While the above title may conjure up images of Star Wars-esque galactic battles, the epic clash between the LINE-1 (L1) retrotransposon and repressive forces takes place on the scale of microns instead. This war has been waging in the human genome for thousands of years: L1 attempts to replicate and integrate into the genome, while epigenetic modifications attempt to keep it at bay. Fearlessly, a battalion of scientists led by Geoffrey Faulkner (Mater Research Institute, Australia) have delved into the fray to uncover L1’s strategy.
This tactical team laid out their plan of attack: They analyzed 24 human hippocampal neurons at the single-cell level using Illumina whole genome sequencing (at ~47x coverage) coupled with retrotransposon capture sequencing (RC-seq) and L1 insertional profiling to detect somatic L1 retrotransposition. They then used PCR-free bisulfite sequencing to assess locus-specific DNA methylation, and utilized human embryonic stem cells, neural progenitor cells, and neurons to look at DNA methylation during neuronal development.
Here’s the action report:
- They identified a somatic L1 insertion present in ~25% of sample neurons, likely arising from a neuronal progenitor cell
- This L1 insertion has a 31 nucleotide 5’ truncation, but is competent to retrotranspose
- 5’ truncated L1s are globally hypomethylated and have increased mRNA expression
- Truncated L1 variants lack a sufficient YY1 transcription factor binding site
- Disruption of YY1 binding site, either by truncation or point mutation, correlates with L1 promoter hypomethylation
It’s still not entirely clear how YY1 is mediating L1 promoter methylation (and in turn, L1 repression), but the authors hypothesize that YY1 could recruit DNA methyltransferases. And while truncated L1 can successfully evade YY1 repression, it’s not the only trick up its sleeve. The L1 element can also become active by hitching a ride downstream of a strong promoter or highly expressed gene, or via hypomethylation in tumors.
Go behind enemy LINEs and get the full tactical report over at Molecular Cell, August 2019.