Characterization of DNA hydroxymethylation profile in cervical cancer

Cervical cancer is one of the most common gynecological tumors in females. DNA methylation alteration is a type of epigenetic decoration that controls the gene transcriptional regulation and is essential for the pathological progression of cervical cancer to reflect the prognosis and therapeutic sensitivity in clinical practice. Beyond DNA methylation, DNA hydroxymethylation considered as a more stable biomarker draws the outline of the reversible cycle from DNA methylation and demethylation. However, the landscape of 5-hydroxymethylcytosine (5hmC) distributed in the genome is never characterized in cervical cancer. In this study, we presented the whole 5-methylcytosine (5mC) and 5hmC profile in cervical cancer of I-IIa and IIb to IV stages and cervicitis tissues as control by dot plot assay and immunohistochemistry. We observed that the total 5mC was up-regulated while 5hmC was down-regulated in cervical cancer group compared to the control group. Furthermore, we investigated the distribution of 5mC and 5hmC on genomic DNA by MeDIP- and hMeDIP-Seq. 53 differential methylation/hydromethylation regions (DMRs/DHMRs) displayed a continuously increasing or decreasing trend of 5mC or 5hmC from cervicitis to I-IIa and from I-IIa to IIb-IV stages of cervical cancer. Thirty-seven DMRs and DHMRs have a similar variation trend while the other 8 have the opposite trend compared between CSCC and cervicitis. Moreover, the DMR/DHMR associated genes were closely related to Wnt, MAPK, Rap1 and other important signaling pathways. Finally, 5hmC beyond 5mC at the genes such as ACTG1, SALL3, DNAJA3, SERPINB6, CDC14B and CALN1 were considered as the putative novel hallmarks for cervical cancer diagnosis and prognosis. Altogether, this study first describes the DNA hydroxymethylation atlas of cervical cancer and shows a list of novel genes transcriptionally regulated by DNA methylation and hydroxymethylation.