Research activity information

• Left atrial single-cell transcriptomics reveals amphiregulin as a surrogate marker for atrial fibrillation.

  Yuya Suzuki, Takuo Emoto, Shunsuke Sato, Takeshi Yoshida, Mitsuhiko Shoda, Hiromi Endoh, Manabu Nagao, Tomoyo Hamana, Taishi Inoue, Tomohiro Hayashi, Eriko Nitta, Hiroki Konishi, Kunihiko Kiuchi, Mitsuru Takami, Kimitake Imamura, Masayuki Taniguchi, Masatoshi Inoue, Toshihiro Nakamura, Yusuke Sonoda, Hiroyuki Takahara, Kazutaka Nakasone, Kyoko Yamamoto, Kenichi Tani, Hidehiro Iwai, Yusuke Nakanishi, Shogo Yonehara, Atsushi Murakami, Ryuji Toh, Takenao Ohkawa, Tomoyuki Furuyashiki, Ryo Nitta, Tomoya Yamashita, Ken-Ichi Hirata, Koji Fukuzawa

  Atrial fibrillation (AF) is strongly associated with strokes, heart failure, and increased mortality. This study aims to identify the monocyte-macrophage heterogeneity and interactions of these cells with non-immune cells, and to identify functional biomarkers in patients with AF. Therefore, we assess the single cell landscape of left atria (LA), using a combination of single cell and nucleus RNA-seq. Myeloid cells in LA tissue are categorized into five macrophage clusters, three monocyte clusters, and others. Cell-Chat analysis revealed that monocytes and IL1B+ macrophages send epidermal growth factor (EGF) signals to fibroblasts. Amphiregulin (AREG) is the most upregulated gene in monocytes and IL1B+ macrophages in the AF group, compared with healthy controls from other groups. Serum AREG levels are higher in patients with persistent AF. These data suggested that EGF signaling pathway could be a therapeutic target for AF and serum AREG levels provide an effective biomarker for predicting persistent AF.

  Dec. 2024, Communications biology, 7(1) (1), 1601 - 1601, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I.

  Hiromichi Okuma, Yumiko Saijo-Hamano, Hiroshi Yamada, Aalaa Alrahman Sherif, Emi Hashizaki, Naoki Sakai, Takaaki Kato, Tsuyoshi Imasaki, Satoshi Kikkawa, Eriko Nitta, Miwa Sasai, Tadashi Abe, Fuminori Sugihara, Yoshimasa Maniwa, Hidetaka Kosako, Kohji Takei, Daron M Standley, Masahiro Yamamoto, Ryo Nitta

  Irgb6 is a priming immune-related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell-autonomous immunity. However, the molecular mechanism by which immunity-related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro. Structural analysis unveiled an atypical conformation of nucleotide-free Irgb6-T95D, resulting from a conformational change in the G-domain that allosterically modified the PV membrane-binding interface. In silico docking corroborated the disruption of the physiological membrane binding site. These findings provide novel insights into a T. gondii-induced allosteric inactivation mechanism of Irgb6.

  Nov. 2023, Genes to cells : devoted to molecular & cellular mechanisms, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Amyloid deposition through endocytosis in vascular endothelial cells.

  Seiji Nishikage, Akira Fujisawa, Hiromi Endoh, Hirotaka Sakamoto, Tomohide Suzuki, Maki Kanzawa, Shinichi Ishii, Mitsumasa Okano, Eriko Nitta, Kimikazu Yakushijin, Hidesaku Asakura, Kandai Nozu, Ryo Nitta, Yoshio Katayama, Kazuhiko Sakaguchi

  No mechanistic lead is known for establishing AL amyloid deposits in organs. We here report an electron microscopic (EM) analysis in a case of intestinal AL amyloidosis before initiating treatment for amyloidosis. The dense deposits of amyloid fibrils are concentrated around the small blood vessels in the submucosal area in intestinal tissue. Surprisingly, we observed endothelial cells (ECs) of blood vessels containing plenty of endocytotic (pinocytotic) and transcytotic vesicles at the luminal side and above the basement membrane, indicating the one-way active trafficking of either immunoglobulin light chain or pre-assembled amyloid fibrils from the luminal side of ECs to the extraluminal area of ECs. Immunoelectron microscopy displayed that the immuno-gold signals were observed in the vascular cavity and the subendothelial area of amyloid deposits. However, there is no sign of immunoglobulin light chain in pinocytotic vesicles. Therefore, the intestinal ECs may actively pump out mainly the pre-assembled amyloid fibrils (not light chains) from the blood stream into the subendothelial area as a physiological function.

