Long noncoding RNAs in cell-fate programming and reprogramming

Abstract

In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of regulators of gene expression. lncRNAs exhibit several distinctive features that confer unique regulatory functions, including exquisite cell- and tissue-specific expression and the capacity to transduce higher-order spatial information. Here we review evidence showing that lncRNAs exert critical functions in adult tissue stem cells, including skin, brain, and muscle, as well as in developmental patterning and pluripotency. We highlight new approaches for ascribing lncRNA functions and discuss mammalian dosage compensation as a classic example of an lncRNA network coupled to stem cell differentiation.

Figure 1. lncRNAs control differentiation and self-renewal

Several lncRNAs that regulate specific somatic tissue stem cell renewal or differentiation and their protein partners are depicted. Some lncRNAs maintain the stem cell state while others promote a differentiation program. Their functions are often facilitated by protein partners that impart the ability to activate or repress gene expression or post-transcriptionally regulate other RNAs.

Figure 2. lncRNAs program active and silent chromatin states

(Top) In ESCs active chromatin is achieved and maintained through multiple mechanisms. Cis acting lncRNAs can recruit the MLL/WDR5 complex to deposit H3K4me3 at promoters. Enhancer regions can transcribe enhancer RNAs (eRNAs); some enhancer-like RNAs bring Mediator to promoters to contribute to gene activation. Additionally, through interactions with the nascent transcribed RNA, canonical silencing factors such as PRC2 and DNMT1 are titrated away from active chromatin. (Bottom) Chromatin also employs many lncRNA-based mechanisms to stay silent. Ezh2 and JAIRD2 (subunits of PRC2) may bind lncRNAs to facilitate specific chromatin targeting or to enhance PRC2 complex assembly and stability. Additionally, when nascent RNA production is low, DNMT1 can interact with the chromatin and act to silence through DNA methylation.

Figure 3. lncRNAs mark ESC state and reprogramming success

X-chromosome inactivation (XCI) is a key step in the commitment of ESCs to differentiated cell types. The network on lncRNAs, signaling pathways, and protein effectors that control XCI are depicted. These features can distinguish the stemness of different ESC states and iPSC quality.