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Research Articles

Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

Yotaro Ochi, Ayana Kon, Toyonori Sakata, Masahiro M Nakagawa, Naotaka Nakazawa, Masanori Kakuta, Keisuke Kataoka, Haruhiko Koseki, Manabu Nakayama, Daisuke Morishita, Tatsuaki Tsuruyama, Ryunosuke Saiki, Akinori Yoda, Rurika Okuda, Tetsuichi Yoshizato, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Shinichi Kotani, Yasunori Kogure, Nobuyuki Kakiuchi, Tomomi Nishimura, Hideki Makishima, Luca Malcovati, Akihiko Yokoyama, Kengo Takeuchi, Eiji Sugihara, Taka-Aki Sato, Masashi Sanada, Akifumi Takaori-Kondo, Mario Cazzola, Mineko Kengaku, Satoru Miyano, Katsuhiko Shirahige, Hiroshi I. Suzuki and Seishi Ogawa
Yotaro Ochi
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Ayana Kon
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Toyonori Sakata
3Laboratory of Genome Structure and Function, Research Division for Quantitative Life Sciences, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
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Masahiro M Nakagawa
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Naotaka Nakazawa
4Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan.
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Masanori Kakuta
5Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Keisuke Kataoka
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Haruhiko Koseki
6Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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Manabu Nakayama
7Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kisarazu, Japan.
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Daisuke Morishita
8Chordia Therapeutics Inc., Kanagawa, Japan.
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Tatsuaki Tsuruyama
9Department of Drug and Discovery Medicine, Pathology Division, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Ryunosuke Saiki
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Akinori Yoda
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Rurika Okuda
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Tetsuichi Yoshizato
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Kenichi Yoshida
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Yusuke Shiozawa
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Yasuhito Nannya
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Shinichi Kotani
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Yasunori Kogure
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Nobuyuki Kakiuchi
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Tomomi Nishimura
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Hideki Makishima
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Luca Malcovati
10Department of Molecular Medicine, University of Pavia, Pavia, Italy.
11Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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Akihiko Yokoyama
12Tsuruoka Metabolomics Laboratory, National Cancer Center, Yamagata, Japan.
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Kengo Takeuchi
13Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
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Eiji Sugihara
14Research and Development Center for Precision Medicine, University of Tsukuba, Ibaraki, Japan.
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Taka-Aki Sato
14Research and Development Center for Precision Medicine, University of Tsukuba, Ibaraki, Japan.
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Masashi Sanada
15Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
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Akifumi Takaori-Kondo
2Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Mario Cazzola
10Department of Molecular Medicine, University of Pavia, Pavia, Italy.
11Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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Mineko Kengaku
4Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan.
16Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
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Satoru Miyano
5Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Katsuhiko Shirahige
3Laboratory of Genome Structure and Function, Research Division for Quantitative Life Sciences, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
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Hiroshi I. Suzuki
17David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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  • For correspondence: sogawa-tky@umin.ac.jp hisuzuki-tky@umin.ac.jp
Seishi Ogawa
1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
18Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
19Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
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  • For correspondence: sogawa-tky@umin.ac.jp hisuzuki-tky@umin.ac.jp
DOI: 10.1158/2159-8290.CD-19-0982 Published June 2020
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Abstract

STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer–promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer–promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer–promoter loops in STAG2/RUNX1–deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2–cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2–RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis.

Significance: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer–promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.

This article is highlighted in the In This Issue feature, p. 747

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:836–53

  • Received August 20, 2019.
  • Revision received February 5, 2020.
  • Accepted March 16, 2020.
  • Published first April 5, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (6)
June 2020
Volume 10, Issue 6
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Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes
Yotaro Ochi, Ayana Kon, Toyonori Sakata, Masahiro M Nakagawa, Naotaka Nakazawa, Masanori Kakuta, Keisuke Kataoka, Haruhiko Koseki, Manabu Nakayama, Daisuke Morishita, Tatsuaki Tsuruyama, Ryunosuke Saiki, Akinori Yoda, Rurika Okuda, Tetsuichi Yoshizato, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Shinichi Kotani, Yasunori Kogure, Nobuyuki Kakiuchi, Tomomi Nishimura, Hideki Makishima, Luca Malcovati, Akihiko Yokoyama, Kengo Takeuchi, Eiji Sugihara, Taka-Aki Sato, Masashi Sanada, Akifumi Takaori-Kondo, Mario Cazzola, Mineko Kengaku, Satoru Miyano, Katsuhiko Shirahige, Hiroshi I. Suzuki and Seishi Ogawa
Cancer Discov June 1 2020 (10) (6) 836-853; DOI: 10.1158/2159-8290.CD-19-0982

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Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes
Yotaro Ochi, Ayana Kon, Toyonori Sakata, Masahiro M Nakagawa, Naotaka Nakazawa, Masanori Kakuta, Keisuke Kataoka, Haruhiko Koseki, Manabu Nakayama, Daisuke Morishita, Tatsuaki Tsuruyama, Ryunosuke Saiki, Akinori Yoda, Rurika Okuda, Tetsuichi Yoshizato, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Shinichi Kotani, Yasunori Kogure, Nobuyuki Kakiuchi, Tomomi Nishimura, Hideki Makishima, Luca Malcovati, Akihiko Yokoyama, Kengo Takeuchi, Eiji Sugihara, Taka-Aki Sato, Masashi Sanada, Akifumi Takaori-Kondo, Mario Cazzola, Mineko Kengaku, Satoru Miyano, Katsuhiko Shirahige, Hiroshi I. Suzuki and Seishi Ogawa
Cancer Discov June 1 2020 (10) (6) 836-853; DOI: 10.1158/2159-8290.CD-19-0982
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