LncRNAs H19 and MEG3 as Universal Indicators of Metabolic Derangements?

H19 and MEG3 are imprinted genes that are transcribed into long noncoding RNAs that are only expressed from their maternal alleles (Rachmilewitz et al., 1992; Benetatos et al., 2011). Dysregulation of both of these genes, together with their various allelic forms and numerous interacting microRNAs (miRNAs), has been implicated in numerous types of pathologies. The human lncRNA H19 gene, located on chromosome 11p15.5, is a maternally expressed gene (the paternal allele is never expressed during normal fetal development) that plays key roles during embryogenesis (Gabory et al., 2006, 2010); it is downregulated postnatally (Thorvaldsen et al., 1998). There are multiple differentially methylated regions, located upstream of the transcription start of H19 that act as a methylation-sensitive insulator (Gao et al., 2014). Its aberrant re-expression later in life, through loss of imprinting through changes in methylation status of the gene was originally associated with numerous malignancies, including colorectal cancer (Cui et al., 2002), breast cancer (Adriaenssens et al., 1998; Berteaux et al., 2005), esophageal cancer (Hibi et al., 1996; Gao et al., 2014), bladder cancer (Luo et al., 2013), and pancreatic ductal adenocarcinoma, the last through induction of an epithelial-mesenchymal transition that promotes cell invasion and migration (Ma et al., 2014).

Mechanistic investigations have indicated that the lncRNA H19 may also trigger tumorigenesis by serving as a precursor molecule for miRNAs or competitive endogenous RNAs (Keniry et al., 2012; Xia et al., 2014; Matouk et al., 2016). For example, it has been reported that miR-675, derived from H19, may decrease the expression of the retinoblastoma gene and, therefore, increase the growth and development of colorectal cancer cells (Tsang et al., 2010). H19's various allelic forms have also more recently been associated with multiple other inflammatory diseases, including atherosclerosis (Pan, 2017) and the risk of coronary artery disease (CAD) (Gao et al., 2015). In the case of CAD the T variant of the rs217727 locus was associated with an increased risk (Gao et al., 2015). Similarly, the T allele of re217727 has also been associated with an increased risk of type 2 diabetes mellitus (T2DM) (Ghaedi et al., 2018) and gastric cancer (Yang et al., 2015).

Similar to H19, MEG3 is a maternally imprinted gene—expressed only from the maternally-inherited human chromosome 14. It has at least a dozen different spliceoforms, all of which serve as lncRNAs. It is expressed in the placenta during normal development and is also regarded as a tumor suppressor gene and an anti-angiogenesis factor. It has been demonstrated to be downregulated in many neoplasias, including hepatocellular carcinoma (Braconi et al., 2011; Zhuo et al., 2016), bladder cancer (Ying et al., 2013), glioma (Wang et al., 2012), gastric cancer (Yan et al., 2014), and colorectal cancer (Cao et al., 2016).

In this issue of Genetic Testing and Molecular Biomarkers, Wang et al. have extended the role of H19 and MEG3 to the risk of osteoarthritis (OA). In their report they show that the A allele of the H19 rs217727 locus significantly increased the risk of OA; this is in contrast to the increased risk associated with the T allele for CAD, T2DM, and gastric cancer. They also found that the A allele of the MEG3 gene rs7158663 locus was (in comparison with the G allele) associated with a significantly increased risk of OA. Interestingly they begin to get at the mechanism underlying their findings of increased risk for the A alleles of the rs217727 and rs7158663 loci as they found they were associated with increased plasma levels of not only the lncRNAs themselves, but also of their multiple interacting miRNAs. Thus, they speculate that the lncRNAs alter the expression of their target RNAs.

All of these findings with regard to the many and varied roles these lncRNA genes play—in a very wide range of pathological conditions—reinforces the concept that imprinted genes play outsized roles in normal and aberrant developmental processes. Thus, it is likely that the reason these, and other genes, are imprinted is because their effects on the fate of the organism are so great that they must be tightly controlled.