GSE172142
The proline and serine rich protein PROSER1 mediates O-GlcNAcylation of TET2 to regulate DNA demethylation on UTX-dependent enhancers and CpG islands [hMeDIP-seq]
DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2 and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. Affinity purification of PROSER1 resulted in the identification of OGT and TET1-3. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. Additionally, PROSER1, UTX, OGT, and TET1/2 colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, and TET1/2 at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional downregulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands. Overall design: Identify if 5hmC was reduced in PROSER1 KO cells at enhacers and CpG islands.