Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes
Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes
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DOI：
10.1158/2159-8290.cd-19-0982
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发表时间：
2020-06-01
期刊：
影响因子：
28.2
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Ochi, Yotaro;Kon, Ayana;Ogawa, Seishi
STAG 2编码一种粘附素组分，并且在髓样新生儿中经常突变，显示出与其他驱动因子（包括RUNX 1）的高度显著的共突变模式。然而，粘着蛋白突变的白血病发生的分子基础仍然知之甚少。在这里，我们展示了STAG 2和RUNX 1之间的相互作用在造血中的增强子-启动子环和转录的调节中的关键作用。STAG 2和RUNX 1的联合缺失，共定位于增强子丰富的CTCF缺陷位点，协同减弱增强子-启动子环，特别是在RNA聚合酶II和介体富集的位点，并使基因表达失调，导致小鼠造血干/祖细胞（HSPC）的骨髓偏斜扩增和骨髓增生异常综合征（MDS）。在STAG 2/RUNX 1缺陷细胞中减弱的增强子-启动子环与具有高基础转录暂停的基因的下调相关，这对于HSPC的调节是重要的。高暂停基因的下调也在STAG 2-粘附素突变的原发性白血病样品中得到证实。我们的研究结果突出了独特的STAG 2-RUNX 1在基因调控中的相互作用，并为粘着蛋白突变的白血病发生提供了见解。我们证明了STAG 2和造血的主要转录因子RUNX 1之间的相互作用在MDS发展中的关键作用，并进一步揭示了它们对高阶染色质结构的调节，特别是增强子-启动子环，以及转录暂停和由粘蛋白缺乏引起的选择性基因失调之间的联系。
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.