  Nov. 2023, Experimental hematology, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• CD47 promotes peripheral T cell survival by preventing dendritic cell–mediated T cell necroptosis

  Satomi Komori, Yasuyuki Saito, Taichi Nishimura, Datu Respatika, Hiromi Endoh, Hiroki Yoshida, Risa Sugihara, Rie Iida-Norita, Tania Afroj, Tomoko Takai, Okechi S. Oduori, Eriko Nitta, Takenori Kotani, Yoji Murata, Yoriaki Kaneko, Ryo Nitta, Hiroshi Ohnishi, Takashi Matozaki

  Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has remained unclear. We here show that T cell–specific CD47-deficient ( Cd47^ΔT ) mice have a markedly reduced number of T cells in peripheral tissues. Direct interaction of CD47-deficient T cells with cDCs resulted in activation of the latter cells, which in turn induced necroptosis of the former cells. The deficiency and cell death of T cells in Cd47^ΔT mice required expression of its receptor signal regulatory protein α on cDCs. The development of CD4 ⁺ T helper cell–dependent contact hypersensitivity and inhibition of tumor growth by cytotoxic CD8 ⁺ T cells were both markedly impaired in Cd47^ΔT mice. CD47 on T cells thus likely prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function.

  Proceedings of the National Academy of Sciences, Aug. 2023, Proceedings of the National Academy of Sciences, 120(33) (33), English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Structural model of microtubule dynamics inhibition by Kinesin-4 from the crystal structure of KLP-12 –tubulin complex

  Shinya Taguchi, Juri Nakano, Tsuyoshi Imasaki, Tomoki Kita, Yumiko Saijo-Hamano, Naoki Sakai, Hideki Shigematsu, Hiromichi Okuma, Takahiro Shimizu, Eriko Nitta, Satoshi Kikkawa, Satoshi Mizobuchi, Shinsuke Niwa, Ryo Nitta

  Abstract Kinesin superfamily proteins are microtubule-based molecular motors driven by the energy of ATP hydrolysis. Among them, the kinesin-4 family is a unique motor that inhibits microtubule dynamics. Although mutations of kinesin-4 cause several diseases, its molecular mechanism is unclear because of the difficulty of visualizing the high-resolution structure of kinesin-4 working at the microtubule plus-end. Here, we report that KLP-12, a C. elegans kinesin-4 ortholog of KIF21A and KIF21B, is essential for proper length control of C. elegans axons, and its motor domain represses microtubule polymerization in vitro. The crystal structure of the KLP-12 motor domain complexed with tubulin, which represents the high-resolution structural snapshot of inhibition state of microtubule-end dynamics, revealed the bending effect of KLP-12 for tubulin. Comparison with the KIF5B-tubulin and KIF2C-tubulin complexes, which represent the elongation and shrinking forms of microtubule ends, respectively, showed the curvature of tubulin introduced by KLP-12 is in between them. Taken together, KLP-12 controls the proper length of axons by modulating the curvature of the microtubule ends to inhibit the microtubule dynamics.

  Cold Spring Harbor Laboratory, Feb. 2022

  Link to Kobe Univ. Repository (Kernel)


• クロマチンリモデリング因子BRMは造血幹細胞を静止期に維持する(The chromatin remodeling factor BRM maintains a quiescent state of the hematopoietic stem cells)

  宮地 洋希, 桐山 大輝, 川端 野乃子, 糸川 直樹, 小出 周平, 山下 真幸, 大島 基彦, 今崎 剛, 須田 年生, 岩間 厚志, 仁田 亮, 仁田 英里子

  (一社)日本血液学会, Sep. 2021, 日本血液学会学術集会, 83回, OS1 - 4, English


• CAMSAP2 organizes a γ-tubulin-independent microtubule nucleation centre

  Tsuyoshi Imasaki, Satoshi Kikkawa, Shinsuke Niwa, Yumiko Saijo-Hamano, Hideki Shigematsu, Kazuhiro Aoyama, Kaoru Mitsuoka, Mari Aoki, Ayako Sakamoto, Yuri Tomabechi, Naoki Sakai, Mikako Shirouzu, Shinya Taguchi, Yosuke Yamagishi, Tomiyoshi Setsu, Yoshiaki Sakihama, Takahiro Shimizu, Eriko Nitta, Masatoshi Takeichi, Ryo Nitta

  Microtubules are dynamic polymers consisting of αβ-tubulin heterodimers. The initial polymerization process, called microtubule nucleation, occurs spontaneously via αβ-tubulin. Since a large energy barrier prevents microtubule nucleation in cells, the γ-tubulin ring complex is recruited to the centrosome to overcome the nucleation barrier. However, detachment of a considerable number of microtubules from the centrosome is known to contribute to fundamental processes in cells. Here, we present evidence that minus-end-binding calmodulin-regulated spectrin-associated protein 2 (CAMSAP2) serves as a strong nucleator for microtubule formation from soluble αβ-tubulin independent of γ-tubulin. CAMSAP2 significantly reduces the nucleation barrier close to the critical concentration for microtubule polymerization by stabilizing the longitudinal contacts among αβ-tubulins. CAMSAP2 clusters together with αβ-tubulin to generate nucleation intermediates, from which numerous microtubules radiate, forming aster-like structures. Our findings suggest that CAMSAP2 supports microtubule growth by organizing a nucleation centre as well as by stabilizing microtubule nucleation intermediates.

