Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, NIH, Bethesda, MD 20892-0850, USA.
Semin Cell Dev Biol. 2010 Aug;21(6):646-54. doi: 10.1016/j.semcdb.2010.05.001. Epub 2010 May 19.
The nutrient-sensing hexosamine signaling pathway modulates the levels of O-linked N-acetylglucosamine (O-GlcNAc) on key targets impacting cellular signaling, protein turnover and gene expression. O-GlcNAc cycling may be deregulated in neurodegenerative disease, cancer, and diabetes. Studies in model organisms demonstrate that the O-GlcNAc transferase (OGT/Sxc) is essential for Polycomb group (PcG) repression of the homeotic genes, clusters of genes responsible for the adult body plan. Surprisingly, from flies to man, the O-GlcNAcase (OGA, MGEA5) gene is embedded within the NK cluster, the most evolutionarily ancient of three homeobox gene clusters regulated by PcG repression. PcG repression also plays a key role in maintaining stem cell identity, recruiting the DNA methyltransferase machinery for imprinting, and in X-chromosome inactivation. Intriguingly, the Ogt gene resides near the Xist locus in vertebrates and is subject to regulation by PcG-dependent X-inactivation. OGT is also an enzymatic component of the human dosage compensation complex. These 'evo-devo' relationships linking O-GlcNAc cycling to higher order chromatin structure provide insights into how nutrient availability may influence the epigenetic regulation of gene expression. O-GlcNAc cycling at promoters and PcG repression represent concrete mechanisms by which nutritional information may be transmitted across generations in the intra-uterine environment. Thus, the nutrient-sensing hexosamine signaling pathway may be a key contributor to the metabolic deregulation resulting from prenatal exposure to famine, or the 'vicious cycle' observed in children of mothers with type-2 diabetes and metabolic disease.
营养感应己糖胺信号通路调节关键靶标上的 O-连接 N-乙酰葡萄糖胺 (O-GlcNAc) 水平，影响细胞信号转导、蛋白质周转和基因表达。O-GlcNAc 循环可能在神经退行性疾病、癌症和糖尿病中失调。模式生物的研究表明，O-连接 N-乙酰葡萄糖胺转移酶 (OGT/Sxc) 对于多梳组 (PcG) 抑制同源基因至关重要，同源基因簇负责成年身体形态。令人惊讶的是，从苍蝇到人，O-GlcNAcase (OGA, MGEA5) 基因嵌入 NK 簇中，NK 簇是受 PcG 抑制调节的三个同源盒基因簇中最古老的。PcG 抑制在维持干细胞身份、招募用于印迹的 DNA 甲基转移酶机制以及 X 染色体失活中也起着关键作用。有趣的是，Ogt 基因位于脊椎动物的 Xist 基因座附近，受 PcG 依赖的 X 失活调控。OGT 也是人类剂量补偿复合物的酶组成部分。这些“进化发育”关系将 O-GlcNAc 循环与高级染色质结构联系起来，为营养物质可用性如何影响基因表达的表观遗传调控提供了线索。启动子处的 O-GlcNAc 循环和 PcG 抑制代表了营养信息可能在宫内环境中跨代传递的具体机制。因此，己糖胺信号通路可能是产前暴露于饥饿或 2 型糖尿病和代谢疾病母亲的孩子中观察到的“恶性循环”导致代谢失调的关键因素。
