Functional evaluation of transposable elements as enhancers in mouse embryonic and trophoblast stem cells

Elife. 2019 Apr 23;8:e44344. doi: 10.7554/eLife.44344.

Abstract

Transposable elements (TEs) are thought to have helped establish gene regulatory networks. Both the embryonic and extraembryonic lineages of the early mouse embryo have seemingly co-opted TEs as enhancers, but there is little evidence that they play significant roles in gene regulation. Here we tested a set of long terminal repeat TE families for roles as enhancers in mouse embryonic and trophoblast stem cells. Epigenomic and transcriptomic data suggested that a large number of TEs helped to establish tissue-specific gene expression programmes. Genetic editing of individual TEs confirmed a subset of these regulatory relationships. However, a wider survey via CRISPR interference of RLTR13D6 elements in embryonic stem cells revealed that only a minority play significant roles in gene regulation. Our results suggest that a subset of TEs are important for gene regulation in early mouse development, and highlight the importance of functional experiments when evaluating gene regulatory roles of TEs.

Keywords: chromosomes; embryonic stem cells; enhancers; gene expression; genetics; genomics; mouse; transposable elements; trophoblast stem cells.

Plain Language Summary

Much of what is known about genetics has come from studying only a tiny fraction of the genome’s sequence, the part that primarily codes for proteins. But the genome has many other features outside these regions, some of which play an important biological role. Transposable elements – repetitive sequences that are present in many species – make up around half of the mouse genome. They are ‘selfish’ elements, in that the spread of them within the genome does not necessarily benefit the host organism. But sometimes transposable elements can be ‘domesticated’, and used to the host’s advantage. For example, transposable elements can generate new genes. In other cases, their non-coding sequences can regulate the activity of other nearby genes or even those elsewhere in the genome. It remains unclear to what extent transposable elements have shaped genome regulation throughout evolution. One idea is that the spread of transposable elements can help to establish large regulatory networks – whereby many genes are collectively regulated to produce a specific output. But it has not been fully explored how effective transposable elements are at regulating gene expression. Now, Todd et al. investigate whether particular transposable elements, that are suspected to boost the activity of other genes, are essential for normal gene expression in early mouse development. Todd et al. genetically edited stem cells from the inner and outer layer of the early mouse embryo to find transposable elements that promote gene expression. Whilst some transposable elements were found to be important for gene regulation, not all of the candidates tested were needed to maintain expression levels. To widen the search, several transposable elements were turned off simultaneously by compacting specific stretches of DNA so that they could no longer be activated. When 34 transposable elements were inactivated at once, it emerged that only three transposable elements had a significant impact on gene expression. These findings suggest that whether or not a given transposable element regulates gene expression cannot be predicted solely from profiling the structure and sequence of the genome. This highlights why it is important to interrogate the effect transposable elements have ona gene's role within a cell. Transposable elements are largely disregarded in genomics due to technical difficulties in analysing these repetitive stretches of DNA. But characteristic variations within a population may in part be driven by differences in these parts of the genome, which may also be implicated in diseases such as cancer. Identifying which transposable elements are important for driving gene expression, and linking their actions to specific traits could aid the discovery of important genetic variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Transposable Elements*
  • Embryonic Stem Cells / physiology*
  • Gene Expression Regulation, Developmental*
  • Mice
  • Trophoblasts / physiology*

Substances

  • DNA Transposable Elements

Associated data

  • GEO/GSE122856
  • GEO/GSE49847
  • GEO/GSE44288
  • GEO/GSE90045
  • GEO/GSE29184
  • GEO/GSE22557
  • GEO/GSE42207
  • GEO/GSE67867
  • GEO/GSE66390
  • GEO/GSE94694
  • GEO/GSE84236
  • GEO/GSE71156
  • GEO/GSE39406
  • GEO/GSE81681
  • GEO/GSE48519
  • GEO/GSE62150
  • GEO/GSE54016
  • GEO/GSE96107