  Cold Spring Harbor Laboratory, Mar. 2021


• 【細胞機能の構造生物学】細胞骨格の構造生物学 微小管結合タンパク質

  吉川 知志, 仁田 英里子, 今崎 剛, 仁田 亮

  (公財)金原一郎記念医学医療振興財団, Aug. 2020, 生体の科学, 71(4) (4), 298 - 303, Japanese


• Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature.

  Eriko Nitta, Naoki Itokawa, Shogo Yabata, Shuhei Koide, Li-Bo Hou, Motohiko Oshima, Kazumasa Aoyama, Atsunori Saraya, Atsushi Iwama

  Polycomb-group proteins are critical regulators of stem cells. We previously demonstrated that Bmi1, a component of polycomb repressive complex 1, defines the regenerative capacity of hematopoietic stem cells (HSCs). Here, we attempted to ameliorate the age-related decline in HSC function by modulating Bmi1 expression. The forced expression of Bmi1 did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression of Bmi1 augmented the multi-lineage repopulating capacity of aged HSCs. Chromatin immunoprecipitation-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression of Bmi1 strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation of Bmi1 expression is a potential approach against impairments in HSC function with aging.

  Jan. 2020, Biochemical and biophysical research communications, 521(3) (3), 612 - 619, English, International magazine

  [Refereed]

  Scientific journal


• Bmi1 restricts the adipogenic differentiation of bone marrow stromal cells to maintain the integrity of the hematopoietic stem cell niche.

  Yuko Kato, Li-Bo Hou, Satoru Miyagi, Eriko Nitta, Kazumasa Aoyama, Daisuke Shinoda, Satoshi Yamazaki, Wakako Kuribayashi, Yusuke Isshiki, Shuhei Koide, Sha Si, Atsunori Saraya, Yumi Matsuzaki, Maarten van Lohuizen, Atsushi Iwama

  The polycomb group protein Bmi1 maintains hematopoietic stem cell (HSC) functions. We previously reported that Bmi1-deficient mice exhibited progressive fatty changes in bone marrow (BM). A large portion of HSCs reside in the perivascular niche created partly by endothelial cells and leptin receptor+ (LepR+) BM stromal cells. To clarify how Bmi1 regulates the HSC niche, we specifically deleted Bmi1 in LepR+ cells in mice. The Bmi1 deletion promoted the adipogenic differentiation of LepR+ stromal cells and caused progressive fatty changes in the BM of limb bones with age, resulting in reductions in the numbers of HSCs and progenitors in BM and enhanced extramedullary hematopoiesis. This adipogenic change was also evident during BM regeneration after irradiation. Several adipogenic regulator genes appeared to be regulated by Bmi1. Our results indicate that Bmi1 keeps the adipogenic differentiation program repressed in BM stromal cells to maintain the integrity of the HSC niche.

  Aug. 2019, Experimental hematology, 76, 24 - 37, English, International magazine

  [Refereed]

  Scientific journal


• Recent progress in structural biology: lessons from our research history

  Nitta R, Imasaki T, Nitta E

  May 2018, Microscopy (Oxf), 67, 187 - 195, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Structural insights into the altering function of CRMP2 by phosphorylation

  Takuya Sumi, Tsuyoshi Imasaki, Mari Aoki, Naoki Sakai, Eriko Nitta, Mikako Shirouzu, Ryo Nitta

  Japan Society for Cell Biology, Feb. 2018, Cell Structure and Function, 43(1) (1), 15 - 23, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• The nicotinic acetylcholine receptor α7 subunit is an essential negative regulator of bone mass

  Kazuaki Mito, Yuiko Sato, Tami Kobayashi, Kana Miyamoto, Eriko Nitta, Atsushi Iwama, Morio Matsumoto, Masaya Nakamura, Kazuki Sato, Takeshi Miyamoto

  Nature Publishing Group, Mar. 2017, Scientific Reports, 7, 45597, English

  [Refereed]

  Scientific journal


• Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes

  Shuhei Koide, Motohiko Oshima, Keiyo Takubo, Satoshi Yamazaki, Eriko Nitta, Atsunori Saraya, Kazumasa Aoyama, Yuko Kato, Satoru Miyagi, Yaeko Nakajima-Takagi, Tetsuhiro Chiba, Hirotaka Matsui, Fumio Arai, Yutaka Suzuki, Hiroshi Kimura, Hiromitsu Nakauchi, Toshio Suda, Yoichi Shinkai, Atsushi Iwama

  Aug. 2016, BLOOD, 128(5) (5), 638 - 649, English

  [Refereed]

  Scientific journal


• Regulation of hematopoietic stem cell integrity through p53 and its related factors

  Masayuki Yamashita, Eriko Nitta, Toshio Suda

  2016, HEMATOPOIETIC STEM CELLS IX, 1370(1) (1), 45 - 54, English

  [Refereed]

