Jia Haiqun, Morris Charles D, Williams Roy M, Loring Jeanne F, Thomas Elizabeth A
Departments of Molecular and Cellular Neuroscience and.
Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):E56-64. doi: 10.1073/pnas.1415195112. Epub 2014 Dec 22.
Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington's disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner.
越来越多的证据表明，表观遗传因素可深刻影响基因表达，进而影响疾病的抗性或易感性。表观遗传药物，如组蛋白脱乙酰酶（HDAC）抑制剂，正逐渐进入临床实践，尽管其确切作用机制尚不清楚。为了确定与HDAC抑制相关的机制，我们对用靶向HDAC1/3的抑制剂HDACi 4b处理的脑和肌肉样本进行了微阵列分析。微阵列数据集的通路分析表明DNA甲基化与HDAC抑制显著相关。使用Infinium HumanMethylation450 BeadChip对来自正常对照和亨廷顿舞蹈病（HD）患者的人成纤维细胞中HDACi 4b引起的DNA甲基化变化进行进一步评估，结果显示在正常细胞和HD细胞中，HDAC抑制改变的甲基化CpG位点有一个有限但重叠的子集。在Y染色体连锁基因的改变位点中，编码赖氨酸（K）特异性去甲基化酶5D的KDM5D在正常细胞和HD细胞以及从药物处理的雄性小鼠精子中分离的DNA中的几个CpG位点处甲基化增加。此外，我们证明，与载体处理的雄性HD转基因小鼠的F1代后代相比，药物处理的雄性HD转基因小鼠的F1代后代显示出显著改善的HD疾病表型，这与雄性后代中枢神经系统中Kdm5d表达增加和组蛋白H3赖氨酸4（K4）（H3K4）甲基化减少有关。此外，我们表明在突变的HD纹状体细胞中过表达Kdm5d可显著改善代谢缺陷。这些发现表明，HDAC抑制剂可通过不同表观遗传机制之间的相互作用引发跨代效应，从而以有益的方式影响疾病表型。
