Non-coding 886 (nc886/vtRNA2-1), the epigenetic odd duck - implications for future studies

Non-coding 886 (nc886, VTRNA2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability, and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNAs has been redefined multiple times and are still under debate and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of the nc886 locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets. Here, we aim to summarise the existing literature regarding nc886, discuss how the characteristics of nc886 give rise to contradictory results, and reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how the nc886 methylation pattern distribution is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.