  Scientific journal


• Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

  Masayuki Yamashita, Eriko Nitta, Toshio Suda

  Jul. 2015, CELL STEM CELL, 17(1) (1), 23 - 34, English

  [Refereed]

  Scientific journal


• Diploid, not polyploid: new platelet producers

  Eriko Nitta, Atsushi Iwama

  Oct. 2014, BLOOD, 124(17) (17), 2620 - 2622, English

  Scientific journal


• Nucleostemin is indispensable for the maintenance and genetic stability of hematopoietic stem cells

  Masayuki Yamashita, Eriko Nitta, Go Nagamatsu, Yoshiko Matsumoto Ikushima, Kentaro Hosokawa, Fumio Arai, Toshio Suda

  Nov. 2013, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 441(1) (1), 196 - 201, English

  [Refereed]

  Scientific journal


• Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism

  Eriko Nitta, Masayuki Yamashita, Kentaro Hosokawa, MingJi Xian, Keiyo Takubo, Fumio Arai, Shinichiro Nakada, Toshio Suda

  Apr. 2011, BLOOD, 117(16) (16), 4169 - 4180, English

  [Refereed]

  Scientific journal


• Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins

  Akihide Yoshimi, Susumu Goyama, Naoko Watanabe-Okochi, Yumiko Yoshiki, Yasuhito Nannya, Eriko Nitta, Shunya Arai, Tomohiko Sato, Munetake Shimabe, Masahiro Nakagawa, Yoichi Imai, Toshio Kitamura, Mineo Kurokawa

  Mar. 2011, BLOOD, 117(13) (13), 3617 - 3628, English

  [Refereed]

  Scientific journal


• EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

  S. Goyama, E. Nitta, T. Yoshino, S. Kako, N. Watanabe-Okochi, M. Shimabe, Y. Imai, K. Takahashi, M. Kurokawa

  Jan. 2010, LEUKEMIA, 24(1) (1), 81 - 88, English

  [Refereed]

  Scientific journal


• Evi-1 promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-beta signaling

  Tomohiko Sato, Susumu Goyama, Eriko Nitta, Masataka Takeshita, Mayumi Yoshimi, Masahiro Nakagawa, Masahito Kawazu, Motoshi Ichikawa, Mineo Kurokawa

  Jul. 2008, CANCER SCIENCE, 99(7) (7), 1407 - 1413, English

  [Refereed]

  Scientific journal


• AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1

  M. Takeshita, M. Ichikawa, E. Nitta, S. Goyama, T. Asai, S. Ogawa, S. Chiba, M. Kurokawa

  Jun. 2008, LEUKEMIA, 22(6) (6), 1241 - 1249, English

  [Refereed]

  Scientific journal


• Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL

  Sahoko Matsuoka, Yuichi Oike, Ichiro Onoyama, Atsushi Iwama, Fumio Arai, Keiyo Takubo, Yoichi Mashimo, Hideyuki Oguro, Eriko Nitta, Keisuke Ito, Kana Miyamoto, Hiroki Yoshiwara, Kentaro Hosokawa, Yuka Nakamura, Yumiko Gomei, Hiroko Iwasaki, Yasuhide Hayashi, Yumi Matsuzaki, Keiko Nakayama, Yasuo Ikeda, Akira Hata, Shigeru Chiba, Keiichi I. Nakayama, Toshio Suda

  Apr. 2008, GENES & DEVELOPMENT, 22(8) (8), 986 - 991, English

  [Refereed]

  Scientific journal


• A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study

  E. Nitta, K. Izutsu, T. Sato, Y. Ota, K. Takeuchi, A. Kamijo, K. Takahashi, K. Oshima, Y. Kanda, S. Chiba, T. Motokura, M. Kurokawa

  Feb. 2007, ANNALS OF ONCOLOGY, 18(2) (2), 364 - 369, English

  [Refereed]

  Scientific journal


• Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP

  E Nitta, K Izutsu, Y Yamaguchi, Y Imai, S Ogawa, S Chiba, M Kurokawa, H Hirai

  Sep. 2005, ONCOGENE, 24(40) (40), 6165 - 6173, English

  [Refereed]

  Scientific journal


• AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues

  Y Yamaguchi, M Kurokawa, Y Imai, K Izutsu, T Asai, M Ichikawa, G Yamamoto, E Nitta, T Yamagata, K Sasaki, K Mitani, S Ogawa, S Chiba, H Hirai

  Apr. 2004, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(15) (15), 15630 - 15638, English

  [Refereed]

  Scientific journal


• The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1

  Y Imai, M Kurokawa, Y Yamaguchi, K Izutsu, E Nitta, K Mitani, M Satake, T Noda, Y Ito, H Hirai

  Feb. 2004, MOLECULAR AND CELLULAR BIOLOGY, 24(3) (3), 1033 - 1043, English

  [Refereed]

  Scientific journal


• The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1

  Y Imai, M Kurokawa, Y Yamaguchi, K Izutsu, E Nitta, K Mitani, M Satake, T Noda, Y Ito, H Hirai

