lncRNAs in development and disease: from functions to mechanisms

Abstract

Differential expression of long non-coding RNAs (lncRNAs) during differentiation and their misregulation in cancer highlight their potential as cell fate regulators. While some example lncRNAs have been characterized in great detail, the functional in vivo relevance of others has been called into question. Finding functional lncRNAs will most probably require a combination of complementary approaches that will greatly vary depending on their mode of action. In this review, we discuss the different tools available to dissect genetically lncRNA requirements and how each is best suited to studies in particular contexts. Moreover, we review different strategies used to select candidate lncRNAs and give an overview of lncRNAs described to regulate development and cancer through different mechanisms.

Keywords: cancer; development; long non-coding RNAs.

Figure 1.

Different approaches for disrupting lncRNAs. Methods such as knockdown and CRISPRi affect the RNA itself or reduce the transcription of the lncRNA. Knockdown can be achieved in a variety of ways (siRNA, shRNA, LNA, ASO). CRISPRi is most efficient if Cas9 is fused to repressor domains (e.g. KRAB). These methods can also be transient. Insertion of an early terminator sequence or complete deletion of the locus or promoter are achieved via genome engineering and are non-reversible.

Figure 2.

Themes in lncRNA functions. LncRNAs have been described to play multiple roles affecting gene expression at the transcriptional level via interactions with chromatin remodelling complexes, direct binding to the DNA as an RNA–DNA triplex, or facilitating chromatin looping (a), interacting with RNA processing machinery or affecting mRNA stability (b) or directly regulating protein function (c).