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DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes

机译:DNMT1通过与组蛋白修饰酶的相互作用来调节基因表达而没有其催化活性

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摘要

While DNA methyltransferase1 (DNMT1) is classically known for its functions as a maintenance methyltransferase enzyme, additional roles for DNMT1 in gene expression are not as clearly understood. Several groups have shown that deletion of the catalytic domain from DNMT1 does not abolish repressive activity of the protein against a reporter gene. In our studies, we examine the repressor function of catalytically inactive DNMT1 at endogenous genes. First, potential DNMT1 target genes were identified by searching for genes up-regulated in HCT116 colon cancer cells genetically disrupted for DNMT1 (DNMT1−/− hypomorph cells). Next, the requirement for DNMT1 activity for repression of these genes was assessed by stably restoring expression of wild-type or catalytically inactive DNMT1. Both wild-type and mutant proteins are able to occupy the promoters and repress the expression of a set of target genes, and induce, at these promoters, both the depletion of active histone marks and the recruitment of a H3K4 demethylase, KDM1A/LSD1. Together, our findings show that there are genes for which DNMT1 acts as a transcriptional repressor independent from its methyltransferase function and that this repressive function may invoke a role for a scaffolding function of the protein at target genes.
机译:虽然DNA甲基转移酶1(DNMT1)以其作为维持甲基转移酶的功能而闻名,但DNMT1在基因表达中的其他作用尚不清楚。几组研究表明,从DNMT1删除催化结构域不会消除蛋白质对报道基因的抑制活性。在我们的研究中,我们检查了内源基因上无催化作用的DNMT1的阻遏物功能。首先,通过搜索在遗传上被DNMT1破坏的HCT116结肠癌细胞(DNMT1-/-亚型细胞)中上调的基因,确定潜在的DNMT1靶基因。接下来,通过稳定地恢复野生型或无催化作用的DNMT1的表达来评估抑制这些基因对DNMT1活性的要求。野生型和突变型蛋白都能够占据启动子并抑制一组靶基因的表达,并在这些启动子上诱导活性组蛋白标记的消耗和H3K4脱甲基酶KDM1A / LSD1的募集。在一起,我们的发现表明,存在某些基因,其中DNMT1充当转录阻遏物,而与其甲基转移酶功能无关,并且该阻抑功能可能在靶基因上激活蛋白质的支架作用。

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