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EnglishSTAG2 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.
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| Titolo: | Combined Cohesin–RUNX1 deficiency synergistically perturbs chromatin looping and causes myelodysplastic syndromes |
| Autori: | |
| Data di pubblicazione: | 2020 |
| Rivista: | |
| 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. |
| Handle: | http://hdl.handle.net/11571/1368994 |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
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