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

ABSTRACT: Covalent modifications of RNA and DNA both regulate numerous biological processes, including development and cancer. The most abundant modification of RNA is that of N6-methyladenosine(m6A), while in the case of DNA, the CpG cytosine methylation characterizes cis-regulatory elements for spatial-temporal gene regulation. Recent studies establish a role for RNA m6A in regulating chromatin through histone modifications. However, whether there is also interplay between RNA and DNA methylation remains unknown. We address this question by studying regulation of the primate-specific transposable element (TE), LTR7/HERV-H, that is specifically activated in human embryonic stem cells (hESCs). Exploiting a novel proteomic approach, we find the RNA m6A-reader, YTHDC2, binds to LTR/HERV-H chromatin through interaction with m6A-modified HERV-H transcripts. Significantly, YTHDC2 recruits DNA demethylase, TET1, to activate LTR7/HERV-H via 5-hydroxymethycytosine(5hmC)-mediated DNA methylation. Furthermore, the YTHDC2/LTR7-axis prevents neural conversion of hESCs. Our results establish previously unknown crosstalk between RNA m6A and DNA methylation and new mechanisms controlling TE activity and hESC fate. We focused on the regulation of the primate-specific TE family, LTR7/HERV-H that is specifically active in the pluripotent human embryonic stem cells (hESCs) then silenced in differentiated lineages. We develop CARGO-BioID, a CRISPR-based TE-centric proteomics approach, to identify the proteins associated with thousands of copies of endogenous LTR7/HERV-H loci and potentially regulate their activity in hESCs. We found YTHDC2 and TET1 interact with each other and subsequently regulate m6A level on HERVH transcripts and 5hmC level on HERV-H genomic loci, which is critical for LTR7/HERV-H activities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224672 | GEO | 2023/05/12

REPOSITORIES: GEO