Do you have a junk drawer at your house? Perhaps it’s full of old take-out menus, dead batteries, rubber bands, and other purposeless things? Since their discovery, transposable elements, including the LINE-1 retrotransposon, have been relegated to the “junk drawer” of the human genome. At best LINE-1 has been called useless, and at worst it has been linked to cancer and other diseases. But now, researchers in the lab of Dr. Ramalho-Santos, at the University of California, San Francisco, have uncovered a vital role for LINE-1 in mouse embryonic stem cell (ESC) development, salvaging it from the depths of the genomic junk drawer.
This perceptive team noticed that LINE-1 RNA was expressed at high levels in early embryos (LINE-1 has been shown to be necessary during early development), but there was a low rate of retrotransposition—leading them to believe that LINE-1 RNA could have an important function outside the canonical retrotransposon activity. A meticulous investigation utilizing LINE-1 RNA knockdown in mouse embryonic stem cells (ESCs) revealed that LINE-1 is way more than just “junk” after all! They found that LINE-1 RNA can act as a scaffold for Nucleolin (a protein involved in ribosome synthesis) and Kap1 (a chromatin binding protein) and works to facilitate Nucleolin/Kap1 complex binding to specific loci on chromatin. They uncovered two main roles for LINE-1 RNA:
- LINE-1 RNA is essential for mouse ESC self-renewal
- LINE-1 acts as an RNA scaffold to facilitate Nucleolin/Kap1 binding to rDNA loci, inducing rRNA expression
- Elevated rRNA levels are needed for the heavy translational burden of renewing ESCs
- LINE-1 RNA regulates ESC exit from the 2-cell (2C) stage and transition from maternal control to zygotic genome activation
- LINE-1 represses genes involved in the 2C-transition via repression of the Dux transcription factor, a key activator of the 2C-program
- LINE-1 RNA directly interacts with Dux gene loci, facilitating Nucleolin/Kap1 binding
This novel function for the LINE-1 retrotransposon as a regulator of embryonic stem cell identity raises further questions about the roles of other transposable elements in the human genome. First author Michelle Percharde shares, “When I saw all the LINE1 RNA that’s present in the nucleus of developing cells, I agreed there must be some role it’s playing. Why let your cells make so much of this RNA if it’s either dangerous or doing nothing? When we saw that cells were changing identity when we removed LINE1 RNA, that was our real ‘Aha!’ moment that told us we were on to something.”
Senior Author Miguel Ramalho-Santos concludes, “These genes have been with us for billions of years and have been the majority of our genomes for hundreds of millions of years. I think it’s fair to ask if the 1.5 percent of protein-coding genes are the free-riders, and not the other way around. We now think these early embryos are playing with fire but in a very calculated way. This could be a very robust mechanism for regulating development.”
LINE up to read the full article in Cell, July 2018