Long noncoding RNAs: new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells

Abstract

Maintenance of the pluripotent state or differentiation of the pluripotent state into any germ layer depends on the factors that orchestrate expression of thousands of genes through epigenetic, transcriptional, and post-transcriptional regulation. Long noncoding RNAs (lncRNAs) are implicated in the complex molecular circuitry in the developmental processes. The ENCODE project has opened up new avenues for studying these lncRNA transcripts with the availability of new datasets for lncRNA annotation and regulation. Expression studies identified hundreds of long noncoding RNAs differentially expressed in the pluripotent state, and many of these lncRNAs are found to control the pluripotency and stemness in embryonic and induced pluripotent stem cells or, in the reverse way, promote differentiation of pluripotent cells. They are generally transcriptionally activated or repressed by pluripotency-associated transcription factors and function as molecular mediators of gene expression that determine the pluripotent state of the cell. They can act as molecular scaffolds or guides for the chromatin-modifying complexes to direct them to bind into specific genomic loci to impart a repressive or activating effect on gene expression, or they can transcriptionally or post-transcriptionally regulate gene expression by diverse molecular mechanisms. This review focuses on recent findings on the regulatory role of lncRNAs in two main aspects of pluripotency, namely, self renewal and differentiation into any lineage, and elucidates the underlying molecular mechanisms that are being uncovered lately.

FIG. 1.

LncRNA–transcription factor regulatory feedback loop in pluripotency. Color images available online at www.liebertpub.com/scd

FIG. 2.

Molecular mechanisms of lncRNA regulation. (a) Cis-acting and trans-acting gene expression regulation. (b) lncRNA Mira acting as a guide to the chromatin-modifying epigenetic activator MLL1 for exerting activating histone marks on the Mira gene locus, leading to activation of Hoxa6 and Hoxa7 gene expression. (c) lncRNA Neat1 mediating post-transcriptional regulation of mRNAs by facilitating formation of nuclear paraspeckles and aiding in nuclear retention of mRNAs with inverted repeats in their 3′-UTR. Color images available online at www.liebertpub.com/scd