Epigenomic landscape of 5-hydroxymethylcytosine reveals its transcriptional regulation of lncRNAs in colorectal cancer

Background: DNA methylation at the 5 position of cytosine (5mC) can be converted to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation family. The loss of global levels of 5hmC has been regarded as a hallmark in various cancers. 5-hydroxymethylcytosine is distributed at protein-coding gene bodies and promoters; however, the role and distribution of 5hmC at long non-coding RNAs (lncRNAs) is not clear. We investigated the distribution and regulatory roles of 5hmC for lncRNAs in colorectal cancer (CRC). Methods: We integrated genome-wide profiles of 5hmC, 5mC, transcriptome and histone marks in CRC patients and examined the 5hmC-based clinical outcomes in patients. Results: 5-hydroxymethylcytosine was distributed at lncRNA loci and positively correlated with lncRNA transcription. Dysreulated CRC lncRNAs were regulated by 5hmC directly or through abnormal activities of typical and super-enhancers and promoters modified by 5hmC. In addition, 5hmC was involved in long-range chromatin interactions at lncRNA loci. Finally, lncRNAs regulated by differential 5hmC marks were correlated with different clinical outcomes and tumour status in patients. Conclusions: 5-hydroxymethylcytosine is critical in regulating the transcription of lncRNA and serve as novel biomarkers for clinical prognosis in CRC.