Dream teams come in all shapes and sizes, from the 1970 Brazil football team to the Mercedes F1 team of the 2010s. A new epigenetic alliance formed between RNA methylation and DNA demethylation recently made its competitive debut and now shows how teamwork makes the dream work! A synergistic team led by Dongxin Lin, Jian Zheng (Sun Yat-sen University Cancer Center, China), and Jianjun Chen (Beckman Research Institute of City of Hope, California) describe how the dream team-like coupling of RNA methylation to DNA demethylation controls chromatin accessibility and gene transcription and shows how epigenetic teamwork makes the transcriptional dream work!
Let’s hear a play-by-play account of how teamwork between the epitranscriptome and epigenome from Deng and colleagues:
- Analysis of public datasets reveals that RNA N6-methyladenosine (m6A) associates with proximal DNA 5-methylcytosine (5mC) demethylation in normal human cells, which leads to increased accessible chromatin (as measured using ATAC-seq) and gene expression
- Parallel RNA m6A-sequencing and whole-genome bisulfite sequencing show how the loss of the METTL3 m6A methyltransferase decreases m6A, increasing proximal 5mC levels, and reduces associated gene expression
- Mechanistically, the m6A reader FXR1 binds to m6A and co-transcriptionally recruits the DNA 5-methylcytosine dioxygenase TET1, starting the DNA demethylation process at nearby loci
- METTL3 loss reduces FXR1 and TET1 binding to chromatin (measured by CUT&Tag), showing that m6A regulates FXR1-mediated TET1 recruitment
- Dysregulation of the m6A–5mC regulatory axis also has relevance to tumorigenesis
- Esophageal squamous cell carcinoma (ESCC) cells display significantly higher m6A levels than adjacent normal tissues, lower 5mC levels, and increased chromatin accessibility and expression of oncogenes such as WNT7B and BCL6
- METTL3, FXR1, and TET1 display ESCC-specific overexpression and interact with m6A and 5mC; therefore, they have potential as biomarkers/therapeutic targets (e.g., METLL3 inhibitors in leukemia)
This epitranscriptome and epigenome teamwork defines RNA methylation-coupled DNA demethylation as a regulatory process that significantly impacts transcription; however, the team notes the need to explore additional mechanisms by which m6A regulates DNA demethylation and examine whether DNA methylation can impact RNA modifications. Finally, they also want to thoroughly investigate the potential importance of this mechanism to cancer development.
See how this epigenetic dream team regulates transcription at Nature Genetics, September 2022.