Journal
CANCER DISCOVERY
Volume 10, Issue 6, Pages 836-853Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0982
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Funding
- MEXT/JSPS KAKENHI [JP26221308, JP26253060, JP17J05245, JP18K16084, JP19H03560]
- MEXT as Priority Issue on Post-K computer (Integrated Computational Life Science to Support Personalized and Preventive Medicine) [hp180198, hp190179]
- Japan Agency for Medical Research and Development (AMED) [JP15cm0106056, JP19cm0106501, JP16ck0106073, JP19ck0106250, JP19cm0106138]
- Scientific Research on Innovative Areas [15H05909, 15H05912, JP15H05979, 15H05976, 19H04806]
- Stem Cell Aging and Disease [14430052]
- JST CREST [JPMJCR18S5]
- Takeda Science Foundation
- Naito Foundation
- TERUMO LIFE SCIENCE FOUNDATION
- Yasuda Medical Foundation
- JSPS Core-to-Core Program
- United States Public Health Service from the NIH [R01-GM034277, R01-CA133404, P01-CA042063]
- Koch Institute Support (core) grant from the National Cancer Institute [P30-CA14051]
- Whitehead Institute for Biomedical Research
- Novo Nordisk
- Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy [20125]
- Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy (AIRC 5 x 1000 project) [21267]
- Grants-in-Aid for Scientific Research [19H04806] Funding Source: KAKEN
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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 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.
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