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  • Review Article
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Non-coding RNAs as regulators of embryogenesis

Nature Reviews Genetics volume 12, pages 136–149 (2011)Cite this article

Subjects

Key Points

  • Genome-wide transcriptome analyses have demonstrated that a large fraction of the genome is transcribed. Many newly identified transcripts do not to encode proteins but function as non-coding RNAs (ncRNAs).

  • Both small ncRNAs (for example, microRNAs (miRNAs)) and large ncRNAs (for example, large intergenic ncRNAs (lincRNAs)) have emerged as important regulators of embryogenesis. Several ncRNAs promote developmental transitions and maintain developmental states.

  • Mutations in the miRNA biogenesis pathway have revealed global requirements for miRNAs during embryogenesis.

  • miRNAs sharpen and promote developmental transitions. For example, specific miRNAs accelerate the deadenylation and clearance of maternal mRNAs.

  • miRNAs regulate cell fate specification by modulating various signalling pathways.

  • miRNAs participate in bistable loops that stabilize alternative cell fate decisions. For example, let-7 and LIN28 establish a toggle switch between pluripotent and differentiated cell fates.

  • Long ncRNAs (lncRNAs) establish stably maintained chromatin states during imprinting and dosage compensation. The mammalian lncRNA Xist, for example, is essential for silencing one of the two X chromosomes in mammalian females.

  • lncRNAs can serve as scaffolds for the assembly of chromatin-modifying complexes and transcriptional regulators. For example, the lncRNA HOTAIR establishes a repressive chromatin state at multiple loci.

  • lncRNAs and miRNAs have important roles in the gene regulatory networks that govern cell fate specification (for example, neural development and differentiation) and morphogenesis (for example, the epithelial-to-mesenchymal transition).

Abstract

Non-coding RNAs (ncRNAs) are emerging as key regulators of embryogenesis. They control embryonic gene expression by several means, ranging from microRNA-induced degradation of mRNAs to long ncRNA-mediated modification of chromatin. Many aspects of embryogenesis seem to be controlled by ncRNAs, including the maternal–zygotic transition, the maintenance of pluripotency, the patterning of the body axes, the specification and differentiation of cell types and the morphogenesis of organs. Drawing from several animal model systems, we describe two emerging themes for ncRNA function: promoting developmental transitions and maintaining developmental states. These examples also highlight the roles of ncRNAs in ensuring a robust commitment to one of two possible cell fates.

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Figure 1: miR-430 — a multitasking microRNA family during embryogenesis.
Figure 2: Regulation of pluripotency by microRNAs.
Figure 3: RNAs control alternative cell fate decisions.
Figure 4: Imprinting and dosage compensation.
Figure 5: RNAs modulate chromatin.
Figure 6: Non-coding RNAs regulate neural development.
Figure 7: Regulation of the epithelial-to-mesenchymal transition by non-coding RNAs.

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Acknowledgements

We thank G.-L. Chew and O. Minkina for critical reading of the manuscript, and E. Valen, E. Alvarez-Saavedra, S. Cohen, R. Gregory, O. Hobert and members of the Schier laboratory for discussions. This work was supported by US National Institutes of Health grants to A.F.S. and J.L.R. and by fellowships from the European Molecular Biology Organization (ALTF 372-2009) and The Human Frontier Science Program (LT-000307/2010) to A.P.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Andrea Pauli & Alexander F. Schier

  2. The Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA

    Andrea Pauli, John L. Rinn & Alexander F. Schier

  3. Harvard Stem Cell Institute, Harvard University, Cambridge, 02138, Massachusetts, USA

    John L. Rinn & Alexander F. Schier

  4. Center for Brain Science, Harvard University, Cambridge, 02138, Massachusetts, USA

    Alexander F. Schier

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  1. Andrea Pauli
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Supplementary information

Supplementary information S1 (table)

Complexity of non-coding RNAs in animals (PDF 272 kb)

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SUPPLEMENTARY INFORMATION

S1 (table)

