Epigenetic regulation of protein-coding and MicroRNA genes by the gfi 1-interacting tumor suppressor PRDM5
Epigenetic regulation of protein-coding and MicroRNA genes by the gfi 1-interacting tumor suppressor PRDM5
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DOI：
10.1128/mcb.00762-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Horwitz, Marshall S.
中科院分区：
文献类型：
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作者：
Duan, Zhijun;Person, Richard E.;Horwitz, Marshall S.
Gfi 1转录调控造血，其突变产生中性粒细胞减少症。在努力确定Gfi 1相互作用的蛋白质，并产生新的候选基因引起中性粒细胞减少症，我们进行了酵母双杂交筛选Gfi 1。在其他Gfi 1相互作用蛋白中，我们发现了一个以前未表征的含有PR结构域的肿瘤抑制因子家族成员PRDM 5。PRDM 5有16个锌指，我们发现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Gfi 1靶点的基因。PRDM 5在表观遗传学上调节转录类似于Gfi 1：它招募组蛋白甲基转移酶G9 a和I类组蛋白脱乙酰酶到其靶基因启动子，并对合成报告基因表现出阻遏活性;然而，在内源性靶基因上，除了阻遏物外，它还充当激活剂。有趣的是，PRDM 5激活的基因，而不是它抑制的基因，也是Gfi 1的靶点，这表明了一种竞争机制，通过这种机制，两个阻遏物可以合作成为转录激活因子。在血小板减少症患者中，我们鉴定了干扰转录功能的PRDM 5蛋白序列变异体，表明其在造血中具有潜在的重要作用。
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.