Lessons from reverse-genetic studies of lncRNAs

The functions of long noncoding RNAs (lncRNAs) have mainly been studied using cultured cell lines, and this approach has revealed the involvement of lncRNAs in a variety of biological processes, including the epigenetic control of gene expression, post-transcriptional regulation of mRNA, and cellular proliferation and differentiation. Recently, increasing numbers of studies have investigated the functions of lncRNAs using gene-targeted model mice, largely confirming the physiological importance of lncRNA-mediated regulation in individual animals. In some cases, however, the results obtained by studies using knockout mice have been somewhat inconsistent with those of the preceding cell-based analyses. In this review, I will summarize the lessons that we are learning from the reverse-genetic studies of lncRNAs, namely the importance of noncoding DNA elements, the weak correlation between expression level and phenotypic prominence, the existence of tissue- and condition-specific phenotypes and incomplete penetrance, and the function of lncRNAs as precursor molecules. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.