Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.

中文翻译：

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HDAC1和PRC2介导小鼠红白血病中SPI1/PU.1依赖性基因抑制的组合控制

虽然最初被描述为转录激活因子，但 SPI1/PU.1 是造血的主要参与者，其改变与血液系统恶性肿瘤相关，具有抑制转录的能力。在这里，我们研究了红细胞谱系中基因抑制的机制，其中 SPI1 通过阻断分化发挥致癌功能。我们显示SPI1 通过结合位于基因间或基因体区域的活性增强子来抑制基因。HDAC1 作为 SPI1 诱导的转录抑制的协同介质，通过使一组基因中的 S​​PI1 结合增强子去乙酰化，包括那些参与红细胞分化的基因。增强子去乙酰化影响启动子乙酰化、染色质可及性和 RNA pol II 占有率。除了 HDAC1 的活动，当 SPI1 位于增强子序列时，polycomb 抑制复合物 2 (PRC2) 通过在启动子序列上沉积 H3K27me3 来增强基因抑制。此外，我们的研究确定了 PRC2 和 HDAC1 复合物在介导 SPI1 转录抑制活性方面的协同关系，最终诱导对白血病细胞存活的协同不利影响。我们的研究结果强调了白血病细胞转录抑制机制的重要性，涉及 SPI1 与表观遗传调节因子 PRC2 和 HDAC1 之间的复杂功能联系。我们的研究确定了 PRC2 和 HDAC1 复合物在介导 SPI1 转录抑制活性方面的协同关系，最终诱导对白血病细胞存活的协同不利影响。我们的研究结果强调了白血病细胞转录抑制机制的重要性，涉及 SPI1 与表观遗传调节因子 PRC2 和 HDAC1 之间的复杂功能联系。我们的研究确定了 PRC2 和 HDAC1 复合物在介导 SPI1 转录抑制活性方面的协同关系，最终诱导对白血病细胞存活的协同不利影响。我们的研究结果强调了白血病细胞转录抑制机制的重要性，涉及 SPI1 与表观遗传调节因子 PRC2 和 HDAC1 之间的复杂功能联系。