Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes
Open Access
- 5 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (6), 836-853
- https://doi.org/10.1158/2159-8290.cd-19-0982
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. 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. 747Keywords
Funding Information
- MEXT
- JSPS (JP26221308, JP26253060)
- JSPS (JP17J05245)
- JSPS (JP18K16084)
- JSPS (JP19H03560)
- Personalized and Preventive Medicine (hp180198, hp190179)
- Japan Agency for Medical Research and Development (JP15cm0106056, JP19cm0106501, JP16ck0106073, JP19ck0106250)
- Japan Agency for Medical Research and Development (JP19cm0106138)
- Scientific Research on Innovative Areas (15H05909, 15H05912)
- Scientific Research on Innovative Areas (JP15H05979)
- Scientific Research on Innovative Areas (15H05976)
- Scientific Research on Innovative Areas (19H04806)
- Stem Cell Aging and Disease (14430052)
- JST CREST (PMJCR18S5)
- Takeda Science Foundation
- Naito Foundation
- Terumo Life Science Foundation
- Yasuda Medical Foundation
- JSPS
- United States Public Health Service (R01-GM034277, R01-CA133404)
- United States Public Health Service NIH (P01-CA042063)
- Koch Institute Support NCI (P30-CA14051)
- Associazione Italiana per la Ricerca sul Cancro (#20125)
- AIRC (#21267)
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