The RNA m6A reader YTHDC2 recruits TET1 to demethylate transposable elements DNA and prevent neural fate of human pluripotent stem cells

Transposable elements (TEs) are parasitic DNA that account for over half of the human genome. While most TEs are silenced by the host, many TEs exhibit spatial-temporal regulatory activity and control host gene expression. The balance between TE repression and activation is critical for genome integrity, development, and diseases. In eukaryotes, despite knowledge of host-mediated TE-silencing mechanisms, how TEs evade the host surveillance machinery is not well-understood. Here, by developing a TE-centric proteomic approach, we find that the RNA N6-methyladenosine(m6A)-reader YTHDC2 binds to the chromatin of primate-specific TE LTR7/HERV-H in human embryonic stem cells (hESCs), through its interaction with m6A-modified HERV-H RNAs. Significantly, YTHDC2 recruits TET1 to prevent LTR7/HERV-H silencing via 5-Hydroxymethylcytosine(5hmC)-mediated DNA demethylation; and the YTHDC2/LTR7-axis regulates the switch of pluripotency versus neural conversion of hESCs. Together, we uncover the underappreciated TE-encoded anti-silencing mechanisms and link RNA m6A-modification to DNA methylation regulation.