研究者詳細 - 久保田　翔

論文 - 久保田　翔

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Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions 査読

Sho Kubota, Yuqi Sun, Mariko Morii, Jie Bai, Takako Ideue, Mayumi Hirayama, Supannika Sorin, Eerdunduleng, Takako Yokomizo-Nakano, Motomi Osato, Ai Hamashima, Mihoko Iimori, Kimi Araki, Terumasa Umemoto, Goro Sashida

The EMBO Journal 43 ( 13 ) 2661 - 2684 2024年5月

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2-overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis.

DOI： 10.1038/s44318-024-00122-4

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その他リンク： https://www.embopress.org/doi/full/10.1038/s44318-024-00122-4

TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia 査読

Mariko Morii, Sho Kubota, Mihoko Iimori, Takako Yokomizo-Nakano, Ai Hamashima, Jie Bai, Akiho Nishimura, Masayoshi Tasaki, Yukio Ando, Kimi Araki, Goro Sashida

Leukemia 38 ( 6 ) 1275 - 1286 2024年5月

Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs. 査読国際誌

Takako Yokomizo-Nakano, Ai Hamashima, Sho Kubota, Jie Bai, Supannika Sorin, Yuqi Sun, Kenta Kikuchi, Mihoko Iimori, Mariko Morii, Akinori Kanai, Atsushi Iwama, Gang Huang, Daisuke Kurotaki, Hitoshi Takizawa, Hirotaka Matsui, Goro Sashida

The Journal of experimental medicine 220 ( 7 ) 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. We herein demonstrated that a prior stimulation with bacterial and viral products followed by loss of the Tet2 gene facilitated the development of MDS via up-regulating the target genes of the Elf1 transcription factor and remodeling the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Trif signaling but did not increase genomic mutations. The pharmacological inhibition of Plk function or the knockdown of Elf1 expression was sufficient to prevent the epigenetic remodeling in HSCs and diminish the enhanced clonogenicity and the impaired erythropoiesis. Moreover, this Elf1-target signature was significantly enriched in MDS HSPCs in humans. Therefore, prior infection stress and the acquisition of a driver mutation remodeled the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Trif-Plk-Elf1 axis, which promoted the development of MDS.

DOI： 10.1084/jem.20220962

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Overexpression of RUNX3 represses RUNX1 to drive transformation of myelodysplastic syndrome. 査読国際誌

Takako Yokomizo-Nakano, Sho Kubota, Jie Bai, Ai Hamashima, Mariko Morii, Yuqi Sun, Seiichiro Katagiri, Mihoko Iimori, Akinori Kanai, Daiki Tanaka, Motohiko Oshima, Yuka Harada, Kazuma Ohyashiki, Atsushi Iwama, Hironori Harada, Motomi Osato, Goro Sashida

Cancer research 80 ( 12 ) 2523 - 2536 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematological malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pan-cytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1 binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS.

DOI： 10.1158/0008-5472.CAN-19-3167

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[Enhancer hijacking via disease-specific chromosomal translocation in blastic plasmacytoid dendritic cell neoplasm]. 招待査読

Sho Kubota

臨床血液 2020年

Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm. 査読国際誌

Sho Kubota, Kenji Tokunaga, Tomohiro Umezu, Takako Yokomizo-Nakano, Yuqi Sun, Motohiko Oshima, Kar Tong Tan, Henry Yang, Akinori Kanai, Eisaku Iwanaga, Norio Asou, Takahiro Maeda, Naomi Nakagata, Atsushi Iwama, Kazuma Ohyashiki, Motomi Osato, Goro Sashida

Nature communications 10 ( 1 ) 3943 - 3943 2019年8月

Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in its Dissociation from Chromatin and the Nuclear Matrix. 査読

Sho Kubota, Mariko Morii, Ryuzaburo Yuki, Noritaka Yamaguchi, Hiromi Yamaguchi, Kazumasa Aoyama, Takahisa Kuga, Takeshi Tomonaga, Naoto Yamaguchi

The Journal of biological chemistry 290 ( 17 ) 10891 - 10904 2015年4月

Phosphorylation of KRAB-associated Protein 1 (KAP1) at Tyr-449, Tyr-458, and Tyr-517 by Nuclear Tyrosine Kinases Inhibits the Association of KAP1 and Heterochromatin Protein 1α (HP1α) with Heterochromatin 査読

Sho Kubota, Yasunori Fukumoto, Kazumasa Aoyama, Kenichi Ishibashi, Ryuzaburo Yuki, Takao Morinaga, Takuya Honda, Noritaka Yamaguchi, Takahisa Kuga, Takeshi Tomonaga, Naoto Yamaguchi