  Feb. 2004, MOLECULAR AND CELLULAR BIOLOGY, 24(3) (3), 1033 - 1043, English

  [Refereed]

  Scientific journal

• MAPs: microtubule associated proteins

  吉川知志, 仁田英里子, 今崎剛, 仁田亮

  2020, 生体の科学, 71(4) (4)


• Hematopoietic stem cell aging and hematopoietic malignancies

  NITTA ERIKO, 岩間 厚志

  日本臨床社, Sep. 2016, 日本臨床, 74(9) (9), 1502 - 1507, Japanese

  Introduction scientific journal


• 【老化制御と疾患-エイジング研究の進歩-】 老化制御と疾患 造血幹細胞の老化と造血腫瘍

  岩間厚志

  日本臨床社, Sep. 2016, 日本臨床, 74(9号) (9号), 1502 - 1507, Japanese

  Introduction scientific journal


• CHROMATIN REMODELING FACTOR BRM IS ESSENTIAL FOR THE MAINTENANCE OF HSC QUIESCENCE

  Eriko Nitta, Masayuki Yamashita, Motohiko Oshima, Atsushi Iwama, Toshio Suda

  Sep. 2015, EXPERIMENTAL HEMATOLOGY, 43(9) (9), S85 - S85, English

  Summary international conference


• 【がん幹細胞-新しい医療を求めて-】 がん幹細胞化のメカニズム

  岩間厚志

  日本臨床社, May 2015, 日本臨床, 73(5号) (5号), 733 - 738, Japanese

  Introduction scientific journal


• The cancer stem cell model in hematological malignancies

  NITTA ERIKO, 岩間 厚志

  日本臨床社, May 2015, 日本臨床, 73(5) (5), 733 - 738, Japanese

  Introduction scientific journal


• Maintenance of hematopoietic stem cell integrity and regulation of leukemogenesis by p53 and its coactivator Aspp1

  YAMASHITA Masayuki, NITTA Eriko, SUDA Toshio

  Hematopoietic stem cells (HSCs) are predominantly in a quiescent state, thereby avoiding depletion due to various stresses. However, quiescent HSCs are vulnerable to mutagenesis due to low-fidelity DNA repair. The mechanism by which HSCs avoid mutation accumulation remains to be elucidated. HSCs are normally resistant to apoptosis because of their abundant expressions of pro-su

  The Japanese Society of Hematology, 2015, Rinsho Ketsueki, 56(12) (12), 2426 - 2433, Japanese

  Introduction scientific journal


• p53 Co-Activator Aspp1 Induces Apoptosis in Damaged Hematopoietic Stem Cells and Prevents Malignant Transformation

  Masayuki Yamashita, Eriko Nitta, Toshio Suda

  Dec. 2014, BLOOD, 124(21) (21), English

  Summary international conference


• CHROMATIN REMODELING FACTOR BRM PROTECTS HSCS FROM ROS STRESS VIA MAINTAINING QUIESCENCE

  Eriko Nitta, Masayuki Yamashita, Atsushi Iwama, Toshio Suda

  Aug. 2014, EXPERIMENTAL HEMATOLOGY, 42(8) (8), S54 - S54, English

  Summary international conference


• CHROMATIN REMODELING FACTOR SMARCA2 CONTRIBUTES TO MAINTAIN HEMATOPOIETIC STEM CELL QUIESCENCE

  Eriko Nitta, Masayuki Yamashita, Toshio Suda

  Aug. 2013, EXPERIMENTAL HEMATOLOGY, 41(8) (8), S38 - S38, English

  Summary international conference


• ASPP1 (APOPTOSIS-STIMULATING PROTEIN OF P53, 1) INDUCES HEMATOPOIETIC STEM CELL CYCLING AND APOPTOSIS IN RESPONSE TO CELLULAR STRESS

  Masayuki Yamashita, Eriko Nitta, Toshio Suda

  Aug. 2012, EXPERIMENTAL HEMATOLOGY, 40(8) (8), S34 - S35, English

  Summary international conference


• 【テロメア異常と血液病】 造血幹細胞におけるテロメア・テロメラーゼ

  須田年生

  May 2012, 血液フロンティア, 22(6号) (6号), 927 - 934, Japanese

  Introduction scientific journal


• Cancer stem cell concepts: lesson from leukemia

  NITTA ERIKO, 須田 年生

  日本臨床社, Oct. 2009, Japanese journal of clinical medicine, 67(10) (10), 1863 - 1867, Japanese

  Introduction scientific journal


• 【骨髄性白血病 病因・治療研究の進歩】 病因・病態解明 白血病幹細胞の潮流

  須田年生

  日本臨床社, Oct. 2009, 日本臨床, 67(10号) (10号), 1863 - 1867, Japanese

  Introduction scientific journal


• 老年医学の展望 幹細胞における老化とがんの制御機構

  須田年生

  May 2009, 日本老年医学会雑誌, 46(3号) (3号), 195 - 199, Japanese

  Introduction scientific journal


• Aging and cancer in hematopoietic stem cells

  NITTA Eriko, SUDA Toshio

  日本老年医学会, May 2009, Japanese journal of geriatrics, 46(3) (3), 195 - 199, Japanese

