Rafehi Haloom, El-Osta Assam
Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia.
Department of Pathology, The University of Melbourne, Parkville, VIC 3052, Australia.
Noncoding RNA. 2016 May 25;2(2):4. doi: 10.3390/ncrna2020004.
While clinical and pre-clinical trials indicate efficacy of histone deacetylase (HDAC) inhibitors in disease mediated by dynamic lysine modification, the impact on the expression of non-coding RNAs (ncRNAs) remains poorly understood. In this study, we investigate high throughput RNA sequencing data derived from primary human endothelial cells stimulated with HDAC inhibitors suberanilohydroxamic acid (SAHA) and Trichostatin A (TSA). We observe robust regulation of ncRNA expression. Integration of gene expression data with histone 3 lysine 9 and 14 acetylation (H3K9/14ac) and histone 3 lysine 4 trimethylation (H3K4me3) datasets identified complex and class-specific expression of ncRNAs. We show that EP300 target genes are subject to histone deacetylation at their promoter following HDAC inhibition. This deacetylation drives suppression of protein-coding genes. However, long intergenic non-coding RNAs (lincRNAs) regulated by EP300 are activated following HDAC inhibition, despite histone deacetylation. This increased expression was driven by increased H3K4me3 at the gene promoter. For example, elevated promoter H3K4me3 increased lincRNA expression despite broad EP300-associated histone deacetylation. In conclusion, we show that HDAC inhibitors regulate the expression of ncRNA by complex and class-specific epigenetic mechanisms.
虽然临床和临床前试验表明组蛋白去乙酰化酶（HDAC）抑制剂在由动态赖氨酸修饰介导的疾病中具有疗效，但对非编码RNA（ncRNA）表达的影响仍知之甚少。在本研究中，我们调查了源自用HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA）和曲古抑菌素A（TSA）刺激的原代人内皮细胞的高通量RNA测序数据。我们观察到ncRNA表达受到强烈调控。将基因表达数据与组蛋白3赖氨酸9和14乙酰化（H3K9/14ac）以及组蛋白3赖氨酸4三甲基化（H3K4me3）数据集整合，确定了ncRNA的复杂且类别特异性表达。我们表明，HDAC抑制后，EP300靶基因的启动子会发生组蛋白去乙酰化。这种去乙酰化会导致蛋白质编码基因受到抑制。然而，尽管发生了组蛋白去乙酰化，但由EP300调控的长链基因间非编码RNA（lincRNA）在HDAC抑制后会被激活。这种表达增加是由基因启动子处H3K4me3增加所驱动的。例如，尽管与EP300相关的组蛋白广泛去乙酰化，但启动子H3K4me3升高仍增加了lincRNA的表达。总之，我们表明HDAC抑制剂通过复杂且类别特异性的表观遗传机制调控ncRNA的表达。
