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 KogureNobuyuki 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, Seishi Ogawa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

STAG2 encodes a cohesin component and is frequently mutated in myeloid neo-plasms, 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 myelodys-plastic 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.

Original languageEnglish
Pages (from-to)836-853
Number of pages18
JournalCancer Discovery
Volume10
Issue number6
DOIs
Publication statusPublished - 2020 Jun

ASJC Scopus subject areas

  • Oncology

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