Journal of Biological Chemistry 288 ( 24 ) 17871 - 17883 2013年6月

Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress 査読

Haruna Kurogi, Nobumasa Takasugi, Sho Kubota, Ashutosh Kumar, Takehiro Suzuki, Naoshi Dohmae, Daisuke Sawada, Kam Y.J. Zhang, Takashi Uehara

ACS Chemical Biology 19 ( 12 ) 2429 - 2437 2024年11月

Epigenetic Regulation of CXC Chemokine Expression by Environmental Electrophiles Through DNA Methyltransferase Inhibition 査読

Tomoki Tsuchida, Sho Kubota, Shizuki Kamiuezono, Nobumasa Takasugi, Akihiro Ito, Yoshito Kumagai, Takashi Uehara

International Journal of Molecular Sciences 25 ( 21 ) 11592 - 11592 2024年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.

DOI： 10.3390/ijms252111592

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Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice 査読

Ryohei Miki, Ryosuke Nomura, Yuta Iijima, Sho Kubota, Nobumasa Takasugi, Takao Iwawaki, Masatake Fujimura, Takashi Uehara

Archives of Toxicology 2024年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.

DOI： 10.1007/s00204-024-03902-3

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その他リンク： https://link.springer.com/article/10.1007/s00204-024-03902-3/fulltext.html

Epigenetic Regulation of Carbonic Anhydrase 9 Expression by Nitric Oxide in Human Small Airway Epithelial Cells 査読

Yuto Moriya, Sho Kubota, Yuta Iijima, Nobumasa Takasugi, Takashi Uehara

Biological and Pharmaceutical Bulletin 47 ( 6 ) 1119 - 1122 2024年6月

Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling 査読

Atsushi Morimoto, Nobumasa Takasugi, Yuexuan Pan, Sho Kubota, Naoshi Dohmae, Yumi Abiko, Koji Uchida, Yoshito Kumagai, Takashi Uehara

Journal of Biological Chemistry 300 ( 3 ) 105679 - 105679 2024年3月

Multiple myeloma–associated DIS3 gene is essential for hematopoiesis, but loss of DIS3 is insufficient for myelomagenesis 査読

Hiroto Ohguchi, Yasuyo Ohguchi, Sho Kubota, Kan Etoh, Ai Hamashima, Shingo Usuki, Takako Yokomizo-Nakano, Jie Bai, Takeshi Masuda, Yawara Kawano, Takeshi Harada, Mitsuyoshi Nakao, Takashi Minami, Teru Hideshima, Kimi Araki, Goro Sashida

Blood Neoplasia 1 ( 1 ) 100005 - 100005 2024年3月

Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 1 査読

Rikako Taniguchi, Yuto Moriya, Naoshi Dohmae, Takehiro Suzuki, Kengo Nakahara, Sho Kubota, Nobumasa Takasugi, Takashi Uehara

Journal of Pharmacological Sciences 154 ( 3 ) 209 - 217 2024年3月

Transcriptome analysis in various cell lines exposed to nitric oxide. 査読

Tohta Mizushima, Sho Kubota, Yuta Iijima, Nobumasa Takasugi, Takashi Uehara

The Journal of toxicological sciences 49 ( 6 ) 281 - 288 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Nitric oxide (NO) plays a physiological role in signal transduction and excess or chronic NO has toxic effects as an inflammatory mediator. NO reversibly forms protein S-nitrosylation and exerts toxicological functions related to disease progression. DNA methyltransferases, epigenome-related enzymes, are inhibited in enzymatic activity by S-nitrosylation. Therefore, excess or chronic NO exposure may cause disease by altering gene expression. However, the effects of chronic NO exposure on transcriptome are poorly understood. Here, we performed transcriptome analysis of A549, AGS, HEK293T, and SW48 cells exposed to NO (100 μM) for 48 hr. We showed that the differentially expressed genes were cell-specific. Gene ontology analysis showed that the functional signature of differentially expressed genes related to cell adhesion or migration was upregulated in several cell lines. Gene set enrichment analysis indicated that NO stimulated inflammation-related gene expression in various cell lines. This finding supports previous studies showing that NO is closely involved in inflammatory diseases. Overall, this study elucidates the pathogenesis of NO-associated inflammatory diseases by focusing on changes in gene expression.

