Regulation of mammalian cell differentiation by long non-coding RNAs

Abstract

Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development.

Figure 1

Mechanisms of lncRNA function. Studies have described a range of mechanisms by which lncRNAs regulate their targets; many seem to depend on specific features of primary sequence, secondary structure and genomic positioning of lncRNA effector transcripts. (1) Several lncRNAs act as RNA decoys, titrating transcription factors away from their DNA targets by directly binding to them as target mimics [12,98]. (2) Others work at the post-transcriptional level as microRNA target site decoys, titrating microRNA effector complexes away from their mRNA targets [63,64,65]. lncRNAs, the microRNA target sites of which lack the structural sequence features needed for transcript degradation, have the overall effect of ‘sponging’ their microRNA regulators. (3) Many lncRNAs seem to bind to specific combinations of regulatory proteins, potentially acting as scaffold elements within ribonucleoprotein complexes [59,98]. (4) Recruitment of chromatin-modifying complexes to their DNA targets in cis has also emerged as a well-characterized function for several mammalian lncRNAs [57,58]. Recruitment in trans is not depicted [56]. A few lncRNAs seem to modulate direct processing of their mRNA targets, including translation (5), splicing (6) and degradation (7) [60,61,62]. lncRNA, long non-coding RNA; mRNA, messenger RNA, RNP, Ribonucleoprotein.

Figure 2

Regulation of mammalian cell differentiation by lncRNAs. Examples are shown of lncRNAs implicated in modulating the differentiation of specialized cells from their progenitors. (A) Many lncRNAs are required for maintenance of the pluripotent state of ES cells, thereby antagonizing differentiation into specialized lineages [10,11,98]. Others favour differentiation [57], and yet others contribute to dedifferentiation of specialized cells into iPS cells [75]. (B) Other lncRNAs are important for the maintenance of adult epidermal lineage progenitor cells [76,77]. (C) Several lncRNAs transcribed from Hox clusters regulate the transcription of Hox genes in cis [57,58,87] or in trans [56], contributing to the distinct epigenetic profiles of Hox loci across cells from distinct anatomical positions. [82,83,84,87]. (D) lncRNAs have also been associated with the development of cells from haematopoietic [50,86,87] and vascular endothelial lineages (E; [88]). (F) Differentiation of muscle cells is also regulated by lncRNAs [65]. (G) Many lncRNAs are differentially expressed and specifically localized across neural tissues during development and disease. Many of them modulate differentiation of progenitors into excitatory, inhibitory or retinal photoreceptor neurons, whereas others favour oligodendrocyte differentiation [93,94,95,96,97,98]. ANCR, anti-differentiation ncRNA; EGO, eosinophil granule ontogeny; ES, embryonic stem; Evf2, embryonic ventral forebrain 2; HOTAIR, HOX antisense intergenic RNA; HOTAIRM1, HOX antisense intergenic RNA myeloid 1; HOTTIP, HOXA transcript at the distal tip; Hox, homeobox; iPS, induced pluripotent stem; linc-MD1, linc muscle differentiation 1; lincRNA-EPS, lincRNA erythroid pro-survival; lincRNA-ROR, lincRNA regulator of reprogramming; lncRNA, long non-coding RNA; Nkx2.2as, natural killer cell-associated antigen 2 locus 2 antisense; RMST, Rhabdomyosarcoma 2 associated transcript; RNCR2, retinal non-coding RNA 2; PINC, pregnancy-induced ncRNA; Tie-1AS, tyrosine kinase with immunoglobulin-like and EGF-like domains 1, antisense; Vax2os1, ventral anterior homeobox-containing gene 2 opposite strand transcript.

Figure 3

Integrating lncRNAs to known regulatory networks of mammalian cell differentiation. A first step towards integrating lncRNA functions with those of microRNAs, transcription factors and chromatin modifiers during differentiation of mammalian cells is to explore their mutual regulatory relationships. Some examples of these relationships are depicted. lncRNAs (red RNAs and red arrows) can regulate microRNAs as target site decoys, directly bind to transcription factors as target mimics or as allosteric regulators, and participate in assembly of chromatin-modifying complexes as structural components and recruiters to genomic targets. microRNAs (green RNAs and arrows) post-transcriptionally regulate RNAs from transcription factor, chromatin modifier or lncRNA loci by directly base-pairing to short stretches of RNA. Transcription factors (blue proteins and arrows) can regulate transcription of all the other regulators by directly binding to their promoters. Similarly, chromatin modifiers (orange proteins and arrows) also regulate transcription of the other network components through chromatin modification. Regulatory relationships between microRNAs and chromatin modifier are not depicted. lncRNA, long non-coding RNA.