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. 2013 Oct;10(10):1579-85.
doi: 10.4161/rna.26165. Epub 2013 Aug 22.

The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis

Phillip Grote  1 , Bernhard G Herrmann  1
Affiliations

The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis

Phillip Grote et al. RNA Biol. 2013 Oct.

Abstract

Epigenetic control mechanisms determine active and silenced regions of the genome. It is known that the Polycomb Repressive Complex 2 (PRC2) and the Trithorax group/Mixed lineage leukemia (TrxG/Mll) complex are able to set repressive and active histone marks, respectively. Long non-coding RNAs (lncRNAs) can interact with either of these complexes and guide them to regulatory elements, thereby modifying the expression levels of target genes. The lncRNA Fendrr is transiently expressed in lateral mesoderm of mid-gestational mouse embryos and was shown to interact with both PRC2 and TrxG/Mll complexes in vivo. Gene targeting revealed that loss of Fendrr results in impaired differentiation of tissues derived from lateral mesoderm, the heart and the body wall, ultimately leading to embryonic death. Molecular data suggests that Fendrr acts via dsDNA/RNA triplex formation at target regulatory elements, and directly increases PRC2 occupancy at these sites. This, in turn, modifies the ratio of repressive to active marks, adjusting the expression levels of Fendrr target genes in lateral mesoderm. We propose that Fendrr also mediates long-term epigenetic marks to define expression levels of its target genes within the descendants of lateral mesoderm cells. Here we discuss approaches for lncRNA gene knockouts in the mouse, and suggest a model how Fendrr and possibly other lncRNAs act during embryogenesis.

Keywords: Fendrr; Polycomb Repressive Complex 2; embryogenesis; epigenetic control; histone modification; lncRNA; long non-coding RNA; mouse.

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Figures

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Figure 1. ChIRP (Chromatin Isolation by RNA purification) analysis shows that Fendrr interacts with target promoters in embryonic stem cells differentiated in vitro. Fourteen biotinylated oligonucleotides tiling the Fendrr transcript were combined in even and odd numbered pools. (A) Each oligo-pool specifically precipitated the Fendrr transcript. (B) At least one pool of tiling oligos co-precipitated the target promoters of Foxf1 and Pitx2, but not the control promoters of Dll1, Tcf15, or Irx3.
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Figure 2.Fendrr anchors PRC2 to specific target sites. Schematic drawing illustrating binding of the Fendrr/PRC2 complex through a 40-nucleotide stretch (red) to specific recognition sequences in target promoters, e.g., that of Foxf1 and Pitx2, thus increasing PRC2 occupancy and H3K27 trimethylation at these sites.
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Figure 3. Model of immediate and long-term effects of Fendrr acting via PRC2 on epigenetic modification and gene expression. The ratio of repressive H3K27me3 (blue) to active H3K4me3 (red) marks determines the level of gene expression. Histone marks set in the lateral mesoderm are maintained in the descendants of these cells until they are modified by other site-specific regulators resulting, for instance, in an increase in the repressive or a reduction in the active marks within cardiac mesoderm (indicated by arrows). In the case of Foxf1, this leads to a dominating repressive mark and silencing of the gene in wild-type cardiac mesoderm. In Fendrr mutant cells, anchoring of PRC2 to the Foxf1 promoter fails, thus skewing the H3K27me3/H3K4me3 ratio and leading to an increased Foxf1 expression level. The subsequent histone modifications which normally take place in cardiac mesoderm are not able to correct the false prior epigenetic marks set in the lateral mesoderm cells and thus, Foxf1 cannot be silenced.
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