  Introduction scientific journal


• Evi-1 Interacts with Histone Methyltransferases for Transcription Repression and Bone Marrow Transformation

  Susumu Goyama, Eriko Nitta, Munetake Shimabe, Tetsuya Yoshino, Shinichi Kako, Motoshi Ichikawa, Yoichi Imai, Tsuyoshi Takahashi, Akira Hangaishi, Mineo Kurokawa

  Nov. 2008, BLOOD, 112(11) (11), 787 - 788, English

  Summary international conference


• 白血病標的遺伝子Evi‐1によるヒストンメチル化修飾を介した転写制御機構

  合山進, 仁田英里子, 島辺宗健, 吉野哲也, 市川幹, 今井陽一, 高橋強志, 黒川峰夫

  30 Sep. 2008, 臨床血液, 49(9) (9), 880, Japanese


• Implication of AML1/RUNX1 function in the homeostasis and leukemic transformation of hematopoietic stem cells

  Motoshi Ichikawa, Masataka Takeshita, Susumu Goyama, Takashi Asai, Eriko Nitta, Masahiro Nakagawa, Masahito Kawazu, Shigeru Chiba, Seishi Ogawa, Mineo Kurokawa

  Nov. 2007, BLOOD, 110(11) (11), 98B - 98B, English

  Summary international conference


• AML1‐Evi‐キメラ遺伝子によるマウス骨髄前駆細胞形質転換の検討(続報)

  竹下昌孝, 市川幹, 仁田英里子, 合山進, 小川誠司, 千葉滋, 黒川峰夫

  30 Sep. 2007, 臨床血液, 48(9) (9), 858, Japanese


• Oligomerization of Evi-1 contributes to recruitment of transcriptional corepressor CtBP and repression of TGF-beta signaling

  E Nitta, K Izutsu, Y Yamaguchi, Y Imai, S Ogawa, S Chiba, M Kurokawa, H Hirai

  Nov. 2004, BLOOD, 104(11) (11), 703A - 704A, English

  Summary international conference


• AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues.

  H Hirai, Y Yamaguchi, M Kurokawa, Y Imai, K Izutsu, T Asai, M Ichikawa, G Yamamoto, E Nitta, T Yamagata, K Mitani

  Nov. 2002, BLOOD, 100(11) (11), 31A - 31A, English

  Summary international conference

• 造血幹細胞を制御する遺伝子1.ポリコーム遺伝子ほかエピジェネティクス制御遺伝子／造血器腫瘍アトラス第5版

  NITTA ERIKO, 岩間 厚志

  Others, 日本医事新報社, 2016, Japanese

  Scholarly book


• 骨髄の構造／Principles and practice 血液・造血器・リンパ系.

  NITTA ERIKO, 岩間 厚志

  Others, 文光堂, 2015, Japanese

  Scholarly book


• Hematopoietic Stem Cell Aging and Oxidative Stress.／Stem Cells: From Basic Research to Therapy: Basic Stem Cell Biology, Tissue Formation during Development, and Model Organisms. Vol.1, p88-107.

  Cheong J-W, Nakamura-Ishizu A, NITTA ERIKO, Suda T

  Others, CRC Press, 2014, English

  Scholarly book

• クロマチンリモデリングから解き明かす造血幹細胞のエピジェネティクス制御

  仁田 英里子

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, Apr. 2021 - Mar. 2024

  老齢BRMノックアウトマウスをドナーとした骨髄移植にて、若齢マウスでは連続移植で初めて見られた長期再構築能の低下が、老齢BRMノックアウトマウスでは一次移植から早期に観察されることが明らかとなり、BRMは特に加齢に伴う造血幹細胞の機能維持に貢献していることが示唆された。 BRMが造血幹細胞を維持するメカニズムとして、微小環境ニッチに注目した。胸骨ホールマウント免疫染色を用いて5-FU投与などによる骨髄損傷後の類洞構造の回復を観察し、BRMが微小環境ニッチを制御して造血幹細胞を維持する可能性を明らかにした。さらにBRMノックアウトマウスの骨髄ニッチは老齢マウスに類似していることを突き止め、BRMは骨髄微小環境の老化に関与する可能性を示唆した。現在その分子メカニズム等について詳細を解析しているところである。 造血幹細胞を用いて行ったRNA シークエンスの結果、BRMは免疫応答に関わる遺伝子群の発現に関与する可能性が示唆されたため、BRMノックアウトマウスに細菌エンドトキシンであるLPSを投与して免疫応答を観察し、BRMが免疫細胞の特定の分化に関わることを明らかにした。感染に応答してBRMが免疫細胞への分化を制御する分子機構を解明するため、さらにRNAシーケンスおよびATACシーケンスを行って解析を進めている。 また、クロマチンリモデリング複合体の基本的なサブユニットについてin vitroで再構成を行い、得られたタンパク質を合わせて複合体を形成させ、電子顕微鏡による観察を開始した。正しいクロマチンリモデリング複合体と思われる像がいくつか得られたが、今後単粒子解析にデータを供するには均一なサンプルを大量に得る必要があるため、タンパク質発現系の改良を行っている。


• エピジェネティクス機構による造血幹細胞の老化制御メカニズム

  仁田 英里子

  学術研究助成基金助成金／基盤研究(C), Apr. 2017 - Mar. 2020, Principal investigator

  Competitive research funding


• Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature.

