子ネットワーク 液性免疫応答を制御するBach2転写因子ネットワーク

    五十嵐 和彦, 武藤 哲彦, 落合 恭子

    実験医学　25　(10)　1562-1567　2007/06

    Publisher: (株)羊土社

    ISSN： 0288-5514

  14. B細胞-形質細胞分化における転写因子Bach2の機能 (遺伝子医学MOOK6)

    落合恭子, 武藤哲彦, 五十嵐和彦

    遺伝子医学MOOK6　75-79　2006/10

  15. MRSAはMSSAに比べヒト抗菌ペプチドに対して感受性が低いか?

    應原 一久, 小松澤 均, 落合 恭子, 西 裕美, 栗原 英見, 菅井 基行

    日本細菌学雑誌　59　(1)　145-145　2004/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

  16. マウス上皮細胞の抗菌ペプチドの発現

    落合 恭子, 應原 一久, 小松澤 均, 菅井 基行, 橋本 公二, 佐山 浩二

    日本細菌学雑誌　58　(1)　281-281　2003/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

  17. ヒト歯肉上皮細胞が産生する抗菌ペプチドの歯周病原菌に対する抗菌活性及び発現様式

    應原 一久, 落合 恭子, 小松澤 均, 山田 作夫, 栗原 英見, 菅井 基行, 内田 雄士, 柴 秀樹

    日本細菌学雑誌　58　(1)　281-281　2003/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

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Presentations 8

  1. 転写因子とクロマチン制御因子による細胞分化制御の遺伝子発現ネットワーク

    The 42th Annual Meeting of the Molecular Biology Society of Japan　2019/12/05

  2. 転写因子結合DNAモチーフの多様性が制御する細胞分化

    OCHIAI Kyoko

    The 41th Annual Meeting of the Molecular Biology Society of Japan　2018/11/28

  3. The diversity of IRF4 DNA binding motifs governs cell fate during plasma cell differentiation International-presentation Invited

    OCHIAI Kyoko

    7th Meeting of the Asian Forum of Chromosome and Chromatin Biology　2018/11/15

  4. Gene regulatory networks of B-to-plasma cell differentiation orchestrated by IRF4 and its partner transcription factors

    OCHIAI Kyoko

    The 46th Annual Meeting of the Japanese Society for Immunology　2017/12/14

  5. Gene Regulatory Networks Composed by Transcription Factors Orchestrate Plasma Cell Differentiation

    OCHIAI Kyoko

    The 2017 Japan-NIH Joint Symposium on Advances in Biomedical Research and Disease　2017/02/16

  6. Dynamics of IRF4-dependent gene activation and repression during plasma cell differentiation

    OCHIAI Kyoko, OKAMURA Yasunobu, KINOSHITA Kengo, IGARASHI Kazuhiko

    The 45th Annual Meeting of the Japanese Society for Immunology　2016/12

  7. 転写因子による細胞分化・増殖抑制 転写因子IRF4が支配する胚中心B細胞および形質細胞分化誘導の遺伝子発現ネットワーク

    落合 恭子, 近藤 晴香, 岡村 容伸, 木下 賢吾, 五十嵐 和彦

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　2015/12/02

  8. Organization of Plasma Cell Diff erentiation via Epigenome-related Complex

    OCHIAI Kyoko, IGARASHI Kazuhiko

    The 36th Annual Meeting of the Molecular Biology Society of Japan　2013/12/06

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Research Projects 7

  1. BACH2遺伝子発現プログラムによるIRF4蓄積制御と抗体産生制御機構の解明

    落合 恭子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2023/04/01 - 2027/03/31

