腺瘤中核DNA甲基化降低和线粒体转录本变化与线粒体DNA甲基化无关。
Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation.
作者信息
Morris M J, Hesson L B, Poulos R C, Ward R L, Wong J W H, Youngson N A
机构信息
1Department of Pharmacology, School of Medical Sciences, UNSW Sydney, Sydney, NSW Australia.
2Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW Australia.
出版信息
Biomark Res. 2018 Dec 29;6:37. doi: 10.1186/s40364-018-0151-x. eCollection 2018.
BACKGROUND
Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). Mitochondria have multiple copies of a 16 kb circular genome that contains genes that are vital for their function. While DNA methylation is known to alter the nuclear genome in CRC, it is not clear whether it could have a similar influence in mtDNA; indeed, currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. Thus our goal here was to determine whether the methylation state of mtDNA is linked to mitochondrial gene transcription in colorectal adenomas, and to assess its suitability as a biomarker in CRC.
METHODS
To investigate the relationship between DNA methylation and mitochondrial transcripts in adenomas, we performed RNA-sequencing and Whole Genome Bisulphite Sequencing (WGBS) of mtDNA-enriched DNA from normal mucosa and paired adenoma patient samples.
RESULTS
Transcriptional profiling indicated that adenomas had reduced mitochondrial proton transport versus normal mucosa, consistent with altered mitochondrial function. The expression of 3 tRNAs that are transcribed from mtDNA were also decreased in adenoma. Overall methylation of CG dinucleotides in the nuclear genome was reduced in adenomas (68%) compared to normal mucosa (75%, < 0.01). Methylation in mtDNA was low (1%) in both normal and adenoma tissue but we observed clusters of higher methylation at the ribosomal RNA genes. Levels of methylation within these regions did not differ between normal and adenoma tissue.
CONCLUSIONS
We provide evidence that low-level methylation of specific sites does exist in the mitochondrial genome but that it is not associated with mitochondrial gene transcription changes in adenomas. Furthermore, as no large scale changes to mtDNA methylation were observed it is unlikely to be a suitable biomarker for early-stage CRC.
背景
线粒体功能改变和核基因组DNA甲基化模式的大规模变化都是结直肠癌（CRC）的特征。线粒体有一个16 kb环状基因组的多个拷贝，该基因组包含对其功能至关重要的基因。虽然已知DNA甲基化会改变CRC中的核基因组，但尚不清楚它是否会对线粒体DNA产生类似影响；事实上，目前线粒体基因组（mtDNA）甲基化是否发生存在争议。因此，我们这里的目标是确定mtDNA的甲基化状态是否与结直肠腺瘤中的线粒体基因转录相关，并评估其作为CRC生物标志物的适用性。
方法
为了研究腺瘤中DNA甲基化与线粒体转录本之间的关系，我们对来自正常黏膜和配对腺瘤患者样本的富含mtDNA的DNA进行了RNA测序和全基因组亚硫酸氢盐测序（WGBS）。
结果
转录谱分析表明，与正常黏膜相比，腺瘤的线粒体质子转运减少，这与线粒体功能改变一致。腺瘤中从mtDNA转录的3种tRNA的表达也降低。与正常黏膜（75%，<0.01）相比，腺瘤中核基因组中CG二核苷酸的总体甲基化降低（68%）。正常组织和腺瘤组织中mtDNA的甲基化水平均较低（1%），但我们在核糖体RNA基因处观察到较高甲基化的簇。这些区域内的甲基化水平在正常组织和腺瘤组织之间没有差异。
结论
我们提供的证据表明，线粒体基因组中确实存在特定位点的低水平甲基化，但它与腺瘤中的线粒体基因转录变化无关。此外，由于未观察到mtDNA甲基化的大规模变化，它不太可能是早期CRC的合适生物标志物。
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