RT Journal Article SR Electronic T1 PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101228 DO 10.26508/lsa.202101228 VO 5 IS 1 A1 Xiaokang Wang A1 Wojciech Rosikiewicz A1 Yurii Sedkov A1 Tanner Martinez A1 Baranda S Hansen A1 Patrick Schreiner A1 Jesper Christensen A1 Beisi Xu A1 Shondra M Pruett-Miller A1 Kristian Helin A1 Hans-Martin Herz YR 2022 UL https://www.life-science-alliance.org/content/5/1/e202101228.abstract AB 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, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. 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 and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.