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    本研究目的はIRF4蓄積制御機構の解明である。研究開始当初、IRF4リン酸化がIRF4蓄積による形質細胞分化誘導に関与する可能性を見出していた。そこで、まず同アミノ酸リン酸化がIRF4蓄積に不可欠であるかを検討した。マウス脾臓B細胞に分化誘導刺激を与え、同リン酸化修飾酵素阻害剤を添加し培養したところ、IRF4量は変化しないにも関わらず形質細胞分化が阻害された。このことから、同アミノ酸リン酸化はIRF4蓄積ではなく形質細胞分化を誘導するIRF4の転写因子機能に重要であることが明らかになった。そこで、研究開始時に計画したリン酸化制御の視点からではなく、異なる視点でIRF4蓄積制御機構の解明を進める必要性が生じた。 IRF4蓄積は形質細胞分化を促進するが、転写因子BACH2は形質細胞分化を抑制する。我々の解析から、BACH2欠損マウスB細胞では、野生型マウスB細胞と比較してIrf4転写量は変わらないがタンパク質が顕著に蓄積することがわかった（The EMBO Journal, 2024）。このことから、BACH2欠損マウスB細胞ではIRF4蓄積機構が活性化していることが強く示唆された。そこで、BACH2欠損マウスB細胞を活用したIRF4蓄積制御機構の解明に研究計画を変更した。 具体的には、BACH2欠損B細胞ではIRF4タンパク質が安定化していると想定し、野生型マウスB細胞と比較してBACH2欠損マウスB細胞で特異的にタンパク質発現が高く、かつIRF4と相互作用する因子を抽出する。質量分析を用いて、野生型マウスB細胞と比べてBACH2欠損マウスB細胞でタンパク質量が有意に高い因子を抽出する。そのうち形質細胞分化を誘導したマウスB細胞で同定済のIRF4複合体因子を抽出して詳細な解析へ進める。

  2. Development of anti-cancer strategy by exploiting BACH1 addiction

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

    Institution: Tohoku University

    2020/10/27 - 2025/03/31

  3. 多発性骨髄腫で転写因子IKAROSの不安定化を促進する新規化合物の開発

    落合 恭子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2020/04/01 - 2023/03/31

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    ヒト多発性骨髄腫は、骨髄中の形質細胞がガン化して増殖し骨破壊などを引き起こす疾患である。多発性骨髄腫では転写因子IKAROSが腫瘍増悪に機能していて、IKAROSタンパク質分解を誘導する抗がん剤レプラミドを用いた治療が有効である。しかし、IKAROSはB細胞・T細胞・NK細胞などの免疫細胞分化にも重要であるため、レプラミドを用いた治療は免疫機能低下による感染症などの重篤な副作用が問題になる。この問題を解決するため、レプラミドとは異なる作用機序でIKAROSタンパク質を不安定化させ、低濃度のレプラミドで治療効果を得る薬剤併用療法が重要になる。 本研究では、クロマチン制御因子PC4によるIKAROSタンパク質安定化制御機構に着目する。我々は、ヒト多発性骨髄腫細胞株KMS12PEでPC4をノックダウンするとIKAROSタンパク質が減少し、単独よりも低濃度のレプラミドでIKAROSタンパク質の減少を誘導できることを見出している（Ochiai K. 2020 Cell Reports）。このことから、PC4によるIKAROSタンパク質安定化制御を標的とした薬剤を活用すれば、低濃度レプラミドと併用した治療が可能と考えた。研究開始当初、PC4複合体にIKAROSが同定されたため、PC4-IKAROS間の相互作用がIKAROS安定化に重要だと予想し、両者の相互作用を阻害すれば目的を達成できると考えた。しかし昨年度、PC4はIKAROSとの相互作用に依存せずIKAROSタンパク質を安定化する可能性が浮上した。本年度はその詳細な検討を行うと同時に、PC4-IKAROS間の相互作用以外でレプラミドと併用できる分子機構として、転写因子IRF4によるPC4遺伝子発現制御の分子機構を見出した。

  4. 選択的遺伝子領域の動的ヘテロクロマチン化誘導機構

    落合 恭子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2016/04/01 - 2018/03/31

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    分化刺激により活性化された成熟B細胞は形質細胞へ分化し、車軸状核と呼ばれる特徴的なヘテロクロマチン構造を呈する。一般的に、ヘテロクロマチン構造は種々の細胞において遺伝子抑制と関連することが明らかとなっている。本研究では、形質細胞への分化に伴い特定の遺伝子領域がヘテロクロマチン化される分子機構に着目した。 成熟B細胞が形質細胞へ分化するためには転写因子IRF4が必須であり、その分化過程でIRF4はZinc finger型転写因子Ikarosと新規同定DNA結合モチーフZinc finger-IRF composite elements（ZICEs）に結合し、B細胞活性化に関連する遺伝子群の発現を抑制する。そして、IRF4のZICEへの結合にはIkarosの存在が必須であり、Ikaros-IRF4はヘテロクロマチン関連因子群およびクロマチン制御因子PC4と複合体を形成することから、Ikaros-IRF4によるDNA配列依存的なヘテロクロマチン化機構を想定した。 一方、B細胞特異的PC4遺伝子欠損マウスを作出しB細胞におけるPC4機能の重要性について検討したところ、同マウスでは成熟B細胞の数が減少し形質細胞への分化能が低下することを見出した。このことから、PC4は成熟B細胞と形質細胞分化の双方に重要であることが明らかとなった。さらに、ZICEを保持するIkaros-IRF4抑制標的遺伝子上へのPC4結合が認められたことから、形質細胞分化過程ではZICEを介した遺伝子領域の選択性が生じ、その後PC4によるヘテロクロマチン化が誘導されると予想された。これらの知見は、細胞分化過程において特定の遺伝子領域がヘテロクロマチン化される分子機構解明に貢献すると考えられる。