DOI： 10.2131/jts.49.281

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CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma 査読

Takuro Kameda, Kotaro Shide, Ayako Kamiunten, Yasunori Kogure, Daisuke Morishita, Junji Koya, Yuki Tahira, Keiichi Akizuki, Takako Yokomizo-Nakano, Sho Kubota, Kosuke Marutsuka, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Yuichi Kitai, Tadashi Matsuda, Akinori Yoda, Takayuki Ohshima, Midori Sugiyama, Goro Sashida, Keisuke Kataoka, Seishi Ogawa, Kazuya Shimoda

Communications Biology 5 ( 1 ) 2022年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4⁺ T cell-specific CARD11(E626K) and/or CD4⁺ T cell-specific HBZ, namely CARD11(E626K)^CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)^CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)^CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4⁺ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

DOI： 10.1038/s42003-022-04284-x

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その他リンク： https://www.nature.com/articles/s42003-022-04284-x

HMGN3 represses transcription of epithelial regulators to promote migration of cholangiocarcinoma in a SNAI2-dependent manner. 査読国際誌

Supannika Sorin, Sho Kubota, Sofiane Hamidi, Takako Yokomizo-Nakano, Kulthida Vaeteewoottacharn, Sopit Wongkham, Sakda Waraasawapati, Chawalit Pairojkul, Jie Bai, Mariko Morii, Guojun Sheng, Kanlayanee Sawanyawisuth, Goro Sashida

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 ( 7 ) e22345 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

High mobility group nucleosome-binding protein 3 (HMGN3), a member of the HMGN family, modulates the structure of chromatin and regulates transcription through transcription factors. HMGN3 has been implicated in the development of various cancers; however, the underlying mechanisms remain unclear. We herein demonstrated that the high expression of HMGN3 correlated with the metastasis of liver fluke infection-induced cholangiocarcinoma (CCA) in patients in northeastern Thailand. The knockdown of HMGN3 in CCA cells significantly impaired the oncogenic properties of colony formation, migration, and invasion. HMGN3 inhibited the expression of and blocked the intracellular polarities of epithelial regulator genes, such as the CDH1/E-cadherin and TJAP1 genes in CCA cells. A chromatin immunoprecipitation sequencing analysis revealed that HMGN3 required the transcription factor SNAI2 to bind to and repress the expression of epithelial regulator genes, at least in part, due to histone deacetylases (HDACs), the pharmacological inhibition of which reactivated these epithelial regulators in CCA, leading to impairing the cell migration capacity. Therefore, the overexpression of HMGN3 represses the transcription of and blocks the polarities of epithelial regulators in CCA cells in a manner that is dependent on the SNAI2 gene and HDACs.

DOI： 10.1096/fj.202200386R

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ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration. 査読国際誌

Terumasa Umemoto, Alban Johansson, Shah Adil Ishtiyaq Ahmad, Michihiro Hashimoto, Sho Kubota, Kenta Kikuchi, Haruki Odaka, Takumi Era, Daisuke Kurotaki, Goro Sashida, Toshio Suda

The EMBO journal 41 ( 8 ) e109463 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5-fluorouracil-induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCRhigh ) were enriched within the stem cell fraction at the expense of more proliferative EPCRLow HSCs. These EPCRHigh HSCs were initially more primitive than EPCRLow HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis-regulatory elements in progenitor cell-related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY-dependent histone acetylation promoted differentiation into CD48+ progenitor cells. Collectively, these results indicate that the dynamic control of ACLY-dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.

DOI： 10.15252/embj.2021109463

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The acidic domain of Hmga2 and the domain's linker region are critical for driving self-renewal of hematopoietic stem cell. 査読国際共著国際誌

Yuqi Sun, Sho Kubota, Mihoko Iimori, Ai Hamashima, Haruka Murakami, Jie Bai, Mariko Morii, Takako Yokomizo-Nakano, Motomi Osato, Kimi Araki, Goro Sashida

International journal of hematology 115 ( 4 ) 553 - 562 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

High mobility group AT-hook 2 (Hmga2) is a chromatin modifier protein that plays a critical role in fetal development and leukemia propagation by binding to chromatin and DNA via its AT-hook domains. However, the molecular mechanisms by which Hmga2 activates the expression of target genes to drive the self-renewal of hematopoietic stem cells (HSCs) remain unclear. We generated Rosa26 locus Hmga2 conditional knock-in mice and found that overexpression of Hmga2 promoted self-renewal of normal HSCs, but maintained their fitness in bone marrow, and consequently was not sufficient to initiate malignancy. This result is consistent with previous findings showing that Hmga2 is a proto-oncogene. We also assessed the cellular functions of Hmga2 mutants lacking functional domains and demonstrated that the C-terminus acidic domain of Hmga2 and the domain's linker region were critical for activating genes involved in stem cell signatures, such as the Igf2bp2 gene, to drive proliferation of HSCs. In contrast, overexpression of Hmga1, a member of the Hmga family with a different linker region, did not drive proliferation of HSCs. Our results reveal a critical role for the acidic domain of Hmga2 and the domain's linker region in modulating the transcription and self-renewal functions of HSCs.

DOI： 10.1007/s12185-021-03274-9

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