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Long non-coding RNAs: new players in cell differentiation and development

Key Points

  • Genomes of multicellular organisms produce thousands of different long non-coding RNA (lncRNA) species.

  • lncRNAs have crucial roles in gene expression control during developmental and differentiation processes.

  • lncRNAs can regulate gene expression by several mechanisms in both the nucleus and the cytoplasm.

  • lncRNAs drive the formation of ribonucleoprotein complexes and guide them to specific targets to regulate gene expression.

  • Different in vitro and in vivo systems have shown the importance of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis.

  • lncRNAs can form regulative networks with other RNA species, such as microRNAs and mRNAs.


Genomes of multicellular organisms are characterized by the pervasive expression of different types of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs) belong to a novel heterogeneous class of ncRNAs that includes thousands of different species. lncRNAs have crucial roles in gene expression control during both developmental and differentiation processes, and the number of lncRNA species increases in genomes of developmentally complex organisms, which highlights the importance of RNA-based levels of control in the evolution of multicellular organisms. In this Review, we describe the function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development.

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Figure 1: Models of nuclear lncRNA function.
Figure 2: Models of cytoplasmic lncRNA function.
Figure 3: Pluripotency control.
Figure 4: ncRNAs and muscle differentiation.


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The authors thank members of the Bozzoni and Fatica laboratories for discussion, and J. Rinn, C. Dean and P. Avner for their suggestions. They apologize for papers that are not discussed owing to space limitations. They acknowledge support from FP7-PEOPLE-2011-ITN Project HemID (289611), Telethon (GPP11149), Parent Project Italia, Associazione Italiana per la Ricerca sul Cancro, Italian Institute of Technology “SEED”, Fondo per gli Investimenti per la Ricerca di Base, Programmi di Ricerca di Interesse Nazionale and the EPIGEN Project.

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Correspondence to Irene Bozzoni.

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(miRNAs). Small non-coding RNAs of ~22 nucleotides that are integral components of RNA-induced silencing complex (RISC) and that recognize partially complementary target mRNAs to induce translational repression, which is often linked to degradation. Among the RISC proteins, AGO binds to miRNA and mediates the repressing activity.

Polyadenylation sites

Sequences that are required for the cleavage of primary RNA transcripts that are produced by RNA polymerase II. As a consequence of such cleavage, the 5′ cutoff product becomes polyadenylated, whereas the 3′ product undergoes rapid degradation that induces Pol II release from the DNA and hence transcriptional termination.

Polycomb repressive complex

(PRC). A multiprotein complex that silences target genes by establishing a repressive chromatin state; PRC2 trimethylates histone H3 at lysine 27, which is recognized by PRC1 that mediates chromatin compaction by inducing H2A monoubiquitylation.

MLL1 complex

A multiprotein complex that mediates both histone H3 trimethylation at lysine 4 (H3K4me3) and histone H4 acetylation at lysine 16 (H4K16ac), which are associated with transcriptionally active genes.

Dosage compensation

The process that ensures equal levels of X-linked gene expression in males (XY) and females (XX).

Genomic imprinting

Epigenetic silencing of genes on the basis of their parental origin, which results in monoallelic expression.


A histone lysine methyltransferase that is responsible for dimethylation and trimethylation at histone H3 lysine 9, which creates epigenetic marks that predominantly correlate with transcriptional repression.

Germ layer

Primary germ layers (that is, ectoderm, endoderm and mesoderm) are specified during vertebrate embryogenesis and, through further differentiation, give rise to the organs and tissues of the body.


The ability of a cell to differentiate into one of many cell types.

Induced pluripotent stem cells

(iPSCs). In vitro-derived pluripotent cells that originate from non-pluripotent cells in a process called reprogramming.

Nuclear speckles

A class of nuclear body that is located in interchromatin regions of the nucleoplasm of mammalian cells, which are enriched in pre-mRNA splicing factors.

Zinc-finger nucleases

Artificial proteins that contain a zinc-finger DNA-binding element fused to an endonuclease domain. Double-stranded breaks are produced at specific DNA sequences to induce natural DNA repair. This strategy allows targeted gene deletions, integrations or modifications.

GABAergic interneurons

Neurons of the central nervous system that form a connection between other types of neurons and use the neurotransmitter γ-aminobutyric acid (GABA), which inhibits excitatory responses.


A part of the brain that is specifically responsible for storing and retrieving memories.

Morpholino oligonucleotides

Oligonucleotides that are modified to be highly stable in the cell; they are used as antisense RNA to block cell components from accessing the target site for which they are designed.

Chromatin immunoprecipitation

(ChIP). A method used to determine whether a given protein binds to, or is localized to, specific chromatin loci in vivo.

Duchenne muscular dystrophy

A severe genetic disorder that is characterized by the rapid progression of muscle degeneration, which leads to a loss of ambulation and death. It is due to mutations in the dystrophin gene that prevent its production.

Phylogenetic analysis

Comparison of DNA, RNA or protein sequences in different organisms that enables one to establish their evolutionary relationships.


Construction or creation from a diverse range of available things.

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Fatica, A., Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet 15, 7–21 (2014).

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