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Chromatin accessibility in stem cells unveils progressive transcriptional alterations in myelodysplastic syndrome

Author

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  • Motohiko Oshima

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Naoya Takayama

    (Chiba University, Department of Regenerative Medicine, Graduate School of Medicine)

  • Yaeko Nakajima-Takagi

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Daisuke Shinoda

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Naoki Itokawa

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Shuhei Kurosawa

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Satoshi Kaito

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Takahiro Kamiya

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Yuta Yamada

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Shohei Andoh

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science)

  • Kensuke Kayamori

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science
    Chiba University Hospital, Department of Hematology)

  • Sudip Kumar Paul

    (Chiba University, Department of Regenerative Medicine, Graduate School of Medicine)

  • Maria Alejandra Kanashiro

    (Chiba University, Department of Regenerative Medicine, Graduate School of Medicine)

  • Tomoya Muto

    (Chiba University Hospital, Department of Hematology)

  • Shokichi Tsukamoto

    (Chiba University Hospital, Department of Hematology)

  • Emiko Sakaida

    (Chiba University Hospital, Department of Hematology)

  • Eriko Sato

    (Juntendo University Nerima Hospital, Department of Hematology)

  • Nozomi Yusa

    (the University of Tokyo, Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science)

  • Kazuaki Yokoyama

    (the University of Tokyo, Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science)

  • Yasuhito Nannya

    (the University of Tokyo, Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science)

  • Seiya Imoto

    (The University of Tokyo, Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science)

  • Bahityar Rahmutulla

    (Chiba University, Department of Molecular Oncology, Graduate School of Medicine)

  • Atsushi Kaneda

    (Chiba University, Department of Molecular Oncology, Graduate School of Medicine
    Chiba University, Health and Disease Omics Center)

  • Kiyoshi Yamaguchi

    (The University of Tokyo, Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science)

  • Yoichi Furukawa

    (The University of Tokyo, Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science)

  • Noriko Doki

    (Komagome Hospital, Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center)

  • Koji Eto

    (Chiba University, Department of Regenerative Medicine, Graduate School of Medicine)

  • Kei Nishikawa

    (Edogawa Hospital, Department of Oncology and Hematology)

  • Ye Ding

    (Edogawa Hospital, Department of Oncology and Hematology)

  • Tomohiro Myojo

    (Edogawa Hospital, Department of Oncology and Hematology)

  • Yuka Harada

    (Komagome Hospital, Department of Clinical Laboratory, Tokyo Metropolitan Cancer and Infectious Diseases Center)

  • Hironori Harada

    (Tokyo University of Pharmacy and Life Sciences, Laboratory of Oncology, School of Life Sciences)

  • Atsushi Iwama

    (The University of Tokyo, Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science
    The University of Tokyo, Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences)

Abstract

Myelodysplastic syndrome (MDS) originates from hematopoietic stem cell (HSC) clones with acquired gene mutations. However, the molecular characteristics of MDS stem cells remain poorly understood. Here, we show that the chromatin accessibility profiles of MDS stem cells more accurately reflect disease status than those of progenitor cells and reveal the process of stem cell alterations during disease progression. Characterization of differentially accessible regions (DARs) shows that MDS stem cells acquire progenitor-like chromatin accessibility during disease progression, leading to disruption of the normal stem-progenitor hierarchy. Profiling of transcription factor-binding motifs at DARs further uncovers precocious activation of myeloid transcriptional networks in MDS stem cells, with a concurrent loss of HSC-associated regulatory programs. In particular, increased chromatin accessibility at CEBP target sites represents the myeloid reprogramming status of MDS stem cells. Newly developed “progenitor scores” based on chromatin accessibility stratify disease status and correlate well with prognosis. These findings indicate that chromatin landscapes of MDS stem cells define their cell-autonomous behavior and contribute to disease progression.

Suggested Citation

  • Motohiko Oshima & Naoya Takayama & Yaeko Nakajima-Takagi & Daisuke Shinoda & Naoki Itokawa & Shuhei Kurosawa & Satoshi Kaito & Takahiro Kamiya & Yuta Yamada & Shohei Andoh & Kensuke Kayamori & Sudip K, 2025. "Chromatin accessibility in stem cells unveils progressive transcriptional alterations in myelodysplastic syndrome," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65753-5
    DOI: 10.1038/s41467-025-65753-5
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