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

Abstract

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. To address this question, we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N6-methyladenosine(m6A)-reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with m6A-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 m6A 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.

Regulation and function of transposable elements in cancer genomes

“…Comparing the E006AA-hT and LNCaP prostate cancer cell lines, which have low versus high LINE-1 expression, respectively, they identified known LINE-1 associated TFs such as CTCF and YY1, as well as a novel LINE-1 repressor, dual phosphatase 1 (DUSP1). Sun et al used another variant of proximity labeling called "TurboID" [195] to identify factors bound to primate-specific LTR7/HERV-H in human embryonic stem cells [196], revealing a novel crosstalk between m6A methylation of HERV-H RNAs and DNA methylation of their loci. Specifically, they found that the HERV-H m6A modification binds m6A reader YTHDC2, which subsequently recruits the DNA 5mC demethylase TET1 to maintain expression of LTR7 loci.…”