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首页> 外文期刊>Cell Reports >PRMT4 Blocks Myeloid Differentiation by Assembling a Methyl-RUNX1-Dependent Repressor Complex
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PRMT4 Blocks Myeloid Differentiation by Assembling a Methyl-RUNX1-Dependent Repressor Complex

机译：PRMT4通过组装甲基RUNX1依赖阻遏物复合物阻止髓样分化。

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Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.
机译：定义表观遗传调节剂在造血中的作用已变得至关重要，因为已经在髓样和淋巴性血液系统恶性肿瘤中发现了这些基因的反复突变或异常表达。我们发现PRMT4是一种I型精氨酸甲基转移酶，其在正常和恶性造血功能中的作用未知，在急性粒细胞性白血病患者样品中过表达。 PRMT4的过表达会阻止人干/祖细胞（HSPC）的骨髓分化，而其敲低足以诱导HSPC的骨髓分化。我们证明PRMT4通过RUNX1的甲基化抑制HSPC中miR-223的表达，这会触发包含DPF2的多蛋白阻遏物复合物的装配。作为反馈回路的一部分，PRMT4表达在转录后被miR-223抑制。 PRMT4的耗尽会导致髓样白血病细胞在体外分化，并在体内降低增殖。因此，靶向PRMT4作为急性骨髓性白血病的新疗法具有潜力。

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