Abstract
BackgroundAltered 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.MethodsTo 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.ResultsTranscriptional 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%, P < 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.ConclusionsWe 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.
Highlights
Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC)
Mitochondria contain a separate DNA molecule that is transcribed to code for proteins, ribosomal RNA and transfer RNA which are critical for mitochondrial function
Transcriptome analysis suggests that mitochondrial energy production is reduced in adenomas To find differentially regulated pathways in normal and adenoma tissues, we analysed RNA-seq data from 6 normal mucosal and 12 matched adenoma samples and identified 1846 and 1230 genes that were significantly downregulated and upregulated, respectively in adenomas (P < 0.05 Multiple testing error was controlled with the Benjamini-Hochberg Procedure, the critical value was calculated with a false discovery rate of 25%.)
Summary
Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). 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; currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. DNA methylation of cytosine nucleotides is the most studied and best understood epigenetic modification. It is recognised as an important regulator of gene transcription in plants and animals [5]. Because of the importance of DNA methylation for gene regulation in the nuclear genome there has been great interest in determining whether it has similar importance in mtDNA
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