Glossary

miRNAs

(MicroRNAs). ssRNAs of ∼22 bp that act as guides for RNA-induced silencing complex (RISC)-mediated repression of partially complementary target genes. Biogenesis of most miRNAs requires the stepwise activity of two RNase III endonuclease complexes, nuclear Drosha–DGCR8 and cytoplasmic Dicer.

lncRNAs

(Long non-coding RNAs). Transcripts that resemble protein-coding mRNAs in that they are capped, spliced and polyadenylated RNA polymerase II transcripts; they differ from mRNAs only in their lack of a protein-coding ORF.

endo-siRNAs

(Endogenous small interfering RNAs). Small RNAs that originate, in a Dicer-dependent manner, from long double-stranded (sense–antisense or hairpin) precursors. Initially mainly thought of as a mechanism of host defence against exogenous dsRNA, endo-siRNAs are now known to also regulate endogenous mRNAs in mouse oocytes and Caenorhabditis elegans.

piRNAs

(PIWI-interacting RNAs). Small (24–31 bp) RNAs that are associated with PIWI-clade proteins of the Argonaute family. They ensure genome stability in the germ line of flies, mice and zebrafish by silencing transposable and repetitive elements.

lincRNAs

(Large intergenic non-coding RNAs). A subgroup of long non-coding RNAs (lncRNAs) that originate from intergenic regions.

Drosha

The double-stranded RNA processing enzyme that catalyses the nuclear primary microRNA (pri-miRNA) to precursor miRNA (pre-miRNA) cleavage reaction.

DGCR8

The essential RNA-binding cofactor of Drosha; DGCR8 and Drosha are core proteins of the so-called microprocessor complex that promotes nuclear primary microRNA (pri-miRNA) to precursor miRNA (pre-miRNA) processing during canonical microRNA biogenesis.

Dicer

The dsRNA processing enzyme that catalyses the final cytoplasmic precursor microRNA (pre-miRNA) cleavage reaction to generate mature miRNAs during canonical miRNA biogenesis; Dicer also promotes processing of endogenous small interfering RNA (endo-siRNA) precursors to generate mature endo-siRNAs.

RNA-induced silencing complex

(RISC). The RISC complex contains the single-stranded, ∼22 bp miRNA and proteins of the Argonaute family. The miRNA acts as guide for the Argonaute proteins, which mediate the repression of the target mRNA.

Germ layers

Cell layers that are specified in a transforming growth factor-β (TGFβ)-signalling dependent manner after the initial embryonic cleavage stages. Each of the three primary germ layers (ectoderm, endoderm and mesoderm) gives rise to specific tissues and organs during later embryogenesis.

Deadenylation

The process of removal of the 3′ poly(A) tail of mRNAs, which leads to their destabilization and subsequent degradation; deadenylation is mainly mediated by the CAF1–CCR4 deadenylase complex and contributes to the RNA-induced silencing complex (RISC)-mediated repression of target mRNAs.

Primordial germ cells

(PGCs). Embryonic cells that give rise to germ cells from which the haploid gametes (oocytes in females and sperm in males) differentiate.

Induced pluripotent stem cells

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

Dosage compensation

A process that equalizes levels of X-linked gene expression in XX females and XY males.

Epigenetic

An epigenetic change is an inherited phenotypic change that is caused by mechanisms other than changes in the underlying DNA sequence.

Polycomb

Polycomb group (PcG) proteins are epigenetic regulators of gene expression that silence target genes by establishing a repressive chromatin state. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 (H3K27me3). This repressive histone modification is recognized by PRC1, which has ubiquitylating activity. Because of their role in maintaining states of gene expression, PRCs have key roles in cell fate maintenance and transitions during development.

Hox genes

Hox genes represent an ancestral embryonic patterning mechanism that specifies segmental identities along the anterior–posterior body axis in all bilateria. Hox genes encode homeobox transcription factors that are arranged in clusters. Expression of paralogous Hox genes within a cluster is tightly regulated both spatially and temporally; misexpression causes dramatic alterations in the embryonic body plan (homeotic transformations).

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Pauli, A., Rinn, J. & Schier, A. Non-coding RNAs as regulators of embryogenesis. Nat Rev Genet 12, 136–149 (2011). https://doi.org/10.1038/nrg2904

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