  5. Orchestration of memory B cell differentiation controlled by the regulation of IRF4 protein degradation

    Ochiai Kyoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    In this study, we focused on the molecular mechanism how transcription factors Bach2 and IRF4 regulate cell status between memory B cell and plasma cell. Importantly, Bach2 maintains memory B cell status and represses plasma cell differentiation. We found that IRF4 protein amount was robustly accumulated in Bach2-deficient mouse splenic B cells. Considering that high protein amount of IRF4 promotes plasma cell differentiation, it is suggested that Bach2 controls differentiation by regulating IRF4 protein stability. Since protein stability is often regulated by post-translational modification under signaling pathways, we analyzed post-translational modification of IRF4 upon differentiation stimuli. Furthermore, we identified Bach2 target genes which include signaling molecules. These data suggest that Bach2 is required for the decision whether cell maintains memory B cell status or differentiates to plasma cell by modulating IRF4 protein stability.

  6. エピゲノム制御によるDNA損傷修復機構と細胞分化

    落合 恭子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2013/04/01 - 2015/03/31

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    細胞分化はエピゲノムによる緻密な制御を受けるが、細胞分化過程では遺伝子発現を伴う生理学的事象が生ずる。本研究では、B細胞が形質細胞へと分化する過程で生ずる遺伝子組換え反応であるCSR（Class switch recombination）と分化誘導両者の連続性とエピゲノム制御について着目した。 Mat2α（Methionine adenosyl-transferase 2A）はSAM合成を担う酵素であり、ヒストンを含めたメチル反応に重要な機能を保持する。先行研究より、Mat2α機能によるメチル化関連のCSRのエピゲノム制御の存在が考えられた。そこで、形質細胞分化に伴うCSR領域の経時的ヒストンメチル化を調べたところ、CSRに関連する新たなヒストンメチル化修飾を見出した。 一方、Mat2α複合体には遺伝子核内ポジショニングに関与する核膜タンパク質が含まれていた。そこで、CSR領域の核内ポジショニングとの関連性について検討するため、同核膜タンパク質機能解析を行った。同因子は分化刺激に伴い、転写レベルおよびタンパク質レベルで顕著に減少した。一方、細胞内局在は分化刺激により一過性に核膜周辺への強い局在を示した。同遺伝子をノックダウンしたところ、CSR頻度および分化頻度が顕著に減少した。また、レトロウイルスベクターを用いた同因子過剰発現でも同様にCSR頻度および分化頻度の減少が確認された。すなわち、同因子の一定量および時期特異的発現がCSRおよび形質細胞分化の制御において重要な意義をもつ可能性がある。 本研究によって、CSRと形質細胞分化はエピゲノムレベルで関与しかつ核内ポジショニングも重要であることが示唆された。今後はこれらの観点を統合し、CSRと形質細胞分化のエピゲノム制御解明に向けて三次元的解析を進めていく予定である。

  7. Dynamic regulation of cell differentiation via gene regulatory networks organized by multiple transcription factors

    OCHIAI Kyoko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    Cell type specific transcription factor (TF) regulate cell differentiation via the organization of gene regulatory network (GRN). The aim of this research is focused on the chain reaction of GRNs caused by two different TFs, which have the relation of up- and downstream. The GRN organized by FoxO1, the upstream TF, have been clarified in our previous study. The GRNs organized by the downstream TF, which are the direct target of FoxO1 and activated via FoxO1-GRN, have analyzed. Our new GRNs model will present the molecular mechanism for promoting cell differentiation via multiple TFs.

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