  神戸大学, 国際共著論文インセンティブ, 2020


• Pathological role of the dysregulated polycomb functions in hematological malignancies

  Iwama Atsushi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A), Chiba University, Apr. 2015 - Mar. 2018

  Polycomb-group (PcG) proteins catalyze repressive histone marks. Canonical polycomb repressive complex (PRC) 1 containing Pcgf4/Bmi1 has been implicated in the maintenance of hematopoietic stem cells (HSCs). We analyzed the role of non-canonical PRC1.1 consisting of Pcgf1, Kdm2b, Bcor and Ring1b using conditional knockout mice. We found that PRC1.1 was dispensable for self-renewal capacity of HSCs. Instead, PRC1.1 insufficiency enhanced commitment of hematopoietic stem and progenitor cells (HSPCs) to myeloid lineage and induced myeloid-biased differentiation, eventually leading to the development of lethal myeloproliferative neoplasm (MPN). Comprehensive analyses revealed that master transcriptional factor genes for myeloid differentiation, such as Cebpa, were up-regulated following a reduction in H2AK119ub1 levels in PRC1.1-insufficient HSPCs, resulting in the premature activation of their targets. These results indicate that PRC1.1 negatively regulates myeloid commitment of HSPCs.


• HSC regulation by TERT-binding proteins, chromatin remodeling factor BRG1/BRM

  Nitta Eriko, SUDA Toshio, IWAMA Atsushi, YAMASHITA Masayuki

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Chiba University, Apr. 2014 - Mar. 2017

  Among many players in the epigenetic regulation, the SWI/SNF ATP-dependent chromatin remodeling factor BRG1 has recently been demonstrated to be essential for leukemic stem cell (LSC) maintenance. Whereas BRG1 is implicated in the pathogenesis of Fanconi anemia and bone marrow failure, BRM, the homologue of BRG1, is expressed more specifically in HSCs compared with BRG1 and appeared to be involved in physiological regulation of HSCs. We have demonstrated an essential role of BRM in the maintenance of HSCs using genetically modified BRM-null mice. BRM-null HSCs showed profoundly impaired reconstitution capacity in competitive BMT assays and exhibited more activate cell cycling than wild type HSCs after bone marrow transplantation, suggesting that BRM plays a role in reversion of cycling HSCs into a quiescent state.


• 幹細胞のアポトーシス制御による質的維持と老化制御の分子機構

  公益財団法人 武田科学振興財団, 医学系研究奨励継続, 2016


• 幹細胞因子が制御するストレス応答による老化制御機構

  仁田 英里子

  日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 慶應義塾大学, Apr. 2012 - Mar. 2015

  我々はこれまでの研究結果により、TERTがテロメア長非依存的に造血幹細胞を維持する分子機構を明らかにしてきた。研究を発展させるに当たりさらに異なる機構でTERTが造血幹細胞を維持する可能性を探るため、TERTの結合因子に注目し、核小体因子nucleosteminが造血幹細胞のDNA損傷修復に貢献して造血幹細胞を維持することを明らかにし、論文として発表した。これはTERTがテロメア領域のみならず核小体の恒常性維持を介して造血幹細胞を制御する可能性を示唆しており興味深い。また、上皮幹細胞においてTERTがクロマチンリモデリング因子BRG1と結合しWnt標的遺伝子の発現を維持することが幹細胞制御に重要であることが報告されているため、造血幹細胞におけるクロマチンリモデリング因子BRG1およびその相同分子BRMの重要性を検証した。クロマチンリモデリング因子とは、転写の基本単位ヌクレオソームに結合し能動的にクロマチンを再構築することで、標的遺伝子に対する転写関連タンパク質のアクセスを容易にし、その転写発現を制御する重要な分子である。造血細胞においてBRG1は前駆細胞や分化した細胞の一部にも発現する一方で、BRMは長期再構築能を持つ未分化な造血幹細胞に特異的に発現し分化した細胞では発現が低下していた。このことから我々はBRMノックアウトマウスの造血細胞を解析したところ、競合的造血幹細胞移植においてBRM欠損造血幹細胞は特異的に失われ、BRMが造血幹細胞の長期再構築能維持に必須であることが示された。このときBRM欠損造血幹細胞では細胞周期が活性化しており、BRMは造血幹細胞の静止期維持に貢献することが示唆された。これらの性質は何れも造血幹細胞特異的に見られ、BRMが造血幹細胞の制御に重要な機能を持つことを示唆している。


