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首页> 外文期刊>Molecular and Cellular Biology >Epigenetic Regulation of Protein-Coding and MicroRNA Genes by the Gfi1-Interacting Tumor Suppressor PRDM5
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Epigenetic Regulation of Protein-Coding and MicroRNA Genes by the Gfi1-Interacting Tumor Suppressor PRDM5

机译：Gfi1相互作用的肿瘤抑制基因PRDM5对蛋白质编码和MicroRNA基因的表观遗传调控。

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Gfi1 transcriptionally governs hematopoiesis, and its mutations produce neutropenia. In an effort to identify Gfi1-interacting proteins and also to generate new candidate genes causing neutropenia, we performed a yeast two-hybrid screen with Gfi1. Among other Gfi1-interacting proteins, we identified a previously uncharacterized member of the PR domain-containing family of tumor suppressors, PRDM5. PRDM5 has 16 zinc fingers, and we show that it acts as a sequence-specific, DNA binding transcription factor that targets hematopoiesis-associated protein-coding and microRNA genes, including many that are also targets of Gfi1. PRDM5 epigenetically regulates transcription similarly to Gfi1: it recruits the histone methyltransferase G9a and class I histone deacetylases to its target gene promoters and demonstrates repressor activity on synthetic reporters; on endogenous target genes, however, it functions as an activator, in addition to a repressor. Interestingly, genes that PRDM5 activates, as opposed to those it represses, are also targets of Gfi1, suggesting a competitive mechanism through which two repressors could cooperate in order to become transcriptional activators. In neutropenic patients, we identified PRDM5 protein sequence variants perturbing transcriptional function, suggesting a potentially important role in hematopoiesis.
机译：Gfi1转录控制造血功能，其突变产生中性粒细胞减少。为了鉴定与Gfi1相互作用的蛋白质并产生引起中性粒细胞减少的新候选基因，我们对Gfi1进行了酵母双杂交筛选。在其他与Gfi1相互作用的蛋白中，我们鉴定了PR抑制肿瘤家族PRDM5的一个先前未鉴定的成员。 PRDM5有16个锌指，我们证明它是一种序列特异性的，DNA结合转录因子，靶向造血相关蛋白编码和microRNA基因，包括许多也是Gfi1的靶标。 PRDM5与Gfi1相似，在表观遗传上调节转录：它将组蛋白甲基转移酶G9a和I类组蛋白脱乙酰基酶募集到其靶基因启动子，并在合成报告基因上表现出阻遏物活性。然而，在内源性靶基因上，除阻遏物外，它还起激活剂的作用。有趣的是，与PRDM5阻遏的基因相反，PRDM5激活的基因也是Gfi1的靶标，这表明了一种竞争机制，两个阻遏物可以通过竞争机制协同作用，从而成为转录激活因子。在中性粒细胞减少的患者中，我们确定了扰动转录功能的PRDM5蛋白序列变异，提示在造血过程中可能具有重要作用。

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