Whether you’re a fan of nightclubs, speakeasys, or honkey-tonks, you may have noticed that the population on the dance floor seems to get younger every year. Maybe you’re just getting older, or maybe today’s youth are getting better at getting around the rules.
Like bouncers at a bar, developing cells have DNA methylation to keep transposable elements (TEs) from hopping through the genome like teenagers with fake IDs. Unfortunately, it’s been difficult to study their interaction since many cells don’t survive when methylation is removed and DNA methyltransferases (DNMTs) are mutated. However, a new paper from the lab of Johan Jakobsson (Max Planck Institute for Molecular Genetics, Germany) shows that human neural progenitor cells (hNPCs) are an exception to the rule.
The talented team used CRISPR-Cas9 genome editing technology to delete the maintenance DNA methyltransferase (DNMT1) in hNPCs and found that:
- DNMT1 knockout (KO) drastically reduces the amount of 5mC that is detectable by immunocytochemistry, but still allows hNPCs to grow and divide
- KO cells have much less DNA methylation, according to whole genome bisulfite sequencing (WGBS), which occurs at many classes of TEs including LINE-1s, LTRs, SINEs and SVAs
- The 2152 TE transcripts that are more expressed in KO cells (according to paired-end, strand-specific RNA sequencing) belong to classes of LINE-1s that are evolutionarily young and only found in hominoid genomes
The increased transcriptional presence was specific to young LINE-1s and not other classes of TEs of the same age and length, so the researchers tried to understand what makes these elements so mischievous. They performed ChIP-seq experiments on their cells and found:
- All classes of TEs, both young and old carry the repressive histone mark H3K9me3 and are bound by its co-repressor protein TRIM28
- Transcriptional machinery (RNA Pol II), and the active histone mark H3K27ac are enriched at actively transcribed young LINE-1s in KO cells
Since young LINE-1s seem uniquely able to sneak past repressive barricades and acquire the H3K27ac wristbands that are normally found at enhancers and promoters, the research team wanted to know whether the TEs were using them for the same purpose. They went back into their data and saw that:
- Protein-coding genes within 50kb of activated LINE-1s are upregulated in KO cells even though they already have unmethylated promoters and Pol II and H3K27ac at their transcriptional start sites (TSSs) in control hNPCs
- Many LINE-1s fuse with the exons of protein coding genes and act as alternative promoters
- Genes that are activated by LINE-1 expression have neuronal-related functions, and some have been previously linked to neurodevelopmental disorders
It’s still not exactly clear what helps young LINE-1s get past the repressive chromatin security, but since their moves are random, they might have exciting roles in normal variations of human brain function and evolution!
Feel free to breeze past security and boogey all night with Nature Communications, July 2019.