While many see chit-chat and gossip as a tiresome but inevitable part of life, epigenetic eavesdropping has recently demonstrated that the tight regulation of gene expression relies on some close-quarters methylation crosstalk! The molecular back-and-forth uncovered occurs between the transcription elongation-associated H3K36me3 histone modification and the prevalent and essential post-transcriptional N6-methyladenosine (m6A) mRNA modification. So how do these two disparate methylation marks communicate across the epigenetic landscape and what’s the outcome of this inter-modification chitter-chatter?
To answer these questions, researchers from the lab of Jianjun Chen (Beckman Research Institute of City of Hope, California) put down their coffee cups, quit their yapping, and set off to eavesdrop into the epigenetic chatter:
- Analysis of m6A sequencing and H3K36me3 ChIP-seq results revealed m6A enrichment close to H3K36me3 peaks
- H3K36me3 depletion by SETD2 H3K36me3 methyltransferase knockdown or KDM4A H3K36me3 demethylase overexpression prompts a global reduction in m6A levels, suggesting a close link between the two modifications
- Interestingly, the METTL14 component of the m6A methyltransferase complex recognizes and directly binds to H3K36me3 in an RNA Polymerase II-independent manner
- This binding brings the m6A methyltransferase complex into proximity with RNA polymerase II, allowing co-transcriptional deposition of m6A on actively transcribed nascent RNAs
- This crosstalk explains, in part, the common occurrence of m6A at coding sequences and 3′ untranslated regions of mRNA
- Mouse embryonic stem cells phenocopying METTL14 knockdown by inducible knockdown of SETD2 also display lower levels of H3K36me3 globally and lower levels of m6A on crucial pluripotency-associated transcripts
- Interestingly, reductions in these methylation modifications augmented self-renewal/stemness and reduced signs of differentiation
- These results match a previous finding demonstrating that as m6A levels on pluripotency-associated mRNAs increase, degradation rates also increase, and embryonic stem cells lose their pluripotent characteristics
After all this molecular chatter had died down, the authors had their own inter-personal confab; their end summary highlights the crucial impact of H3K36me3 and METTL14 in determining m6A mRNA levels and how the all-important crosstalk between these two methylation modifications helps to regulate gene expression.
So quit all your gossiping and idle chit-chat and eavesdrop on the methylation crosstalk at Nature, March 2019.