O-GlcNAc transferase regulates transcriptional activity of human Oct4
O-GlcNAc transferase regulates transcriptional activity of human Oct4
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DOI：
10.1093/glycob/cwx055
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发表时间：
2017-10-01
期刊：
影响因子：
4.3
通讯作者：
Wells, Lance
中科院分区：
文献类型：
--
作者：
Constable, Sandii;Lim, Jae-Min;Wells, Lance
O-连接 β-N-乙酰氨基葡萄糖 (O-GlcNAc) 是在许多不同类别的核蛋白和细胞质蛋白中发现的单糖修饰。通过 O-连接 N-乙酰葡糖胺转移酶 (OGT) 进行的这种修饰的添加是动态且可诱导的。 O-GlcNAc 修饰的一类主要蛋白质是转录因子。 O-GlcNAc 通过多种不同的机制调节转录因子特性，包括定位、稳定性和转录激活。胚胎干 (ES) 细胞多能性的维持需要严格调控几个关键转录因子，其中许多转录因子被 O-GlcNAc 修饰。八聚体结合蛋白 4 (Oct4) 是 ES 细胞多能性以及最近诱导多能干 (iPS) 细胞生成所需的关键转录因子之一。 Oct4 的作用通过添加几个翻译后修饰（包括 O-GlcNAc）来调节。先前对小鼠的研究发现，O-GlcNAc 添加的单个位点负责转录调节。这项研究旨在确定这种机制在人类中是否保守。我们在人 Oct4 上绘制了 10 个新的 O-GlcNAc 附着位点，并证实了 OGT 在 Oct4 转录激活中的作用，该位点与小鼠中发现的不同，可以区分不同的 Oct4 靶启动子。此外，我们还发现了 OGT 的潜在新作用，但不包括其催化功能。这些结果证实，人类 Oct4 活性受到 OGT 的调节，其机制与小鼠 Oct4 不同。
O-linked beta-N-acetylglucosamine (O-GlcNAc) is a single sugar modification found on many different classes of nuclear and cytoplasmic proteins. Addition of this modification, by the enzyme O-linked N-acetylglucosamine transferase (OGT), is dynamic and inducible. One major class of proteins modified by O-GlcNAc is transcription factors. O-GlcNAc regulates transcription factor properties through a variety of different mechanisms including localization, stability and transcriptional activation. Maintenance of embryonic stem (ES) cell pluripotency requires tight regulation of several key transcription factors, many of which are modified by O-GlcNAc. Octamer-binding protein 4 (Oct4) is one of the key transcription factors required for pluripotency of ES cells and more recently, the generation of induced pluripotent stem (iPS) cells. The action of Oct4 is modulated by the addition of several post-translational modifications, including O-GlcNAc. Previous studies in mice found a single site of O-GlcNAc addition responsible for transcriptional regulation. This study was designed to determine if this mechanism is conserved in humans. We mapped 10 novel sites of O-GlcNAc attachment on human Oct4, and confirmed a role for OGT in transcriptional activation of Oct4 at a site distinct from that found in mouse that allows distinction between different Oct4 target promoters. Additionally, we uncovered a potential new role for OGT that does not include its catalytic function. These results confirm that human Oct4 activity is being regulated by OGT by a mechanism that is distinct from mouse Oct4.