MRC Laboratory for Molecular and Cell Biology and Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Sci Signal. 2010 Jan 5;3(103):pe1. doi: 10.1126/scisignal.3103pe1.
Gene expression in eukaryotes depends on epigenetic changes that occur on both histones and DNA. Class I histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones and other nuclear proteins, thereby inducing chromatin condensation and transcriptional repression. HDACs belong to a large family of enzymes that undergo posttranslational modifications after the activation of several intracellular pathways. However, the environmental stimuli that change nuclear HDAC functions remain largely unknown. New evidence has demonstrated that the lipid sphingosine-1-phosphate (S1P) inhibits the activity of HDAC1 and HDAC2. Both S1P and sphingosine kinase 2 (SphK2), the enzyme that synthesizes S1P, are assembled in corepressor complexes containing HDAC1 and HDAC2. S1P is among the few endogenous HDAC inhibitors that is synthesized in the nucleus in response to extracellular stimulation, and the first nuclear lipid associated with an epigenetic modification. The discovery of endogenous molecules that regulate HDAC activity in vivo has implications for the development of new therapeutic approaches for a host of human diseases, including cancer and neurodegenerative disorders.
真核生物的基因表达依赖于组蛋白和 DNA 上发生的表观遗传变化。I 类组蛋白去乙酰化酶（HDACs）是一种从组蛋白和其他核蛋白上去除乙酰基的酶，从而诱导染色质凝聚和转录抑制。HDAC 属于一个经过多种细胞内途径激活后发生翻译后修饰的大型酶家族。然而，改变核 HDAC 功能的环境刺激因素在很大程度上仍然未知。新的证据表明，脂质鞘氨醇-1-磷酸（S1P）抑制 HDAC1 和 HDAC2 的活性。S1P 和合成 S1P 的酶——鞘氨醇激酶 2（SphK2）都组装在包含 HDAC1 和 HDAC2 的共抑制复合物中。S1P 是为数极少的在细胞核内响应细胞外刺激合成的内源性 HDAC 抑制剂之一，也是第一个与表观遗传修饰相关的核脂质。发现体内调节 HDAC 活性的内源性分子，为治疗包括癌症和神经退行性疾病在内的多种人类疾病的新疗法的开发提供了思路。