• 幹細胞のアポトーシス制御による質的維持と老化制御の分子機構

  公益財団法人 武田科学振興財団, 医学系研究奨励, 2013


• 老化制御因子による白血病発症抑制の分子機構

  仁田 英里子

  日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 慶應義塾大学, 2009 - 2012

  我々はこれまでATMおよびTERTが協調して造血幹細胞の機能制御を行っており、個体レベルの寿命にまで影響を与えていることを明らかにし、その制御機構として、TERTはATM欠損造血幹細胞をROSストレス状況下に惹起されるアポトーシスから防御していることを証明した。これらの結果から、TERTはATMが制御するDNAダメージなどROS以外の様々なストレスからも造血幹細胞を防御している可能性が示唆される。我々はこれらの結果を論文としてまとめ、昨年、Blood誌にPlenary paperとして掲載された。 そのため24年度は、TERTが関与する造血幹細胞の制御機構を更に発展させるため、TERTと複合体を形成する因子による造血幹細胞の維持制御の分子機構について研究を広げる計画とした。TERTと結合することが報告されている分子のうち、幹細胞制御に関与する可能性があるものについて、造血幹細胞・造血前駆細胞・分化した血液細胞など様々な造血細胞分画に於ける発現をmRNAレベルで探索し、特に造血幹細胞および造血前駆細胞に特異的に発現しているものを同定した。我々はそのうち、核小体タンパク質であるGNL3およびその相同タンパク質GNL3Lに着目した。造血幹細胞で標的分子のノックダウンを行って幹細胞機能を評価する系を構築し、これらの分子をノックダウンした造血幹細胞による造血幹細胞移植を行ったところ、GNL3をノックダウンした造血幹細胞では長期再構築能が劇的に損なわれていた。今後、これらの分子による造血幹細胞の制御機構についてTERTとの関連を踏まえて詳細に解析し、造血幹細胞の老化制御機構について更に明らかにする。


• 幹細胞因子が制御するストレス応答による老化制御機構

  公益財団法人 先進医薬研究振興財団, 血液医学分野 萌芽研究助成, 2011


• テロメア・テロメラーゼ関連因子による骨髄不全疾患の発症機構

  公益財団法人 難病医学研究財団, 医学研究奨励助成金, 2011, Principal investigator


• Accommodative roles of ATM and TERT in hematopoietic stem cell aging.

  NITTA Eriko

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Young Scientists (B), Keio University, 2007 - 2008

  老化やストレス応答に重要な役割を担うATMとTERTについて、特に造血幹細胞の老化制御機構を、ノックアウトマウスを用いて解析した。両分子が協調した分子制御機構により個体レベルでの老化やストレス応答に対して影響することを示唆し、さらに両分子は造血幹細胞に於ける生理的な老化とストレス状況下に誘導される老化の両方の制御に関わり、その細胞レベルでの老化制御は独立した機構で老化が相加的に増強する可能性を示唆した。


• 幹細胞の細胞周期制御機構を司る造血腫瘍関連因子の特定

  仁田 英里子

  日本学術振興会, 科学研究費助成事業, 若手研究(スタートアップ), 慶應義塾大学, 2006 - 2007

  ATMノックアウトマウスの造血幹細胞に於いて、活性酸素の増加とp16^の増加により細胞周期制御が抑制され幹細胞の自己複製能が喪失する機構(申請者の属する研究グループが明らかにしたもの)につき、ATMノックアウトマウス造血幹細胞の解析およびin vitroで活性酸素の増加を再現する系を発展させ、造血幹細胞に於いて老化因子p16^が増加する分子制御機構を詳細に検討した。 その結果、in vitroで活性酸素の増加を再現する系に於いて見られたp16^の発現増加は、ATMノックアウトマウス個体の造血幹細胞に於いては顕著でなく、それに対して、老化に際してp16^の発現を増加することが知られる転写因子Ets1/2の発現が著明に抑制されていることを明らかにした。この現象は若年マウスでは見られず老年マウスで特異的に見られ、このことよりATMノックアウトマウス個体の造血幹細胞に於いてはP16^の発現増加による老化がEts1/2の発現抑制により代償的に調節されていることを示唆した。 この際、老化に於いてEts1/2をターゲットとして転写を抑制するBmi-1、およびEts1/2の協調因子Idファミリータンパク質の発現には変化がなく、Ets1/2が抑制制御を受ける分子機構について現在更に解析を進めている。 このEts1/2による個体老化制御の分子機構については、各分子の強制発現あるいはsiRNAやドミナントネガティブによるノックダウンを用いてgain of function/loss of functionの効果を検証し、ATMノックアウトマウス個体での骨髄移植による造血幹細胞の自己複製能維持や長期再構築能などin vivoに於ける当該分子の役割と各々の分子間の相互関係についての検討を、次年度に予定している.