Could there BE anymore genes affecting DNA methylation? Actually, yes! We always hear about the main cast of the methylation show, the DNMTs and the TETs, but where are all the supporting actors that attract, repel or otherwise interact with these stars? A new show (study) from the studio (lab) of Bastiaan Heijmans (Leiden University Medical Center, The Netherlands), who produced series on the Dutch Famine, age-related methylation patterns, and developmental enhancers, shows us that searching behind the scenes is definitely not a moo point.
The brainy bunch combined RNA-seq and genotype data from 3357 blood samples and identified all the variants that could predict the expression of each gene. They overlapped these genetic instruments (GIs) with methylation array data, using a statistical method similar to mendelian randomization, and found that:
- 818 genes have a specific, directed impact on DNA methylation at 2385 CpGs across the genome
- These genes are enriched for transcription factors, especially those with GIs targeting more than one CpG
- 79% of transcription factor genes belong to the C2H2 zinc finger family
- For many TFs, their predicted CpG targets are enriched for empirically determined binding sites from ChIP-seq
- The list of 818 genes also contains 36 that are core epigenetic factors involved in histone acetylation, according to the EpiFactors database, which highlights the cross-talk between different layers of the epigenome.
For the finale, the savvy scientists highlight the quirky personalities of 5 genes that target the most CpGs. What happens when an immune response protein, a platform protein for histone acetylation factors, a deSUMOylator, and two heterochromatin regulators meet up for coffee at the Centromere Perk?
Senior author Bastiaan Heijman shares, “When we compared notes between disease EWASs, we found intriguing overlap in CpGs. It for example turns out that BMI-associated CpGs are shared with those influences by the inflammatory regulator NFKB, a transcription factor. So, BMI seems to influence methylation through an effect on inflammation, and the CpGs may be on the pathway from BMI to BMI-complication. So, our data may help to understand how external signals are relayed to the epigenome.”
Pivot over to the original article in Genome Biology, August 2020.