Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells

Transposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, development, immunity and diseases, including cancer. However, precisely how this regulation is achieved remains unclear. Here we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N-6-methyladenosine (m(6)A) reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with m(6)A-modified HERV-H RNAs. Unexpectedly, YTHDC2 recruits the DNA 5-methylcytosine (5mC)-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. Functionally, the YTHDC2/LTR7 axis inhibits neural differentiation of hESCs. Our results reveal both an underappreciated crosstalk between RNA m(6)A and DNA 5mC, the most abundant regulatory modifications of RNA and DNA in eukaryotes, and the fact that in hESCs this interplay controls TE activity and cell fate. The N6-methyladenosine reader YTHDC2 recruits TET1 to remove 5-methylcytosine from LTR7/HERV-H loci in human embryonic stem cells. The YTHDC2/LTR7 pathway inhibits neural fate commitment.

Automated summary

Transposable elements (TEs) are parasitic DNA sequences that make up over half of the human genome. The regulation of TEs is crucial for genome integrity, development, immunity, and diseases. A study found that the RNA m(6)A reader, YTHDC2, interacts with m(6)A-modified HERV-H RNAs to bind to LTR7/HERV-H, a primate-specific TE. YTHDC2 recruits the DNA 5mC-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. This interplay between RNA m(6)A and DNA 5mC controls TE activity and cell fate in human embryonic stem cells.